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Review of current transfusion therapy and blood banking practices1
Accepted Manuscript Review of current transfusion therapy and blood banking practices
Emily K. Storch, Brian S. Custer, Michael R. Jacobs, Jay E. Menitove, Paul D. Mintz PII: DOI: Article Number: Reference:
S0268-960X(19)30062-1 https://doi.org/10.1016/j.blre.2019.100593 100593 YBLRE 100593
To appear in:
Blood Reviews
Please cite this article as: E.K. Storch, B.S. Custer, M.R. Jacobs, et al., Review of current transfusion therapy and blood banking practices, Blood Reviews, https://doi.org/10.1016/ j.blre.2019.100593
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ACCEPTED MANUSCRIPT Review of current transfusion therapy and blood banking practices 1
Emily K. Storch1,* [email protected], Brian S. Custer2 [email protected], Michael R. Jacobs3 [email protected], Jay E. Menitove4
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[email protected], Paul D. Mintz5 [email protected]
Food and Drug Administration
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Blood Systems Research Institute; UCSF Department of Laboratory Medicine
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Department of Pathology, Case Western Reserve University, Department of Clinical
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Microbiology, University Hospitals Cleveland Medical Center
Clinical Professor, Department of Pathology and Laboratory Medicine, University of
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Kansas Medical Center Verax Biomedical Incorporated
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Corresponding author.
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This article reflects the views of the author and should not be construed to represent FDA’s views or policies.
ACCEPTED MANUSCRIPT Abstract
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Transfusion Medicine is a dynamically evolving field. Recent high-quality research has reshaped the paradigms guiding blood transfusion. As increasing evidence supports the benefit of limiting transfusion, guidelines have been developed and disseminated into clinical practice governing optimal transfusion of red cells, platelets, plasma and cryoprecipitate. Concepts ranging from transfusion thresholds to prophylactic use to maximal storage time are addressed in guidelines. Patient blood management programs have developed to implement principles of patient safety through limiting transfusion in clinical practice. Data from National Hemovigilance Surveys showing dramatic declines in blood utilization over the past decade demonstrate the practical uptake of current principles guiding patient safety. In parallel with decreasing use of traditional blood products, the development of new technologies for blood transfusion such as freeze drying and cold storage has accelerated. Approaches to policy decision making to augment blood safety have also changed. Drivers of these changes include a deeper understanding of emerging threats and adverse events based on hemovigilance, and an increasing healthcare system expectation to align blood safety decision making with approaches used in other healthcare disciplines.
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Keywords: blood transfusion; red blood cells; platelets; plasma; cryoprecipitate; patient blood management; hemovigilance; cold stored platelets; lyophilized plasma; pathogen reduction.
ACCEPTED MANUSCRIPT 1. Introduction Blood transfusion constitutes an integral component of patient care, with up to 10% of hospitalized patients transfused, depending on the patient
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population.[2] [3] Recognition of the importance of transfusion dates back to
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the 17th century when the first human blood transfusions were performed in
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Paris by Jean Denis in 1667.[4] Modern blood transfusion originated with
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the identification of the major blood groups in 1901 by Karl Landsteiner and the subsequent introduction of pre-transfusion compatibility testing using
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agglutination techniques in 1907.[5, 6] Despite the long history of blood
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transfusion, until recently evidence guiding optimal transfusion practices has
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been limited. Clinical decision making was instead empirically based,
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relying on such paradigms as the “10/30” rule, informed by limited underlying scientific evidence from the 1940s to improve outcomes in
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surgical patients.[7] [8] [9] [10, 11] The past decade has witnessed the
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emergence of strong evidence-based clinical practice guidelines for transfusion of blood and blood components, which has begun to influence clinical medicine,[12] although practice continues to lag behind evidence based recommendations in key metrics such as transfusion of plasma given to non-bleeding patients to correct minimally elevated INRs.[13] [14] It has been suggested that this discrepancy is based at least in part on lack of
ACCEPTED MANUSCRIPT exposure to transfusion medicine knowledge in medical education. [15] [14] This review will highlight key evidence-based guidelines and practice points in clinical transfusion practice, as well as present current and emerging
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concepts in the field of transfusion medicine, including novel blood and
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blood-derived products for transfusion.
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2. Red blood cells
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Red blood cells (RBCs) are derived either from Whole Blood (WB)
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donations or collected by apheresis technology. The volume of an average unit of WB RBCs following plasma removal ranges from 200 to 350 mL,
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and has a hematocrit of 55% to 80%. Depending on the anticoagulant or
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additive solution utilized, the shelf life of a RBC unit ranges from 21 to 42
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days. The average storage age of a transfused RBC unit in the U.S. is 19 days, with 79% of RBCs transfused between day 1 and day 35. [13, 16] One unit of RBC is expected to raise the hemoglobin of an adult patient by 1 g/dL or hematocrit by approximately 3%.[17, 18]
ACCEPTED MANUSCRIPT 2.1.
Indications & current practice
RBCs function to provide oxygen delivery to tissues, and as such are standard treatment for patients who require an increase in oxygen carrying
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capacity and red cell mass. Indications for red cell transfusion include
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patients with symptomatic anemia, decreased bone marrow function (e.g.
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aplastic anemia, chemotherapy), defective red cell production (e.g.
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thalassemia), decreased red cell survival (e.g. hemolytic anemia), acute
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bleeding, those undergoing invasive procedures, and red cell exchange transfusion. Common clinical scenarios requiring RBC transfusion include
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orthopedic surgery, critical care, gastrointestinal bleeding, cardiac surgery
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and acute coronary syndromes. [17] RBCs are the most frequently transfused
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blood product, with approximately 11 million red cells transfused annually. [1] [3]
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While RBC transfusion is common practice to avoid compromised
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peripheral tissue oxygenation, minor decreases in Hgb don’t necessarily indicate poor oxygen delivery (DO 2) or consumption (VO 2) due to compensatory physiologic mechanisms, such as increased cardiac output or altered oxygen extraction by tissues in hypoxemic states. [9] The limits of compensation at which patients are able to tolerate low hemoglobin levels vary by multiple factors including patient co-morbidities, age, baseline
ACCEPTED MANUSCRIPT metabolic function, erythropoietin levels, and nutritional status, therefore complicating the determination of a static ‘transfusion trigger’ across all patient populations and clinical situations. [9, 19]
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Multiple randomized controlled trials (RCTs) evaluating indications and
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outcomes of transfusion have been performed in recent years, providing
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evidence for transfusion strategies in adult patients. [20] [17] [21-23] [24,
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25] [26] [27] A large meta-analysis of 31 trials comparing restrictive (7 to 8 g/dL) to liberal transfusion thresholds (9 to 10 g/dL) including over 12,000
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patients found a similar 30-day mortality between the two groups (risk ratio
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0.97; 95% CI 0.81 to 1.16). [10] Secondary outcomes including risk of
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pneumonia, stroke, myocardial infarction (MI) and thromboembolism were also similar between groups. However the results cannot be generalized to
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all populations, due to variation in study design, including inconsistent
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transfusion thresholds across patient populations. [17] For example, in
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patients with underlying cardiovascular disease in whom compensatory physiological mechanisms to maintain adequate DO 2 are compromised, [9] a threshold of 7 g/dL as opposed to 8 g/dL could impart harm. [9] While the overall results demonstrated that a restrictive vs a liberal transfusion strategy did not impact risk of mortality and adverse outcomes, there were insufficient data to provide recommendations for specific patient subgroups
ACCEPTED MANUSCRIPT including those with acute coronary syndrome, myocardial infarction, stroke, neurological injury and hematological malignancies. An important caveat is that certain subgroups, in particular those with
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underlying cardiovascular disease, have shown benefit from a higher
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transfusion threshold. A trial of over 2000 cardiac surgery patients (TITRe2)
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demonstrated a higher 90-day mortality risk in the subjects receiving a
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restrictive transfusion strategy, although other outcomes including 30-day mortality did not differ between groups. [23] In addition, a meta-analysis of
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trials in patients with cardiovascular disease demonstrated an increased risk
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ratio of 1.78 for myocardial infarction, cardiac arrest or acute coronary
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syndrome (95% CI, 1.18 to 2.70) with a restrictive transfusion strategy. [28] While the other large study in cardiac surgery patients (TRICS III) did not
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show increased mortality from restrictive transfusion, at the time of the
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meta-analysis, longer-term data were not yet available. Of note, an updated
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analysis of the TRICS III trial has recently been published, [29] showing no difference in six-month mortality rates (odds ratio, 0.95; 95% CI, 0.75 to 1.21) with restrictive versus liberal transfusion. In addition, no significant differences were seen between the groups in the primary composite outcome (death from any cause, myocardial infarction, stroke, or new onset renal failure requiring dialysis), or in secondary outcomes (including emergency
ACCEPTED MANUSCRIPT department visits, hospital readmission, or coronary revascularization within 6 months). In order to address these questions, a recently published update of the
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meta-analysis focused on trials of transfusion thresholds in patients with
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cardiovascular disease. [20] The updated meta-analysis included 37 trials
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with over 19,000 patients. No difference was seen between a restrictive and
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a liberal strategy in 30-day mortality in patients undergoing cardiac surgery (risk ratio 0.99; 95% CI, 0.74 to 1.33) or in overall 30-day mortality among
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26 trials (risk ratio, 1.00; 95% CI, 0.86 to 1.16). However two trials[21, 30]
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(n = 154) showed an increased risk of 30-day mortality in patients with acute
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myocardial infarction from the restrictive compared to the liberal strategy group (RR 3.88; 95% CI, 0.83 to 18.13). Given the lack of benefit seen with
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a liberal strategy, and to avoid the potential risks posed by unnecessary
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blood exposure, the authors recommend use of a restrictive transfusion
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strategy of 7 to 8 g/dL in most patient populations, including those undergoing cardiac surgery. However, they were unable to determine whether a restrictive or a liberal strategy is preferable in patients with underlying coronary artery disease or congestive heart failure due to lack of currently available evidence. A recent retrospective cohort of RBC transfusion in patients with moderate anemia (defined as Hgb levels between
ACCEPTED MANUSCRIPT 7 and 10 g/dL) added support to these paradigms. The study showed that following implementation of patient blood management programs, inpatient transfusion of RBC decreased from 31% in 2010 to 23% in 2014 (p <0.001),
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while the adjusted prevalence of rehospitalization within 6 months decreased
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over the same timeframe from 36.5% to 32.8% (P <0.001). Similarly,
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adjusted prevalence of mortality within 6 months decreased from 16.1% to
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15.6% (P=0.004). However the proportion of patients with resolution of moderate anemia decreased from 42% to 34% (P <0.001). [31] These
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findings however are complicated by data showing a severity-dependent
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association between severity of anemia and frequency of 30-day hospital
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readmissions. A recent retrospective study of 152,757 hospitalizations comparing anemia at discharge with hospital readmission showed a
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significant increase in odds of 30-day readmission. For mild anemia (defined
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as Hgb 11-12 g/dL in women, 11-13 g/dL in men) the odds ratio was 1.74
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(95% CI 1.65 to 1.82); 2.76 (95% CI 2.64 to 2.89) for moderate anemia (Hgb 9-11 g/dL); and 3.47 (95% CI 3.30 to 3.65) for severe anemia (Hgb ≤9 g/dL), P <0.001. [32] The efficacy and safety of restrictive versus liberal RBC transfusion for patients with hematological malignancies undergoing intensive treatment or hematopoietic stem cell transplant (HSCT) was recently examined in a meta-
ACCEPTED MANUSCRIPT analysis. [33] Only six studies were deemed eligible for inclusion, of which four were completed (3 randomized controlled trials, 1 non-randomized study), for a total of 240 participants. The restrictive strategy ranged from 7
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to 9 g/dL compared to a range of 8 to 12 g/dL in the liberal strategy. The
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study demonstrated low-quality evidence that a restrictive RBC transfusion
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policy has little effect on 30- or 100-day mortality, bleeding or hospital stay,
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and may decrease the number of RBC transfusions received per patient. A continuing area of investigation in transfusion medicine is the
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appropriate storage age of red cells for transfusion. Storage of red blood
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cells results in physiologic changes measured by in vitro parameters,
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including impaired nitric oxide metabolism,[34] accumulation of lactic acid, decreased pH, ATP, 2,3-DPG, release of inflammatory mediators, and
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increased red cell membrane rigidity, which may reduce oxygen delivery.
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[35] Collectively these changes are referred to as the ‘storage lesion’, [36]
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[37] which may contribute to impaired oxygen uptake and delivery. [18] [38-40]
While in vitro results might suggest that increased storage would impair the quality of red blood cells, multiple randomized controlled trials have failed to demonstrate clinical benefit from transfusing fresher blood (generally stored for fewer than 10 days) compared to blood stored for
ACCEPTED MANUSCRIPT longer periods. [24, 41-43] [44] [45] [46] (See Table 1) [47] While most trials have demonstrated no benefit from transfusion of fresher blood, there is variation amongst the trials in the storage duration of both fresher and
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standard-issue RBC. In a systematic review, the mean storage age for fresher
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RBCs was 12.1 days compared to 19 days for standard issue RBCs in adults.
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[48] In addition, most trials of RBC storage have not assessed the longest-
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term storage, approaching the 42-day expiration date, although this question has been recently addressed, as described below.
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Two trials evaluating storage age of RBCs in adult patients have recently
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been published, likewise finding no benefit of transfusing fresher blood. [24,
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42] The INFORM[42] trial randomized 31,497 subjects at sites in Canada, the United States and Australia and Israel. The primary analysis included
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20,858 subjects who received fresher blood versus standard-issue blood
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(mean storage age 13.0 ± 7.6 days vs 23.6 ± 8.9 days respectively). In-
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hospital mortality was 9.1% in the fresher arm versus 8.7% in the standardissue arm (OR 1.05; 95% CI, 0.95 to 1.16, p = 0.34). The authors concluded that transfusion of fresher blood did not improve in-hospital mortality compared to standard-issue blood. The TRANSFUSE trial[24] randomized 4994 patients in Australia, New Zealand, Ireland, Finland and Saudi Arabia to compare the effect of storage time on 90-day mortality. The primary
ACCEPTED MANUSCRIPT analysis included 4919 adult ICU patients who received the freshest blood in inventory compared to standard-issue blood (mean storage age 11.8 ± 5.3 days vs 22.4 ± 7.5 days respectively). The mortality rate was 24.8% vs
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24.1% in the fresher vs standard-issue arms respectively (OR 1.04; 95% CI,
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0.91 to 1.18, p = 0.57). The authors concluded that transfusion of fresher
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blood did not affect the outcome of 90-day mortality in critically ill patients.
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A meta-analysis including the results of the INFORM and TRANSFUSE trials determined a relative risk of 1.04 (95% CI, 0.98 to 1.10) from
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transfusion of fresher compared to stored blood. [47]
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Two recent studies have evaluated the issue of blood stored to the end of
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the storage period (36-42 days). [49, 50] A secondary analysis of data from the INFORM trial compared patients who received fresher blood to those
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who received a minimum of one unit of end-of-storage blood (i.e. 36-42
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days). [49] No increase in mortality was seen among those receiving the
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oldest blood (HR 0.94, 95% CI, 0.73 to 1.20, p = 0.60). A study using the SCANDAT2 observational database evaluated 30-day and 1-year mortality among 854,862 transfusion recipients in Sweden and Denmark. [50] No difference in mortality in either time frame was seen between patients receiving older blood (stored 30 to 42 days) compared to patients receiving fresher blood (stored 10 to 19 days). The hazard ratio of 30-day and 1-year
ACCEPTED MANUSCRIPT mortality was 0.99 (95% CI, 0.95 to 1.02) and 1.00 (95% CI, 0.98 to 1.02), respectively. Additional analysis of a subset of patients who received over six units of RBC stored for more than 30 days compared to those who
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received fresher blood similarly demonstrated no association between RBC
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storage and mortality.
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A recently published Cochrane review included 22 trials that evaluated
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the effect of storage duration on transfusion outcomes in all patient populations. [51] No difference in the primary outcome of mortality was
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detected between study groups at any of the time points evaluated. Although
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there was heterogeneity among the trials and not all reported on predefined
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secondary outcomes (e.g. incidence of infection, adverse reactions, length of stay), analysis of the available data revealed no significant differences
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between the study groups.
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Table 1. Duration of red blood cell storage and clinical outcome Reference Study population RBC storage duration in Primary days outcome INFORM General population Mean (SD) Mortality Heddle et al., of hospitalized Fresh - 13 (7.6) Fresh – 9.1% NEJM 2016 patients Older – 23.6 (8.9) Older – 8.7% Total patients in Odds ratio 1.05 primary analysis, N (95% CI 0.95 to = 20,858 1.16) Fresh, N = 6936 P = 0.34 Older, N = 13,922 ABLE Critically ill adult Mean (SD) Mortality
ACCEPTED MANUSCRIPT ICU patients Fresh - 6.1 (4.9) Total patients in Standard - 22 (8.4) primary analysis, N = 2412 Fresh, N = 1206 Standard, N = 1206
Fresh – 37% Standard – 35.3% ARD 1.7, (95% CI -2.1 to 5.5)
RECESS Steiner et al., NEJM 2015
Patients 12 years Mean (SD) Fresh - 7.8 (4.8) of age undergoing Older - 28.3 (6.7) complex cardiac surgery Total patients in primary analysis, N = 1098 Fresh, N = 538 Standard, N = 560
Change in the 7day Multiple Organ Dysfunction Score (MODS; range 0-24) Fresh – 8.5±3.6 Older – 8.7±3.6 Estimated treatment effect -0.2 (95% CI 0.6 to 0.3) P = 0.44
TOTAL Dhabangi et al., JAMA 2015
Children aged 6-60 Median (IQR) months with Fresh - 8 (7, 9) malaria or sickle Older - 32 (30, 34) cell disease Total patients in primary analysis, N = 286 Fresh, N = 143 Standard, N = 143
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Lacroix et al., NEJM 2015
Premature infants with birth weights <1250 g in the neonatal ICU
Mean (SD) Fresh – 5.1 (2) Standard – 14.6 (8.3)
Lactate level 3 mmol/L Fresh – 83/143 (58%) Older – 87/143 (61%) Between group difference 0.03 (95% CI, -0.07 to ) P = < .001 Composite measure of major neonatal morbidities as
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Critically ill adult Mean (SD) patients in the ICU Fresh – 11.8 (5.3) Total patients in Standard – 22.4 (7.5) primary analysis, N = 4919 Fresh, N = 2457 Standard, N = 2462
INFORM, 2° analysis Cook et al., Lancet Haematol, 2018
General population of hospitalized patients Total patients in primary analysis, N = 24,736 Fresh, N = 1392 Standard, N = 18,854 Oldest, N = 4480 All transfusion recipients in Sweden and Denmark N = 854,862 Fresh, N = 278,207 Oldest, N = 46,474
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TRANSFUSE Cooper et al., NEJM 2017
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Halmin et al., AIM, 2017 SCANDAT data
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Fresh: ≤ 7 d Oldest: > 35 d
well as death Fresh – 52.7% Standard – 52.9% Relative risk 1.01 (95% CI 0.90 to 1.12) 90-day all-cause mortality Fresh – 24.8% Standard – 24.1% Odds ratio 1.04 (95% CI 0.91 to 1.18) P = 0.57 Mortality Fresh to Oldest Hazard ratio 0.91 (95% CI 0.72 to 1.14) P = 0.40
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Total patients in primary analysis, N = 377 Fresh, N =188 Standard, N = 189
Fresh (ref): 10-19 d Oldest: 30 – 42 d
Mortality 30-day hazard ratio: 0.99 (95% CI, 0.95 to 1.02) 1 year hazard ratio: 1.00 (95% CI, 0.98 to 1.02)
ACCEPTED MANUSCRIPT 2.2.
Guidelines
Multiple evidence-based guidelines have been published on transfusion of red cells in the last five to ten years across a variety of disciplines ranging
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from transfusion medicine to anesthesiology to nephrology. [41, 52] Based
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on evidence from high-quality randomized trials as detailed above, most of
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the guidelines recommend a restrictive transfusion strategy of 7 to 8 g/dL. A
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common theme among the guidelines is that transfusion should not be based strictly on laboratory parameters such as hemoglobin levels, but the clinical
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condition and circumstances of the individual patient should be considered.
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[48, 53] [41, 52] [54]
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Importantly among such guidelines, in 2016 AABB published “Clinical
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Practice Guidelines: Red Blood Cell Transfusion Thresholds and Storage. [48] The recommendations are based on evaluation of 31 randomized
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controlled trials including 12,587 subjects. The guidelines recommend
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withholding transfusion until the hemoglobin level is 7 g/dL or below in hemodynamically stable hospitalized patients, including the critically ill, as opposed to a level of 10 g/dL. For patients undergoing orthopedic surgery, cardiac surgery, and with preexisting cardiovascular disease, a restrictive transfusion level of 8 g/dL is recommended. Recommendations are not provided for patients with acute coronary syndrome,
ACCEPTED MANUSCRIPT hematological/oncological patients with severe thrombocytopenia at risk of bleeding or chronic transfusion-dependent anemia patients due to lack of evidence in these populations. The AABB guidelines also address the issue
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of RBC storage age. Based on evaluation of 13 RCTs (n = 5515) showing no
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benefit from fresher blood, the guidelines recommend that all patients
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Adverse effects
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2.3.
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including neonates, should be transfused with standard-issue blood.
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Adverse effects of red cell transfusion include transfusion associated circulatory overload (TACO) and transfusion related acute lung injury
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(TRALI), transfusion transmitted infection, febrile non-hemolytic
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transfusion reactions (FNHTR), allergic/anaphylactic reactions, transfusion
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associated graft versus host disease (TA-GVHD), and alloimmunization. In addition, RBC transfusions are frequently implicated in hemolytic reactions, both acute hemolytic transfusion reactions (AHTRs) and delayed hemolytic transfusion reactions (DHTRs). In certain patients, most commonly sickle cell disease patients, a complication of delayed hemolytic reactions can lead to potentially lethal complications of hyperhemolysis. [55]
ACCEPTED MANUSCRIPT Alloimmunization is implicated in hemolytic transfusion reactions when clinically significant antibodies are involved. Recipient data collected from 2013 to 2016 from the Recipient Epidemiology and Donor Evaluation
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Study-III (REDS-III) database showed 2% of 319,177 patients had a positive
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antibody screen with at least one clinically significant antibody. Statistically
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significant risk factors for RBC alloimmunization included female sex,
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white race, age, and RhD-negative status. Clinical diagnoses including sickle cell disease or trait, systemic lupus erythematosus, rheumatoid arthritis and
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myelodysplastic syndrome were also significantly associated with increased
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risk of alloimmunization. In contrast, diagnoses of leukemia, solid tumors,
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or solid organ transplant were significantly associated with decreased risk of
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3. Platelets
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developing an alloantibody following RBC transfusion. [56, 57]
Platelet components can be obtained either from single donor apheresis collections or derived from units of WB. A standard adult platelet dose is considered one apheresis unit or a pool of 4 to 6 Whole Blood-derived (WBD) units, [1, 13] and is expected to raise the platelet count by 30,000 to 50,000/µL. Approximately 2 million platelet components are transfused in
ACCEPTED MANUSCRIPT the US annually, of which the majority (~92%) are apheresis platelets. [1] For most indications, WBD and apheresis platelets are considered equally efficacious, as assessed by metrics including hemostatic efficacy, post-
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transfusion increments, and risk of adverse events. [58, 59] Platelets are
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stored at room temperature (20 to 24 C) for 5 to 7 days. Room temperature
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storage limits the shelf-life of platelets compared to other blood products due
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to the risk of bacterial contamination which can result in fatal septic transfusion reactions. [60] [61, 62] To address the risk of platelet
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contamination, testing for bacterial contamination or photochemical
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pathogen inactivation system are used to reduce the risk of transfusion-
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Indications/current practice
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3.1.
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transmitted infection, including sepsis. (see section 7.7.) [63]
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Indications for platelet transfusions can be categorized into prophylactic versus therapeutic therapy. [64] Prophylactic indications for platelet transfusion include prevention of bleeding in patients with treatmentinduced hypoproliferative thrombocytopenia, congenital or acquired platelet dysfunction, and those undergoing invasive procedures. Therapeutic platelet transfusions are given to treat acute hemorrhage. If feasible, platelets should
ACCEPTED MANUSCRIPT be ABO plasma compatible (if not screened for high titer anti-A and anti-B). [65, 66] Decisions governing prophylactic versus therapeutic treatment, appropriate dosage, and optimal thresholds at which to transfuse remain
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topics of continuing interest in Transfusion Medicine. Recent randomized
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controlled trials [67, 68] and systematic reviews [69-73] have addressed
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these questions in various patient population settings, as detailed below.
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3.1.1. Congenital and acquired bone marrow failure
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A recent Cochrane review aimed to evaluate a therapeutic-only versus
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prophylactic platelet transfusion policy in patients with congenital or acquired bone marrow failure disorders, e.g. myelodysplastic syndrome
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(MDS). [73] Eligible study subjects included patients with bone marrow
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failure disorders requiring long-term platelet transfusions, not actively
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treated with a stem cell transplant or intensive chemotherapy. Only one RCT was identified as eligible for inclusion in the review and the study was discontinued due to poor participant recruitment after enrolling only 9 subjects. No study data were reported, and therefore no analysis performed. While no conclusions could be drawn, the review highlights the need for well-designed studies to determine appropriate transfusion policy in patients
ACCEPTED MANUSCRIPT with bone marrow failure, a population exposed to repeated platelet transfusions.
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3.1.2. Prior to surgery
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A 2018 Cochrane review evaluated prophylactic platelet transfusions prior to
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surgery in thrombocytopenic patients. [71] Of five RCTs identified, three small trials (n = 180) were assessed as eligible for inclusion. One trial
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randomized thrombocytopenic patients in the intensive care unit (ICU) to
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receive prophylactic platelet transfusions versus no transfusion. The other
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two trials evaluated prophylactic platelet transfusion compared to alternative therapies, desmopressin and thrombopoietin mimetics
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(romiplostim/eltrombopag) respectively, in patients with liver disease. There
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was insufficient evidence to determine if administering a platelet transfusion
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prior to surgery had an effect on all-cause mortality within 30 days or provided benefit in reducing major or minor bleeding compared to no transfusion or alternative treatment. Likewise, there was insufficient evidence to ascertain a difference in transfusion-related adverse events between groups. The authors concluded that due to the lack of evidence that
ACCEPTED MANUSCRIPT transfusion reduced post-operative bleeding or all-cause mortality, they were unable to recommend prophylactic platelet transfusions in this setting.
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3.1.3. Hematologic malignancy
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Patients with hematologic malignancies represent the patient population in
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which the question of prophylactic versus therapeutic transfusion has been most extensively evaluated and for which the most definitive evidence is
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available. Multiple RCTs and meta-analyses have addressed this question
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and demonstrated that prophylactic platelet transfusion reduces World
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Health Organization (WHO) Grade 2 or greater bleeding in patients with hematological malignancies receiving chemotherapy or allogeneic HSCT.
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[74] [69] [67, 68]
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A 2015 Cochrane review [69] analyzed six RCTs comparing a
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therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with hematological disorders after myelosuppressive chemotherapy or stem cell transplantation. The trials evaluated for the review were conducted between 1978 and 2013 and comprised a total of 1195 subjects. Notable findings comparing the therapeutic-only strategy to the prophylactic strategy included an increased
ACCEPTED MANUSCRIPT number of days with a clinically significant bleeding event (one RCT, 600 participants; mean difference 0.50; 95% CI, 0.10 to 0.90; moderate-quality evidence); shorter time to first bleeding episode (2 RCTs, 801 participants);
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and no difference in the frequency of adverse events (two RCTs, 991
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participants; RR, 1.02; 95% CI, 0.62 to 1.68). There was insufficient
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evidence to determine a difference in the number of subjects with
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severe/life-threatening bleeding or all-cause mortality. The benefit of prophylactic transfusions did not extend to patients receiving autologous
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HSCT. [67, 68, 75] The therapeutic strategy was associated with a
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significant reduction in transfused units. The authors concluded that a
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therapeutic-only strategy compared to a prophylactic platelet transfusion policy is associated with an increased risk of bleeding in hematology
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patients with thrombocytopenia due to myelosuppressive therapy or HSCT),
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and therefore prophylactic platelet transfusions are beneficial in this
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population.
Dosage and thresholds for prophylactic platelet transfusions have also been studied in this population. A 2015 Cochrane review[76] evaluated different doses of prophylactic platelet transfusion in patients with hematologic malignancies undergoing myelosuppressive chemotherapy or HSCT. The review included seven RCTs (n = 1814) in thrombocytopenic
ACCEPTED MANUSCRIPT patients with hematologic malignancies who received low-dose (1.1 x1011/m2 ±25%), standard-dose (2.2 x1011/m2 ±25%), or high-dose (4.4 x1011/m2 ±25%) prophylactic platelet transfusion. There was no difference in
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the number of participants with a clinically significant bleeding event,
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number of days of bleeding, severe/life-threatening bleeding between the
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groups, time to first bleeding episode or all-cause mortality between the
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three treatment arms. A low-dose strategy resulted in an increased median number of platelet transfusions compared to a standard-dose strategy (five
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versus three in the largest study)[77], and a shorter interval between
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transfusions, however, overall the number of platelets transfused was lower.
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A high-dose strategy did not decrease the number of transfusions compared to a standard-dose strategy. A higher rate of transfusion-related adverse
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events was associated with a high-dose strategy. The authors concluded that
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in patients with hematologic disorders who were thrombocytopenic due to
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chemotherapy or HSCT, there was no evidence to suggest that a low-dose transfusion strategy was associated with an increased risk of bleeding compared to higher doses and recommended a change in practice of preferentially using low-dose platelets in hospitalized patients with hematologic malignancies and avoiding high-dose platelet transfusions.
ACCEPTED MANUSCRIPT Different platelet transfusion thresholds for prophylactic platelet transfusion to prevent bleeding in patients with hematologic malignancies after myelosuppressive chemotherapy or HSCT were evaluated in a 2015 systematic review.(See Table 2) [78] Three RCTs (n = 499) comparing a
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standard trigger (10 x 109/L) to a higher trigger (20 x 109/L or 30 x 109/L)
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were included in the review. There was no difference in the number of
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subjects with a clinically significant bleeding episode within 30 days of the start of the study between the standard and the higher trigger groups (3
AN
studies, n = 499; risk ratio (RR) 1.35, 95% CI, 0.95 to 1.90). There was no
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difference in the number of days of bleeding between the standard and the
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higher trigger groups (one study, n = 255; RR 1.71; 95% CI, 0.84 to 3.48, p = 0.162). In two studies reporting the number of subjects with severe or life-
PT
threatening bleeding, there was no difference between the standard and the
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higher trigger groups (n = 421; RR 0.99, 95% CI, 0.52 to 1.88). Overall, no
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difference was seen between the standard and higher trigger groups in risk of any degree of bleeding, including severe/life-threatening, risk of adverse events, or 30-day mortality. A significant reduction was seen in the number of platelet transfusions per participant in the standard trigger group. The authors concluded that based on low-quality evidence, there was no increase in risk of bleeding associated with a standard trigger (10 x 109/L) compared
ACCEPTED MANUSCRIPT to a higher trigger (20 x 109/L or 30 x 109/L), and a standard trigger was associated with a decrease in the number of transfusion episodes compared to a higher trigger.
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Table 2. Platelet transfusion threshold and risk of bleeding Reference Study population Platelet transfusion threshold Wandt et Adult patients with Prophylactic: ≤10 x al., Lancet hematological 109/L 2012 malignancies Therapeutic: at onset undergoing of bleeding chemotherapy or HSCT Total patients in primary analysis, N = 391 Prophylactic, N = 194 Therapeutic, N = 197
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Adult patients with hematological malignancies undergoing chemotherapy or HSCT Total patients in primary analysis, N = 598 Prophylactic, N = 298 Therapeutic, N = 300
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Stanworth et al., NEJM 2013
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Primary/secondary endpoints Risk of Grade 2 or higher bleeding Prophylactic – 19% Therapeutic – 42% P <0.0001 Risk of Grade 4 or higher bleeding Prophylactic – 1% Therapeutic – 5% P = 0.0159
Prophylactic: ≤10 x 109/L No prophylaxis
Risk of Grade 2 or higher bleeding Prophylactic – 43% Therapeutic – 50% Adj diff in proportions – 8.4 percentage points (90% CI, 1.7 – 15.2) P = 0.06 for non-inferiority
ACCEPTED MANUSCRIPT
While significant heterogeneity remains in clinical practice, [79] these RCTs and systematic reviews have provided the foundation for the development of recent evidence-based guidelines, as discussed below. The
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guidelines focus on the main topics addressed in the studies: prophylactic
Guidelines
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3.2.
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transfusion and efficacious platelet dose.
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versus therapeutic platelet transfusion, appropriate threshold for platelet
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Various guidelines addressing the appropriate transfusion of platelets across
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various populations have recently been published, addressing questions of
PT
prophylactic versus therapeutic platelet transfusion, appropriate thresholds
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for platelet transfusion and efficacious platelet dose. [58] [59] [80] [54, 81] The AABB Clinical Practice Guidelines for platelet transfusion are
AC
frequently referenced. [81] The guidelines strongly recommend prophylactically transfusing adult hospitalized patients with therapy-induced hypoproliferative thrombocytopenia at a platelet count <10 x 109/L with up to a single apheresis unit or an equivalent dose of WBD platelets. Other guidelines similarly recommend a threshold of <10 x 109/L in patients with hematologic malignancies undergoing treatment. [59] [80] The AABB
ACCEPTED MANUSCRIPT guidelines recommend prophylactic platelet transfusion at a platelet count <20,000/µL for elective central venous catheter (CVC) placement, <50,000/µL for elective diagnostic lumbar puncture, and <50,000/µL for
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major elective nonneuraxial surgery. AABB recommends against routine
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prophylactic platelet transfusion in patients without thrombocytopenia
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undergoing cardiac surgery with cardiopulmonary bypass, as platelet
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transfusion has been shown to be an independent predictor of adverse outcomes in such situations, including mortality. However platelet
AN
transfusion is recommended if these patients develop perioperative bleeding
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or signs of platelet dysfunction, findings which can develop due to exposure
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to the cardiopulmonary bypass circuit. [82] In patients with intracranial hemorrhage taking antiplatelet agents, AABB is unable to recommend for or
PT
against platelet transfusion due to insufficient evidence.
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Recently published guidelines from the American Society of Clinical
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Oncology (ASCO) provide updated recommendations for platelet transfusion strategies in patients with cancer. [59] For patients undergoing allogeneic HSCT or those receiving therapy for hematologic malignancies, prophylactic platelet transfusion at a threshold of <10 x 109/L is recommended. Based on extrapolation from studies in hematology patients, prophylactic platelet transfusion at a threshold of <10 x 109/L is also
ACCEPTED MANUSCRIPT recommended in patients with solid tumors. The guidelines recommend consideration of transfusion at higher levels in certain circumstances, such as patients exhibiting signs of hemorrhage or sepsis. In adult recipients of
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autologous HSCT and patients with chronic, stable, severe
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thrombocytopenia not receiving active treatment, a therapeutic platelet
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transfusion strategy is recommended, in which transfusions are administered
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only for episodes of clinically significant bleeding. For patients undergoing invasive procedures, the ASCO guidelines recommend similar thresholds as
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AABB of 40,000/µL to 50,000/µL for major procedures and ≥20,000/µL for
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less invasive procedures, e.g. bone marrow biopsies or CVC insertion. In
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addition, the guidelines recommend providing leukocyte-reduced RBCs and platelets to prevent alloimmunization, in particular to patients with AML
PT
undergoing induction chemotherapy.
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Various international guidelines also provide recommendations for
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platelet transfusion strategies, in general alignment with the AABB and ASCO guidelines. [83] [58, 80]. Common recommendations across the guidelines include providing prophylactic platelet transfusions to thrombocytopenic patients receiving intensive therapy at a threshold of <10 x 109/L, routinely using only one standard adult dose for prophylactic transfusions, withholding prophylactic treatment in patients with autologous
ACCEPTED MANUSCRIPT HSCT or with asymptomatic thrombocytopenia due to chronic bone marrow failure, and increasing the platelet transfusion threshold based on patientspecific risk factors for bleeding. General consensus among both U.S. and
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international guidelines emphasizes avoiding the risk of unnecessary
Adverse events
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3.3.
US
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and patient-specific risk factors. [84] [80, 85]
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transfusions, and to guide patient care primarily based on clinical judgment
M
Adverse events associated with platelet transfusion include infectious and
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non-infectious etiologies. Transfusion transmitted infection can be caused by viruses, (e.g. HBV, HIV, West Nile Virus), parasites (e.g. Babesia, malaria),
PT
bacterial contamination, [60] [61, 62], prion diseases (e.g. variant
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Creutzfeld-Jakob disease), and emerging infectious diseases. [86] Common
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non-infectious etiologies due to platelet transfusion include allergic/anaphylactic reactions[87], FNHTRs [88], TRALI and TACO, [89] platelet alloimmunization and hemolytic reactions. [80] Receiving platelet transfusions prior to invasive procedures has been associated with increased risk in multiple observational studies. Prophylactic pre-procedure platelet transfusion was associated with an increased risk of
ACCEPTED MANUSCRIPT thrombosis and mortality in hospitalized patients in a prospective observational trial. [90]. A retrospective cohort study of patients with gastrointestinal (GI) bleeding on antiplatelet medications who received
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platelet transfusions showed a 5.57 increased odds ratio of death compared
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to controls. [91] A randomized trial of platelet transfusion in adults with
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acute intracerebral hemorrhage associated with antiplatelet therapy
US
demonstrated increased odds of death and dependence in patients receiving platelet transfusions compared to standard care (OR, 2.05; 95% CI 1.18 to
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3.56, p = 0.0114). [92] Similarly, a randomized trial of 660 neonates
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compared a threshold of less than 50 x 109/L to a threshold less than 25 x
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109/L. The primary outcome was death or major bleeding up to and including day 28. New major bleeding episodes occurred in 14% of infants
PT
in the high-threshold group compared to 11% in the low threshold group
CE
(HR 1.32; 95% CI 1.00 to 1.74). The primary outcome of death or a new
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major bleeding episode occurred in 26% of infants in the high-threshold group compared to 19% in the low-threshold group (adj OR 1.57; 95% CI, 1.06 to 2.32; P=0.02). Death occurred in 15% of the high-threshold group compared to 10% in the low-threshold group (OR 1.56; 95% CI, 0.95 to 2.55), although this did not reach statistical significance. Ninety percent of patients in the high-threshold group received a platelet transfusion compared
ACCEPTED MANUSCRIPT to 53% in the low-threshold group (HR 2.75; 95% CI, 2.36 to 3.21). [93] A study of prophylactic platelet transfusion prior to interventional radiology procedures demonstrated an association of platelet transfusion with
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increased rates of ICU admission (OR, 1.57; p = .022). [94] However,
IP
studies of other populations undergoing invasive procedures, including
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cardiac surgery have failed to show an association between platelet
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transfusion and increased mortality or morbidity. [95, 96]
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4. Plasma
Plasma constitutes over half of the total blood volume, and contains multiple
PT
coagulation factors, immunoglobulins, albumin and other proteins. Plasma
CE
can be processed by the separation of a WB donation or collected by
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apheresis. The average volume of a plasma unit derived from WB is approximately 250 mL, although apheresis collections can range from 400 to 600 mL.
Plasma products can be frozen following collection and later thawed prior to use, or maintained in a liquid state. Plasma products for transfusion include frozen plasma, liquid plasma, thawed plasma, cryoprecipitate-
ACCEPTED MANUSCRIPT reduced plasma, Solvent/detergent (S/D) plasma and pathogen-reduced plasma. Fresh-frozen plasma (FFP) is separated from RBCs or collected by apheresis and frozen at -18°C or colder within 8 hours of collection. FFP
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contains normal levels of coagulation factors, albumin and
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immunoglobulins. [97] When frozen at -18°C or colder, FFP has a shelf life
CR
of 12 months. Plasma frozen within 24 hours after phlebotomy (FP24) is
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processed similarly to FFP but frozen within 24 hours of collection. While plasma for transfusion is generally referred to as FFP, frozen within 8 hours
AN
of collection, in practice the majority of plasma is FP24, frozen anytime up
M
to 24 hours following collection. FFP and FP24 are generally used
ED
interchangeably, however, FP24 is not indicated to treat deficiencies of labile coagulation factors, e.g. Factors V and VIII. Once thawed, plasma has
PT
a shelf life of 24 hours, stored at 1 to 6°C. Although not an FDA-recognized
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product, thawed plasma stored longer than 24 hours can be relabeled as
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Thawed Plasma and stored up to 5 days. Thawed Plasma is used as a source of nonlabile plasma proteins. Clinical differences between frozen and thawed plasma products have not been demonstrated and Thawed Plasma has been reported to reduce product outdating in hospitals. [98] [99-101] Cryoprecipitate-reduced plasma is prepared by thawing and centrifuging FFP, followed by removal of the cryoprecipitate. The remaining product is
ACCEPTED MANUSCRIPT deficient in fibrinogen, Factor VIII, Factor XIII, von Willebrand Factor (vWF) and fibronectin. It is indicated for transfusion or plasma exchange in patients with thrombotic thrombocytopenic purpura (TTP) or reversal of
Indications/current practice
US
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4.1.
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warfarin coagulopathy (if other therapies are not employed).
Accepted indications for plasma transfusion include as prophylaxis prior to
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performing invasive procedures, to treat bleeding in patients with multiple
M
coagulation factor deficiencies, e.g. disseminated intravascular coagulation
ED
(DIC) or liver disease, in patients undergoing massive transfusion who have dilutional coagulopathy, to manage specific coagulation factor deficiencies
PT
for which a licensed coagulation factor concentrate is not available, for
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warfarin reversal and plasma exchange. [101]
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Inappropriate uses include as a primary means for the expansion of circulatory volume, hypoproteinemia, and correction of congenital or acquired deficiencies of clotting in the absence of bleeding. [102, 103] [97] [101] Importantly, plasma transfusions should not be given to correct minor coagulation test abnormalities in non-bleeding patients, e.g. slightly elevated prothrombin time/international normalized ratio (PT/INR) or activated
ACCEPTED MANUSCRIPT partial thromboplastin time (aPTT). This practice is discouraged because mild to moderate elevations in commonly used coagulation tests such as the PT/INR correlate poorly with bleeding propensity, [104, 105] moderate
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increases in the INR are not corrected by plasma transfusion, [14, 106] and
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multiple randomized and observational studies have shown that prophylactic
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plasma transfusions do not improve bleeding outcomes, [107, 108] but may
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in fact adversely affect clinical outcome. [109] [110, 111] A recent study found that plasma transfusions continue to be administered typically in two-
AN
unit doses for modest elevations in INR, that two-unit transfusions had very
M
little effect on the patient’s INR (median decrease 0.4), and in 20% of
ED
patients, the indication for transfusion was prophylactic preprocedural INR correction in stable non-bleeding patients. [14, 15] In such situations, plasma
PT
transfusion is not expected to affect either the INR or reduce surgical
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bleeding risk, but instead exposes the patient to transfusion associated risks
AC
including TACO, TRALI, anaphylaxis and transfusion-transmitted infection (TTI).
4.2.
Guidelines
ACCEPTED MANUSCRIPT Recent guidelines from the British Society of Hematology address the use of plasma and cryoprecipitate products in various patient groups in the absence of major bleeding. [112] Key practice points emphasize that abnormal
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coagulation tests (PT/aPTT) are poor predictors of bleeding risks in non-
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bleeding patients prior to an invasive procedure; a detailed clinical history
CR
should be routinely assessed on a patient-specific basis prior to undergoing a
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procedure; and the impact of commonly used doses of FFP to correct clotting results or to reduce bleeding risk is very limited for a PT/INR
AN
between 1.5 to 1.9. For patients with prolonged PT likely due to acquired
M
vitamin K deficiency, administration of vitamin K is recommended. The
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guidelines cite insufficient evidence on which to base a recommendation for the optimal dose of FFP for patients with abnormal coagulation tests
PT
undergoing a procedure. The guidelines recommend providing ABO-
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identical products, or low-titer anti-A or anti-B plasma if only ABO non-
AC
identical plasma is available. In 2010 the AABB published Evidence-Based Practice Guidelines for Plasma Transfusion[113] including recommendations that plasma be transfused to patients requiring massive transfusion and to patients with warfarin therapy-related intracranial hemorrhage. The panel found insufficient evidence to recommend for or against transfusion of plasma at a
ACCEPTED MANUSCRIPT plasma:red blood cell ratio of 1:3 or more (indicating more plasma per red cell) during massive transfusion, plasma transfusion in patients undergoing surgery in the absence of massive transfusion, or transfusion of plasma to
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reverse warfarin in patients without intracranial hemorrhage. The guidelines
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recommend against plasma transfusion for other groups of patients, (e.g. in
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the absence of massive transfusion, surgery, bleeding or over-
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anticoagulation), such as patients with acute pancreatitis, organophosphate poisoning, coagulopathy, or acetaminophen poisoning. In these
AN
heterogeneous populations, the available evidence indicated that the adverse
Adverse effects
PT
4.3.
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effects of plasma transfusion outweighed any potential benefit.
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Transfusion of plasma is associated with TRALI, TACO, FNHTRs, allergic
AC
or anaphylactic reactions, and transfusion transmitted infection. The risk of TRALI from plasma transfusion has decreased in recent years since implementation of policies requiring plasma to be selected from primarily male or never-pregnant female donors. [112] [113] Recent evidence suggests that plasma transfusion in surgical procedures may be associated with adverse outcomes. [110] Several studies have
ACCEPTED MANUSCRIPT demonstrated increased rates of bleeding complications in patients receiving prophylactic plasma transfusions to correct preprocedural abnormal coagulation tests in the absence of clinical bleeding. [109, 111, 114] A
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recent retrospective cohort study showed an association between higher
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intraoperative plasma transfusion volumes and inferior perioperative clinical
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outcomes, including increased odds of peri-operative and post-operative
US
RBC transfusion, higher mortality, and fewer hospital and ICU-free days. [14] A meta-analysis of surgical studies showed that transfusion of plasma
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was associated with a trend of increased risk of death (OR 1.22; 95% CI,
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0.73 to 2.03). [115]
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PT
5. Cryoprecipitated Antihemophilic Factor (AHF)
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Cryoprecipitated Antihemophilic Factor (AHF) (cryoprecipitate) contains fibrinogen, Factor VIII, Factor XIII, vWF, and fibronectin. It is prepared by thawing and centrifuging WB-derived or apheresis FFP, followed by removal of the supernatant plasma. [116, 117] The cold-insoluble precipitate is suspended in a small amount of plasma (~15 mL) and refrozen at -18°C or colder within one hour, which permits a shelf-life of one year. FDA and
ACCEPTED MANUSCRIPT AABB Standards require that each unit of cryoprecipitate contain ≥80 IU of Factor VIII and ≥150 mg of fibrinogen, although in practice the average fibrinogen content per unit is significantly higher, in the range of 200 to 250
Indications/current practice
US
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5.1.
IP
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mg. [118]
Although the use of most blood components has been decreasing steadily
AN
over the past decade, the use of cryoprecipitate has increased, both in the
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U.S. and internationally. [1, 112] The reasons for the increase are unclear,
ED
although recent studies in obstetrics, cardiac surgery and trauma showing that acquired hypofibrinogenemia is associated with worse outcomes and
PT
risk of bleeding is a possible factor. [119-122] While cryoprecipitate is
CE
widely used, there is limited evidence to support its efficacy. [118] [117]
AC
[123, 124] Current practice likely still continues to be guided by historical reports suggesting hemostatic insufficiency occurs at fibrinogen levels <1 g/L[125] although this metric has been drawn into question. [126-130] Cryoprecipitate is recommended for fibrinogen replacement in diseases of acquired hypofibrinogenemia, such as liver transplantation, cardiovascular surgery and obstetric hemorrhage. [118, 131] Although
ACCEPTED MANUSCRIPT historically cryoprecipitate was also used to treat Factor VIII deficiency, Factor XIII deficiency, and vWF deficiency, due to the availability of coagulation factor concentrates, it is now used almost exclusively for
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fibrinogen replacement. Newly developed coagulation factor concentrates
IP
are currently considered the standard of care in Factor VIII deficiency,
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congenital fibrinogen deficiency (including hypofibrinogenemia and
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afibrinogenemia), and von Willebrand disease. A Factor XIII concentrate derived from human plasma is also available. However currently licensed
AN
fibrinogen concentrates in the U.S. are not indicated for acquired
Guidelines
PT
5.2.
ED
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hypofibrinogenemia, which remains treated with cryoprecipitate.
CE
Due to the lack of evidence from randomized trials evaluating fibrinogen
AC
replacement, guidelines on the use of cryoprecipitate are mostly based on consensus and vary substantially. [120, 126] [132] The recent British Society of Hematology guidelines[112] found insufficient evidence to recommend a specific threshold at which cryoprecipitate should be transfused or the appropriate dose necessary for prophylaxis in non-bleeding patients undergoing invasive procedures. The guidelines suggest that
ACCEPTED MANUSCRIPT cryoprecipitate can be used in non-bleeding patients with low fibrinogen levels (e.g. <1 g/L) undergoing invasive procedures, however note this recommendation is not evidence-based. In accordance with American
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Association for the Study of Liver Diseases and European Association for
IP
the Study of the Liver recommendations[133, 134], the guidelines
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recommend against prophylactic transfusion of FFP and cryoprecipitate in
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Adverse effects
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5.3.
US
low bleeding risk procedures, such as paracentesis.
ED
While the risks of cryoprecipitate transfusion are in theory similar to those of FFP (e.g. allergic reactions, FNHTRs and TTI), reported adverse
PT
reactions due to cryoprecipitate transfusion are infrequent. [117] While
CE
cryoprecipitate has been associated with adverse reactions of hemolysis due
AC
to transfused isohemagglutinins, thrombosis, and respiratory distress, such reports are rare and mostly limited to case reports or small case series. [135138] Cryoprecipitate has been implicated in rare cases of TRALI. [139] However, this risk has been mitigated since the implementation of policies for collection of plasma for transfusion primarily from male or never-
ACCEPTED MANUSCRIPT pregnant female donors. Large volumes of transfused cryoprecipitate should
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be ABO-plasma compatible.
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IP
6. Granulocytes
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Granulocyte components are collected by cytapheresis from donors stimulated with corticosteroids and/or granulocyte colony-stimulating factor
AN
(G-CSF). Hydroxyethyl starch, a red cell sedimenting agent, is typically
M
used in granulocyte collection to facilitate the separation of granulocytes
ED
from red blood cells. Each unit contains ≥1.0 x 1010 granulocytes and up to 50 mL RBCs as well as small amounts of lymphocytes and platelets. Due to
PT
the RBC content, granulocyte components are ABO matched to the recipient
CE
to avoid hemolytic reactions. Cytomegalovirus (CMV)-seronegative
AC
granulocyte components should be provided if available, particularly to immunosuppressed CMV-seronegative patients. [140] Granulocytes are stored at room temperature, often irradiated, and administered within 24 hours of collection. Although stimulation with G-CSF can produce higher yields of granulocytes than corticosteroid stimulation, due to logistical considerations such as recruiting eligible donors within 24 hours, and
ACCEPTED MANUSCRIPT increased donor adverse side effects such as bone pain and myalgias, many facilities collect granulocytes without G-CSF stimulation.[141]
Indications/current practice
IP
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6.1.
CR
Granulocytes are indicated in patients with life-threatening bacterial and
US
fungal infections who have severe neutropenia (ANC <500/µL), are unresponsive to appropriate therapy following a reasonable period of
AN
treatment, and have a reasonable prospect of recovery. [141] Granulocyte
M
transfusions are also indicated in patients with congenital disorders of
ED
neutrophil function, such as chronic granulomatous disease. However, the clinical efficacy of granulocyte transfusions remains unproven. [140] [142,
PT
143] In clinical practice, granulocytes are prescribed inconsistently and it
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has been reported that as few as 25% of eligible patients receive them. [144-
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146] When administered, higher doses are more likely to provide therapeutic benefit, [141] although may pose a higher risk of adverse effects such as lung injury.
6.2.
Guidelines
ACCEPTED MANUSCRIPT Although granulocyte transfusions have long been used to treat patients with invasive infections, studies have failed to demonstrate a conclusive survival benefit. [60, 141, 142] Due to the lack of definitive evidence and a paucity
T
of well-designed trials, many of which have been underpowered, [141,
IP
142]clinical practice guidelines have yet to be developed. For example, a
CR
Cochrane review evaluating 10 RCTs found no difference in 30-day
US
mortality between patients with neutropenia who received granulocyte transfusions compared to a control group who did not (RR 0.75, 95% CI
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0.54 to 1.04). Nor was a difference seen in reversal of infection between the
M
two groups (RR 0.98, 95% CI 0.81 to 1.19). However, a subgroup analysis
ED
showed fewer infections in the group receiving intermediate-dose granulocyte transfusions (1.0 to 4.0 x 1010 granulocytes) In conclusion, the
PT
authors reported that there was insufficient evidence to determine whether
CE
granulocyte transfusions affect all-cause or infection-related mortality but
AC
acknowledged that the quality of the evidence was very low to low. [143] The lack of consistent evidence has been suggested to result from difficulty in obtaining a sufficient number of granulocytes to provide efficacy and from low enrollment resulting in under-powered studies. For example, the Resolving Infection in Neutropenia with Granulocytes (RING) trial, which studied the efficacy of G-CSF/dexamethasone-mobilized granulocyte
ACCEPTED MANUSCRIPT transfusion in neutropenic patients on chemotherapy with infection, noted no difference in outcome between the treatment group compared to the control group. However, a secondary analysis showed that patients receiving higher
T
doses (0.6 x 109/kg) had a statistically significant better outcome in terms
IP
of clinical course and survival, although the study was statistically
CR
underpowered. [141] A recent review also notes these concerns, concluding
US
that despite conclusive evidence of improvement in clinical outcomes following granulocyte transfusion, this is largely due to low clinical trial
AN
enrollment, and concludes granulocyte transfusions are critical in supporting
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neutropenic patients with life-threatening bacterial or fungal infections.
ED
[144] Similarly a review by West et al. of granulocyte transfusions in
PT
neutropenic patients recognizes the potential benefit of granulocyte transfusions in select circumstances however recommends against routine
CE
granulocyte transfusions in neutropenic patients with localized fungal
AC
infection due to the significant risk posed to patients. [140]
6.3.
Adverse effects
Adverse effects from granulocyte transfusions include febrile reactions, severe pulmonary complications, hypoxia, hypertension, and HLA
ACCEPTED MANUSCRIPT alloimmunization. Granulocyte transfusions also pose a risk of TTI, with
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CMV transmission of particular concern in immunosuppressed populations.
CR
IP
7. Further processing
US
Blood products are frequently modified to prevent adverse transfusion reactions. Common processing steps of products for transfusion include
AN
leukocyte reduction, irradiation and washing. New technologies to prevent
M
pathogen transmission including solvent-detergent treatment and pathogen
ED
inactivation technologies have been developed, however safety and efficacy
CE
Leukocyte reduction
AC
7.1.
PT
considerations remain and surveillance is ongoing. [147]
Leukocyte reduction involves the removal of white blood cells (WBC) from blood components though filtration or during apheresis collection. The purpose of leukocyte reduction is to prevent adverse effects of leukocytes in transfused blood components. The majority (>90%) of RBCs and platelets in the U.S. are leukocyte reduced. [12] Established clinical benefits of
ACCEPTED MANUSCRIPT leukocyte reduction include decreasing FNHTRs [88, 148, 149], preventing HLA alloimmunization[150], and reducing CMV transmission. [151] As CMV is a highly cell-associated virus, removing the WBCs in blood
T
components helps prevent transfusion transmission. [152] Similarly, as HLA
IP
antigens are found on leukocytes, decreasing the concentration of WBCs
CR
reduces the likelihood of HLA alloimmunization. [150] The proposed
US
principal mechanisms for FNHTRs include immune (antibody-mediated) and non-immune etiologies (biologic response mediators). The immune
AN
mechanism involves recipient anti-HLA or anti-HNA reacting with donor
M
WBCs leading to an antigen-antibody reaction accompanied by release of
ED
inflammatory molecules.(see Figure 1) [153] The non-immune mechanism is caused by buildup of cytokines released from WBCs during storage which
PT
act on the hypothalamus to induce febrile symptoms. [153,
CE
154]Leukoreduced components, therefore, cause FNHTRs much less often
AC
than non-leukoreduced components. Leukocyte reduction is not indicated for prevention of TA-GVHD.
7.2.
Irradiation
ACCEPTED MANUSCRIPT Irradiation of cellular blood components delivers 2500 cGy to the product which prevents proliferation of viable T-lymphocytes by causing DNA damage and preventing replication. Irradiation is indicated for the prevention
T
of TA-GVHD. [18, 155] Populations at risk of TA-GVHD include
IP
immunosuppressed patients (due to HSCT or various drug regimens),
CR
recipients of neonatal exchange or intrauterine transfusions, and recipients of
US
blood components from blood relatives or in a population with limited HLA diversity. [155] Accordingly, irradiation of cellular blood components is
AN
indicated for recipients of allogeneic HSCT, transfusion between blood
M
relatives, immunosuppressed patients, intrauterine transfusions and
PT
Washing
CE
7.3.
ED
premature neonates.
AC
Washing of cellular blood components removes the majority of plasma proteins, electrolytes and antibodies, which can be implicated in transfusion reactions, notably allergic/anaphylactic reactions. Washing of cellular products is indicated in patients with repeated and/or severe allergic reactions, those at risk of hyperkalemia, and patients with documented IgA deficiency if blood components from an IgA deficient donor are unavailable.
ACCEPTED MANUSCRIPT [18, 155] While washing is a very effective strategy for preventing allergic reactions with up to a 95% reduction in incidence of allergic reactions to platelet components, [156] a disadvantage is that it can result in substantial
Volume reduction
US
CR
7.4.
IP
T
loss of product.
Volume reduction removes plasma and additive solutions by centrifugation.
AN
It is indicated to manage volume in recipients at risk of transfusion-
M
associated circulatory overload, such as patients with cardiac dysfunction. It
ED
also reduces exposure to plasma proteins which can prevent adverse transfusion events such as allergic reactions, FNHTRs and ABO
CE
PT
incompatibilities. [157, 158]
AC
7.5. Platelet Additive Solution (PAS)
Apheresis platelets can be stored in Platelet Additive Solution (PAS), an isotonic solution composed of varying electrolyte composition (see table 3). There are two approved PAS solutions in the U.S., InterSol® and IsoplateTM. Storage in PAS reduces 65% of the plasma used to store apheresis platelets.
ACCEPTED MANUSCRIPT Allergic transfusion reactions are thought to be due to allergenic proteins in plasma, therefore reduction of plasma volume should decrease allergic reactions. [159] [156] Storage in PAS presents an alternative to 100%
T
plasma storage. Similar to the reduction in transfusion reactions seen with
IP
plasma reduction by washing or volume, storage in PAS has been shown to
CR
reduce allergic reactions[159, 160] and in some studies, febrile reactions,
US
[159, 161] although this has not been seen in all studies. [160] Table 3. Composition of various platelet additive solutions PAS-D Citrate Acetate Magnesium Potassium Gluconate
PAS-E Citrate Phosphate Acetate Magnesium Potassium
AN
PAS-C* Citrate Phosphate Acetate
M
PAS-B Citrate Acetate
ED
PAS-A Citrate Phosphate Potassium
PAS-F† Acetate Magnesium Potassium Gluconate
PAS-G Citrate Phosphate Acetate Magnesium Potassium Glucose
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* Approved in the US as Intersol® † Approved in the US as Isoplate TM
Partly based on: Ringwald J, Zimmermann R, Eckstein R. The new generation of platelet additive
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solution for storage at 22 degrees C: development and current experience. Transfus Med Rev. 2006;20:158-64.
7.6.
Solvent-Detergent treatment
Solvent-detergent (S/D) treatment (Octaplas, Pooled Plasma, Octapharma USA) [161] is a method used in the manufacture of plasma derivatives that
ACCEPTED MANUSCRIPT inactivates lipid-enveloped pathogens by disrupting cellular membranes and inhibiting DNA replication. Octaplas is manufactured from a pool of 630 to 1520 individual donors of a single ABO blood group (A, B, AB, or O). The
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pooled product is treated with S/D reagents [1% tri-n-butyl phosphate
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(TNBP) and 1% octoxynol] for 1 to 1.5 hours at 30°C to inactivate
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enveloped viruses. Octaplas treatment is not effective against non-enveloped
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viruses such as human parvovirus B19 and hepatitis E, therefore the manufacturing plasma pool is tested for these pathogens. Octaplas contains
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comparable levels of coagulation factors to healthy blood donors except
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protein S and alpha-2-antiplasmin, which are decreased due to the solvent
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detergent treatment. It is indicated for the replacement of multiple coagulation factors in patients with acquired deficiency due to liver disease
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and those undergoing cardiac surgery or liver transplant, and for plasma
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exchange in patients with TTP. Studies in these patient populations have
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demonstrated comparable hemostatic and coagulation parameters as conventional plasma products. It is contraindicated in patients with IgA deficiency or severe deficiency of Protein S. Transfusion reactions can occur with ABO group mismatches, therefore the product should be ABO compatible with the patient.
ACCEPTED MANUSCRIPT 7.7.
Pathogen reduction
An FDA approved pathogen inactivation method available in the U.S. for platelets and plasma is Amotosalen (S-59, psoralen derivative) and
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photoactivation by UVA light (INTERCEPT blood system, Cerus
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Corporation). [156] INTERCEPT treatment is a photochemical process in
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which amotosalen (S-59), a chemical that binds nucleic acids, is added to the
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platelet or plasma component; subsequent UVA illumination results in covalent cross-linking of amotosalen-bound nucleic acids, preventing
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replication. The Intercept blood system for plasma is intended to reduce the
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risk of transfusion-transmitted infection (TTI) in Whole Blood-derived or
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apheresis plasma or apheresis platelets. Non-enveloped viruses (e.g. hepatitis A, Hepatitis E, Parvovirus B19, poliovirus) and Bacillus cereus spores are
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resistant to INTERCEPT treatment. Two cases of hepatitis E transmission by
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INTERCEPT-treated plasma have been reported. [162] These components
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are contraindicated in patients with hypersensitivity to amotosalen or other psoralens or neonates treated with phototherapy devices emitting certain wavelengths. [156] Other pathogen inactivation technologies such as riboflavin plus UV light are available and used internationally but are not currently approved in the U.S.
ACCEPTED MANUSCRIPT 8. Blood bank laboratory testing
The blood bank performs pretransfusion testing to determine serologic
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compatibility between the recipient and the donor. Pretransfusion testing of
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patients receiving allogeneic blood includes typing for ABO and Rh and
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performing an antibody screen to detect unexpected antibodies to red cell
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antigens. The ABO group is determined by testing red cells with anti-A and anti-B reagents and testing the serum or plasma with A1 and B reagent red
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cells. Rh type is determined using anti-D reagent. The antibody screen is an
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indirect antiglobulin test (IAT) comprised of commercial red blood cells
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from two to three type O donors who in sum express the most common clinically significant red cell antigens. When clinically significant antibodies
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are detected, further evaluation is required for antibody identification.
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Antibody identification is performed using commercial kits consisting of
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panels of phenotyped donor cells. The final step to ensure compatibility is a crossmatch, performed by direct agglutination (“immediate spin”) in the absence of clinically significant antibodies, or by the antiglobulin technique in the presence of a positive antibody screen.
8.1.
Interference with serological testing
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Recent innovative immunotherapies, while providing revolutionary advances in patient care, have led to complications in blood bank testing. Immunotherapy involves the use of humanized monoclonal antibodies to
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target malignant cells for destruction in coordination with the patient’s
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immune system. [163] [164, 165] Monoclonal antibodies can cause
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interference in ABO and Rh typing, antibody detection and identification. Daratumumab (DARZALEX, Janssen Biotech, Inc.) is a human IgG1k
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monoclonal antibody directed against the CD38 antigen expressed on the
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surface of hematopoietic cells, particularly malignant myeloma cells and
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plasma cells. [166, 167] Daratumumab also targets CD38 expressed on RBCs, resulting in a false positive IAT that affects antibody screens,
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antibody identification panels and IAT crossmatch. The interference can last
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up to 6 months and can prevent antibody detection. ABO/Rh testing
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however is not affected. [168, 169] [170] Denaturing of CD38 with dithiothreitol (DTT) has been shown to successfully allow for subsequent antibody testing. [169-171] Trypsintreated reagent RBCs or CD38-negative RBCs can also be used. [172] Additional mitigation strategies are currently under investigation. [172-174]
ACCEPTED MANUSCRIPT Future CD38 antibody therapies are in development, which may require ongoing evaluation and adjustments in blood bank testing. [169, 175] Anti-CD47 (Hu5F9-G4) is a recently developed monoclonal IgG4
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antibody undergoing clinical trials for treatment of both hematologic and
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solid malignancies. CD47 is a glycoprotein expressed on all cells which
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prevents phagocytosis through interactions with the macrophage receptor
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SIRP. Anti-CD47 can block this signal, allowing for the destruction of certain cancer cells, such as leukemic blasts. [176, 177] A recent study
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investigated the interference of anti-CD47 in pre-transfusion serological
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testing using samples from four patients on anti-CD47 therapy[165] and
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showed that anti-CD47 interfered with all phases of pretransfusion antibody
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screening and crossmatch, including ABO reverse typing. The interference could not be mitigated with DTT or other commonly used denaturing
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enzymatic agents. The most effective solution was to perform multiple RBC
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alloadsorptions with papain-treated RBCs and use monoclonal Gammaclone (Immucor) anti-IgG (which does not detect IgG4 subclass antibodies) in IAT testing. This testing strategy is labor-intensive and not cost effective, and therefore further investigation will be required into feasible testing strategies for patients on anti-CD47 therapy. As monoclonal antibody therapies continue to emerge as transformative therapeutic agents, blood
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9. New and re-emerging products for transfusion
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Since the late 1900s, blood component therapy has been the standard of care
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in transfusion medicine and the driving principle behind the operation of laboratory blood banks. [178] [179] Innovations in refrigerated storage of
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blood components, improved design of blood bags and storage containers,
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preservative and anticoagulation solutions, in concert with product screening
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and donor testing have driven the widespread implementation of component therapy and improved product quality. However, the most common blood
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components for transfusion, (e.g. RBCs, platelets and plasma), require
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specific storage conditions and have limited shelf lives. Processing steps
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may include freezing and thawing for products such as plasma or cryoprecipitate, potentially leading to delays in providing blood for patients requiring urgent transfusions, while platelets require storage at room temperature which shortens the shelf-life to 5-7 days due to concerns of bacterial contamination. These limitations are particularly pronounced on the
ACCEPTED MANUSCRIPT battlefield where urgently needed blood products have to be transported and short product shelf-lives are prohibitive. [180] In consideration of the limitations of currently available products for
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transfusion, recent attention has focused on new products and strategies for
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transfusion. There has been a resurgence of interest in the use of WB for
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trauma resuscitation, a commonly transfused product from World War I until
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the 1970s. [180] Proponents of WB cite benefits of immediate availability, balanced resuscitation without the dilutional factors of anticoagulant
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preservative solutions, increased storage, and hemostatic efficacy.
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Observational studies of civilian patients receiving cold stored low
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isohemagglutinin titer group O Whole Blood (LTOWB) have shown no differences in clinical outcomes in patients receiving conventional
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component therapy compared to LTOWB, with a trend toward lower
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mortality in the LTOWB group. [181]
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With the recognition of the hemostatic efficacy of cold-stored platelets (CSP) contained in WB, platelets stored at 4°C have emerged as a potentially beneficial product. CSP were used commonly until 1969, when data showed they were more rapidly cleared from circulation than room temperature platelets, at which time room temperature platelets became more widely used, although CSP use continued until the early 1980s . [178]
ACCEPTED MANUSCRIPT Although CSP have documented lower recovery and survival, lower yields, and morphologic changes, they have an activated profile, which may result in greater hemostatic efficacy as compared to room temperature platelets,
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especially in acutely bleeding platelets. [182] CSP can also potentially be
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stored for longer periods and have decreased risk of bacterial contamination.
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A Norwegian study of transfusion of 4°C-stored platelets stored for up to 7
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days compared to room temperature platelets stored for up to 7 days in patients undergoing cardiothoracic surgery found no difference in mortality,
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number of thromboembolic events, or length of stay in the ICU, with
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decreased bleeding in the CSP group. [183]
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In addition to CSP, other novel products under development include lyophilized and cryopreserved platelets, [97, 184]freeze dried (lyophilized)
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plasma[185], and hemoglobin substitutes. [186] Although pre-clinical trials
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show promising results, large clinical trials are needed to provide evidence
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of safety and efficacy.
10. Special topics
10.1.
Vein-to-Vein Hemovigilance
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Hemovigilance has been defined as “a set of surveillance procedures covering the whole transfusion chain (from the collection of blood and its
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components to the follow-up of recipients), intended to collect and assess
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information on unexpected or undesirable effects resulting from the
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therapeutic use of labile blood products, and to prevent their occurrence or
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recurrence”.[187] The objective of hemovigilance is to monitor the entire
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vein-to-vein process of transfusion from the selection of donors to posttransfusion outcomes in patients.[188] Hemovigilance programs collect a
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range of transfusion-related outcomes data which can be broadly grouped
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into blood collection, preparation for transfusion, and post-transfusion
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monitoring. In blood collection, the focus is on donors and includes monitoring infectious disease marker rates, adverse events during and after
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collection, and longer-term monitoring of donor health status, such as iron
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depletion. The focus of preparation for transfusion is on use of proper patient and unit identification procedures and laboratory testing for typing and cross-matching, where process mistakes such as labeling errors can lead to “wrong blood in tube” and other preventable errors that present serious and potentially fatal risks to transfusion recipients. In post-transfusion monitoring, the focus is on proper infusion of each component and
ACCEPTED MANUSCRIPT monitoring for signs of potential transfusion reactions that can range from mild to severe, including mortality. When adverse events occur during the transfusion chain, investigations are triggered to establish the degree to
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which causality can be linked to transfusion using imputability criteria. In
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the U.S., donor and recipient fatalities are required to be reported to the
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FDA. Categories from the FDA fatality reporting classification system
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include: definite/certain, probable/likely, possible,
doubtful/unlikely/improbable, ruled out/excluded, or not
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determined/assessable/evaluable. In fiscal year 2016, of the 67 potential
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transfusion-associated fatality reports in the U.S., 43 (64%) were classified
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as either definite/certain, probable/likely or possible, 17 (25%) were classified as either doubtful/unlikely/improbable or not
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determined/assessable/evaluable, and 7 (11%) were classified as ruled
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out/excluded.[189] Causes of fatalities were distributed among allergic
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reactions/anaphylaxis, transfusion associated circulatory overload (TACO), transfusion related acute lung injury (TRALI), ABO-incompatible hemolytic transfusion reactions (HTR), and transfusion-transmitted infections. However, in the U.S. and some other countries reporting of non-fatal adverse events to surveillance and regulatory agencies may be voluntary, raising the important concern of underreporting. Fatalities are known to be
ACCEPTED MANUSCRIPT the proverbial tip of the iceberg with morbidity and near misses thought to be at least two orders of magnitude more common. Hemovigilance programs are implemented in a range of data
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collection approaches in different jurisdictions. The most intensive program
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is active surveillance of transfusion recipients for any sign of risk and
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clinical outcome. Active hemovigilance programs are uncommon because of
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the expense of implementing such programs. However, they provide the highest quality evidence on adverse event rates, due to the collection of data
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on all patients, including those who do and do not experience adverse
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events. Passive hemovigilance programs similarly seek to assess patient risk
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but do so by relying on the reporting of transfusion-related events only in those patients where an adverse event was identified. These data are then
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related back to the overall transfused population to establish rates of adverse
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events. As adverse event reporting is highly variable, passive surveillance is
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less accurate than active surveillance. The serious hazards of transfusion (SHOT) program in the UK provides data showing both preparation for transfusion, and post-transfusion monitoring demonstrate continued need to reduce patient risks. These data consistently show near misses, errors, and adverse events throughout the entire transfusion chain.[139, 190] In the U.S. about 6% of transfusing facilities participate in the National Healthcare
ACCEPTED MANUSCRIPT Safety Network hemovigilance program which has established a common protocol for assessing events.[191] The low participation of acute care facilities indicates that the overall system representation remains
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Palliative transfusion of blood products
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10.2.
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insufficient.
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Despite reports of improvement in survival associated with palliative care, as few as 2% of patients with hematologic malignancies use hospice, [192-195]
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and when they do get referred to hospice, the referral often comes within
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days of death. [194] [196] In a review of over 48,000 cancer patients
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admitted to hospice, those patients with hematological malignancies were more likely to die within 24 hours of hospice enrollment (10.9% vs 6.8%,
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odds ratio 1.66, p<0.001) or within 7 days (36% vs 25.1%, odds ratio 1.68,
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p<0.001) compared to solid tumor patients. [193, 196] As noted in the recent American Society of Hematology survey, lack of transfusion capability was the major barrier to referral of these patients leading to delayed enrollment in hospice. [197-199] The standard practice of hospice services requiring revocation of blood transfusions upon enrollment in this largely transfusion dependent population has created a system that prevents referral of patients
ACCEPTED MANUSCRIPT with hematologic malignancies from receiving palliative care/hospice care in the home. [198, 200] Review of available literature shows transfusions can improve symptoms [201] and provide palliative benefits to these patients,
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hence improving their quality of life despite poor prognosis. [198] Twelve
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before- and after-transfusion studies showed subjective response rates in the
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30-70% range. [202] In a recent study, approximately 80% of patients
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derived symptomatic benefit from symptoms such as fatigue, breathlessness, generalized weakness and dizziness. [201] Patients identify benefit from
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transfusions through home hospice or hospital based systems. [203]
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Increasingly, hematologists have identified that increased access to hospice
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care is necessary for good patient care in patients with hematologic malignancies. Moreover, more than half of hematologist-oncologists are
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likely to increase utilization of hospice for these patients if blood and
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platelet transfusions are provided.
Further barriers to transfusions exist with both cost and logistics of transfusions on hospice. While technically covered by the Medicare hospice benefit, in reality many hospices do not provide transfusions because of lack of adequate reimbursement and logistical capability of in-home transfusions or transporting patients to clinics. Data for safety of in-home transfusions
ACCEPTED MANUSCRIPT exists and is surprisingly long. Transfusion of products for patients with hemophilia [204] dates back to 1972, whereas home-based transfusion strategies of blood products for cancer patients have been safely employed
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by home health agencies in the U.S. since the 1980s. Reactions are noted to
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be minimal with only 1 in 1060 transfused products with a home health
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agency over 5 years, [205] and 1 in 415 in one center’s experience in cancer
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patients. [206] France set forth a dedicated study to evaluate transfusion risk in home-based settings as well as the economic and global health benefits to
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the healthcare system in providing care in the home. It was noted that
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minimal reactions were found, with only 3 mild transfusion related reactions
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in one group of 757 infusions, [207] and in another group only one transfusion event in 148 transfusions. [208] All studies identified that
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structural systems needed to be in place to provide for home-based
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transfusions, but once in place, could safely provide care. [205, 206, 209]
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Transfusion support has the potential to improve the quality of life in patients with terminal malignancies once data for the logistic and safety considerations are adequately embraced by the hematology community.
10.3.
Health economics/cost effectiveness
ACCEPTED MANUSCRIPT The role of health economics in transfusion medicine is controversial because of the complex issues related to society’s expectation that blood products are safe for recipients coupled with the fact that all safety measures
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cannot be implemented due to budget constraints. While no resolution of this
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controversy is expected in the immediate future, health economics is an
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important part of the overall evidence base for blood safety and transfusion
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medicine interventions. Healthcare policy decision makers must consider two broad objectives related to economics. The first is to remain within
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available finances or budgets and the second is to maximize health benefits
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at attainable costs.[210] These two objectives do not necessarily lead to
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consistent decisions or policy. Decision making that stays within the available budget may not maximize health benefits to the transfused
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population. Whereas alternately, attempting to maximize health benefits at
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attainable costs requires making difficult choices between interventions,
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including not selecting options that may be most effective and forgoing the health benefits that could be achieved. Budget impact analysis provides information in a balance-sheet format
of costs and cost savings for the implementation or maintenance of a healthcare intervention over a time period of usually one to five years. Costeffectiveness is an assessment of the ratio of costs to benefits, comparing at
ACCEPTED MANUSCRIPT least two different interventions. [211] Results are often reported as cost per quality-adjusted life year (QALY). Blood safety measures have been shown to exceed traditional thresholds of acceptable costs when compared to other
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interventions in health and medicine. A standard threshold is $50,000-
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$100,000-per quality adjusted life year (QALY) gained. In blood safety,
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cost-effectiveness of adopted interventions frequently exceeds thresholds of
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$1,000,000/QALY. Some have proposed that the adoption of Zika virus testing of donations in 2016 represents an example of inefficient use of
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resources because the risk of transfusion-transmitted Zika virus in the U.S.
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was small and subsequently has further decreased;[212] however at the time
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it was unknown how rapidly the epidemic might spread or potential modes of transmission. Due to these factors and the extreme devastation of
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infection, particularly in neonates, policy was implemented to avert such
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consequences. This policy has subsequently been reconsidered in light of
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recent epidemiologic data. [213] Cost-effectiveness analyses of newer interventions, e.g. pathogen
inactivation, have been applied to assess the economic value of such interventions in different patient populations.[214-216] The health economics of pathogen inactivation for platelets and plasma in the U.S. continues to be one of the barriers to broader adoption. Budget impact
ACCEPTED MANUSCRIPT analyses focused on the cost offsets that can be achieved are being published and such analyses are expected to increase in the near future. [217, 218] The totality of the evidence suggests that shifts in the approach to reimbursement
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for use of pathogen inactivation may be necessary before wider adoption is
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possible.
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Within the domain of patient transfusion, assessment of adopted
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interventions tends to better conform to the standard threshold. Many different analyses have been conducted, for example, the health economics
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of adopting patient blood management programs and the use of cell salvage
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or tranexamic acid to reduce allogeneic blood exposure.[219-223] Studies
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have defined the totality of costs that accrue in the transfusion chain and how alternative approaches may achieve additional health benefits at
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reduced total cost of care and reduced blood exposure. However, studies
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defining the cost-effectiveness of commonly transfused components (RBC,
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platelets, FFP/FP24, etc.) derived from donated blood are limited because of the challenge of completing such studies for the range of indications for which patients are transfused.
11. New safety considerations
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Risk Based Decision Management (RBDM)
The paradigm for system-level decision making in blood safety has received
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scrutiny in the past decade. The concept of the precautionary principle, its
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meaning, and how it defines or mischaracterizes risk tolerability has been
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the source of significant debate in transfusion medicine.[224] An
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international consensus conference held in 2010 to define a Risk-Based Decision Making (RBDM) framework was borne out of the objective to
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provide a structured, consistent process for evaluating and making blood
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safety decisions.[225, 226] The framework is a comprehensive tool that
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links separate lines of evidence together to help decision makers choose proportionate responses to different blood safety threats. The concept of
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proportionate response requires the acceptance that all risks cannot be
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prevented and approaches can be used to define the tolerability of each
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separate risk. RBDM is based on four policy foundations: risk management principles, risk communication and stakeholder participation, assessment principles, and risk tolerability.[227] Ways in which these foundations are defined and how they are incorporated into the process will vary among jurisdictions.
ACCEPTED MANUSCRIPT The framework segments the process into six steps: preparation, problem formulation, participation strategy, assessments, evaluation, and decision. Each step has defined activities, expectations for information that is
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generated, and recommended methods. Preparation and problem formulation
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are not considered trivial, and the careful definition of the exact problem or
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decision that is being faced is a critical part of process. As part of each
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RBDM assessment, specific analytical approaches are recommended in the domains of risk, health economics and outcomes, and social concern. These
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findings are then used to evaluate and choose a course of action for threat or
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problem. Uptake of the RBDM framework has expanded and several
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jurisdictions have published assessments covering a range of topics initially focused on infectious threats in transfusion, including Babesia, malaria and
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HTLV.[228-230] The use of the framework in patient safety considerations
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beyond infectious threats is possible, but to date examples of the use of the
11.2.
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framework beyond infectious threats have not been published.
Bacterial testing of platelets
Room temperature storage of platelets allows initial small bacterial loads to increase to very high inocula, which has limited storage time to 5-7 days and
ACCEPTED MANUSCRIPT necessitated testing for bacterial contamination or use of pathogen reduction technology. [63] Bacterial species associated with contaminated platelets include Gram negative species (e.g., Pseudomonas aeruginosa and
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Enterobacteriaceae) and Gram positive species (e.g., Staphylococcus aureus,
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other Staphylococcus species, Bacillus species and Streptococcus species).
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STR are predominantly associated with transfusion of platelets contaminated
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with bacterial loads above 105 CFU/mL, with more virulent bacterial species (Gram negatives and Staphylococcus aureus) also associated with more
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severe STR. [231]
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In the US testing for bacterial contamination was mandated by AABB in
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2004 and was generally implemented by culture of products 24-36 hours after collection using BacT/ALERT or eBDS systems. [232] Under 21 CFR
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606.145(a), effective March 23, 2016, blood collection establishments and
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transfusion services must assure that the risk of bacterial contamination of
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platelets is adequately controlled using FDA approved or cleared devices, or other adequate and appropriate methods found acceptable for this purpose by FDA. [233]This requirement currently can be met with either bacterial testing or pathogen reduction performed with an FDA-approved pathogen reduction device. [63] As noted above, pathogen reduction of apheresis platelets using amotosalen was approved for use in the US in 2014, and this
ACCEPTED MANUSCRIPT process is increasingly being used. [63] [154] However, despite use of culture since 2004, STR and fatalities, while reduced, continued to occur. Ten fatalities from bacterial contamination of platelet products during the 5-
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year period 2012-2016 were reported to FDA (a rate of approximately 1 per
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million platelet transfusions), 8 associated with apheresis and 2 with pooled
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platelets. [60] Thirty STR from bacterial contamination of platelet products
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during the 7-year period 2010-2016 were reported by the NHSN Hemovigilance Module from 308 facilities (a rate of 19.5 per million platelet
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transfusions), with 26 associated with apheresis and 4 with WB platelets
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(rates of 24 and 8.6 per million, respectively). [234] Considerably higher
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rates of STR have been reported from active surveillance programs: 97 per million by active bacterial surveillance during 2007-2013[235] and 38 per
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million by active clinical surveillance during 2009-2016. [61]
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Various solutions to enhance the safety and availability of platelets for
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transfusion and further reduce STR have been proposed. These solutions include methods to allow platelet storage for up to 5 days or 7 days. Proposed methods for 5-day storage include primary culture followed by secondary culture or secondary rapid testing and pathogen reduction technology. Pathogen reduction technology is not currently approved for 7day storage. For 7-day storage, proposed methods similarly include primary
ACCEPTED MANUSCRIPT culture followed by secondary culture or rapid testing as well as a large volume delayed sampling protocol. [236]
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12. Summary and future considerations
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Transfusion of blood products constitutes a critical component of medical
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care, and is among the most common procedures in hospitalized patients. [3]
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The current era of transfusion medicine is built on a robust historical legacy, which has facilitated its continuing evolution and advancement. [4] Recent
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innovations in transfusion medicine research have redefined the paradigms
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guiding transfusion practice, moving away from standard laboratory triggers
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as the basis for transfusion towards a wholistic consideration of patientspecific factors. While blood transfusion continues to be recognized as a
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life-saving and crucial therapy, increasing evidence points to the benefit of
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limiting unnecessary transfusions, both for avoidance of adverse outcomes and from a cost perspective. The development of patient blood management programs, which focus on patient safety, adherence to guidelines, and consideration of transfusion alternatives, has facilitated the implementation of recommended preventive measures to improve patient safety. New developments in transfusion medicine focus on innovative blood products
ACCEPTED MANUSCRIPT such as cryopreserved platelets and lyophilized plasma that can overcome the limitations of currently available therapies to provide greater
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accessibility and improved quality and availability.
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Practice points * Unnecessary transfusions should be avoided
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* Platelets should be provided prophylactically at a transfusion threshold of <10 x 109/L in patients at risk of bleeding
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* Therapeutic platelet transfusion strategies should be used in non-bleeding patients not at high risk of bleeding
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* Plasma should not be transfused to correct minor abnormalities in coagulation tests as a preventive measure. Plasma should not be transfused for an INR ≤ 2
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* Patient blood management programs can improve patient safety, reduce unnecessary transfusions and provide cost savings
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* Structured evaluation approaches for blood and patient safety are being adopted to facilitate enhanced use of evidence-based practice in transfusion
Research agenda * Studies of hemoglobin thresholds in additional patient subgroups, such as pediatric and neonatal patients, patients on extracorporeal support, and patients with myocardial infarction and acute coronary syndrome to
ACCEPTED MANUSCRIPT determine conclusively if there is an adverse effect of a restrictive RBC transfusion strategy in these populations * Development of new technologies to refine the decision making process for RBC transfusion, such as non-invasive methods of directly assessing tissue oxygenation
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* Investigation of the effects of storage on RBCs and the appropriate storage age for transfusion, as well as possible mitigation of the deleterious effects of storage
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*Development of a viable oxygen therapeutic to replace human RBC transfusion
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* Continuing research into appropriate transfusion parameters for all blood components particularly cryoprecipitate for which there is less available information in order to formulate guidelines
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* Transfusion approach to hemorrhagic shock and massive trauma
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* Further evaluation of a possible association between donor characteristics, (e.g. age, sex, prior pregnancy), and recipient transfusion outcomes
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* Development of a robust in vitro test that will accurately and reliably predict post-transfusion platelet recovery and survival
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* Continuing studies into new products such as cold stored platelets, freezedried plasma and lyophilized plasma to evaluate safety and efficacy * Development of new and advancing technologies, such as pathogen inactivation of whole blood to protect against emerging infectious diseases * Further analysis of health economics and cost-effectiveness in relation to blood safety and availability with consideration of approaches such as patient blood management and reduced RBC exposure that may achieve health benefits at lower cost
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Conflict of interest The author has no conflicts of interest to disclose.
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Acknowledgements We would like to acknowledge the contributions of Jennifer Holter-Chakrabarty, MD, University of Oklahoma, Rachel Cook, MD, MS, Oregon Health & Sciences University, and Sarah Holstein, MD, PhD, University of Nebraska on behalf of the ASH Government Affairs and Palliative Care Committee.
ACCEPTED MANUSCRIPT References
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1. Ellingson KD, Sapiano MRP, Haass KA, Savinkina AA, Baker ML, Chung KW, et al. Continued decline in blood collection and transfusion in the United States-2015. Transfusion. 2017;57 Suppl 2:158898. 2. Karafin MS, Bruhn R, Westlake M, Sullivan MT, Bialkowski W, Edgren G, et al. Demographic and epidemiologic characterization of transfusion recipients from four US regions: evidence from the REDS-III recipient database. Transfusion. 2017;57(12):2903-13. 3. Di Minno G, Navarro D, Perno CF, Canaro M, Gurtler L, Ironside JW, et al. Pathogen reduction/inactivation of products for the treatment of bleeding disorders: what are the processes and what should we say to patients? Ann Hematol. 2017;96(8):1253-70. 4. Farr AD. The first human blood transfusion. Med Hist. 1980;24(2):143-62. 5. Farr AD. Blood group serology--the first four decades (1900--1939). Med Hist. 1979;23(2):21526. 6. Landsteiner K. On agglutination of normal human blood. Transfusion. 1961;1:5-8. 7. Adams RC, Lundy, J.S. Anesthesia in cases of poor surgical risk. Some suggestions for decreasing the risk. Surg Gynecol Obstet. 1942;74:1011-19. 8. Madjdpour C, Spahn DR. Allogeneic red blood cell transfusions: efficacy, risks, alternatives and indications. Br J Anaesth. 2005;95(1):33-42. 9. Wang JK, Klein HG. Red blood cell transfusion in the treatment and management of anaemia: the search for the elusive transfusion trigger. Vox Sang. 2010;98(1):2-11. 10. Carson JL, Stanworth SJ, Roubinian N, Fergusson DA, Triulzi D, Doree C, et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2016;10:CD002042. 11. Roubinian N, Carson JL. Red Blood Cell Transfusion Strategies in Adult and Pediatric Patients with Malignancy. Hematol Oncol Clin North Am. 2016;30(3):529-40. 12. Whitaker BI, Kamani N. Surveys of blood collection and utilization. Transfusion. 2018;58(2):541-2. 13. Sapiano MRP, Savinkina AA, Ellingson KD, Haass KA, Baker ML, Henry RA, et al. Supplemental findings from the National Blood Collection and Utilization Surveys, 2013 and 2015. Transfusion. 2017;57 Suppl 2:1599-624. 14. Warner MA, Hanson AC, Weister TJ, Higgins AA, Madde NR, Schroeder DR, et al. Changes in International Normalized Ratios After Plasma Transfusion of Varying Doses in Unique Clinical Environments. Anesth Analg. 2018;127(2):349-57. 15. Waters JH, Yazer MH. The Mythology of Plasma Transfusion. Anesth Analg. 2018;127(2):338-9. 16. Whitaker B, Rajbhandary S, Kleinman S, Harris A, Kamani N. Trends in United States blood collection and transfusion: results from the 2013 AABB Blood Collection, Utilization, and Patient Blood Management Survey. Transfusion. 2016;56(9):2173-83. 17. Carson JL, Triulzi DJ, Ness PM. Indications for and Adverse Effects of Red-Cell Transfusion. N Engl J Med. 2017;377(13):1261-72. 18. Klein HG, Spahn DR, Carson JL. Red blood cell transfusion in clinical practice. Lancet. 2007;370(9585):415-26. 19. Friedman BA, Burns TL, Schork MA. An analysis of blood transfusion of surgical patients by sex: a question for the transfusion trigger. Transfusion. 1980;20(2):179-88. 20. Carson JL, Stanworth SJ, Alexander JH, Roubinian N, Fergusson DA, Triulzi DJ, et al. Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease. Am Heart J. 2018;200:96-101. 21. Cooper HA, Rao SV, Greenberg MD, Rumsey MP, McKenzie M, Alcorn KW, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol. 2011;108(8):1108-11.
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22. Lacroix J, Hebert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356(16):1609-19. 23. Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA, Angelini GD, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372(11):997-1008. 24. Cooper DJ, McQuilten ZK, Nichol A, Ady B, Aubron C, Bailey M, et al. Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults. N Engl J Med. 2017;377(19):1858-67. 25. Shehata N, Mistry N, da Costa BR, Pereira TV, Whitlock R, Curley GF, et al. Restrictive compared with liberal red cell transfusion strategies in cardiac surgery: a meta-analysis. Eur Heart J. 2018. 26. Villanueva C, Colomo A, Bosch A, Concepcion M, Hernandez-Gea V, Aracil C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11-21. 27. Mazer CD, Whitlock RP, Fergusson DA, Hall J, Belley-Cote E, Connolly K, et al. Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med. 2017;377(22):2133-44. 28. Docherty AB, O'Donnell R, Brunskill S, Trivella M, Doree C, Holst L, et al. Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis. BMJ. 2016;352:i1351. 29. Mazer CD, Whitlock RP, Fergusson DA, Belley-Cote E, Connolly K, Khanykin B, et al. SixMonth Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery. N Engl J Med. 2018;379(13):1224-33. 30. Carson JL, Brooks MM, Abbott JD, Chaitman B, Kelsey SF, Triulzi DJ, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. 2013;165(6):964-71 e1. 31. Roubinian NH, Murphy EL, Mark DG, Triulzi DJ, Carson JL, Lee C, et al. Long-Term Outcomes Among Patients Discharged From the Hospital With Moderate Anemia: A Retrospective Cohort Study. Ann Intern Med. 2018. 32. Koch CG, Li L, Sun Z, Hixson ED, Tang A, Chagin K, et al. Magnitude of Anemia at Discharge Increases 30-Day Hospital Readmissions. J Patient Saf. 2017;13(4):202-6. 33. Estcourt LJ, Malouf R, Trivella M, Fergusson DA, Hopewell S, Murphy MF. Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support. Cochrane Database Syst Rev. 2017;1:CD011305. 34. Stapley R, Owusu BY, Brandon A, Cusick M, Rodriguez C, Marques MB, et al. Erythrocyte storage increases rates of NO and nitrite scavenging: implications for transfusion-related toxicity. Biochem J. 2012;446(3):499-508. 35. Hess JR. Red cell changes during storage. Transfus Apher Sci. 2010;43(1):51-9. 36. Glynn SA. The red blood cell storage lesion: a method to the madness. Transfusion. 2010;50(6):1164-9. 37. D'Alessandro A, Liumbruno G, Grazzini G, Zolla L. Red blood cell storage: the story so far. Blood Transfus. 2010;8(2):82-8. 38. Roback JD. Vascular effects of the red blood cell storage lesion. Hematology Am Soc Hematol Educ Program. 2011;2011:475-9. 39. Roback JD, Neuman RB, Quyyumi A, Sutliff R. Insufficient nitric oxide bioavailability: a hypothesis to explain adverse effects of red blood cell transfusion. Transfusion. 2011;51(4):859-66. 40. Tinmouth A, Fergusson D, Yee IC, Hebert PC, Investigators A, Canadian Critical Care Trials G. Clinical consequences of red cell storage in the critically ill. Transfusion. 2006;46(11):2014-27. 41. Dhabangi A, Ainomugisha B, Cserti-Gazdewich C, Ddungu H, Kyeyune D, Musisi E, et al. Effect of Transfusion of Red Blood Cells With Longer vs Shorter Storage Duration on Elevated Blood Lactate Levels in Children With Severe Anemia: The TOTAL Randomized Clinical Trial. JAMA. 2015;314(23):2514-23. 42. Heddle NM, Cook RJ, Arnold DM, Liu Y, Barty R, Crowther MA, et al. Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion. N Engl J Med. 2016;375(20):1937-45.
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43. Steiner ME, Ness PM, Assmann SF, Triulzi DJ, Sloan SR, Delaney M, et al. Effects of red-cell storage duration on patients undergoing cardiac surgery. N Engl J Med. 2015;372(15):1419-29. 44. Lacroix J, Hebert PC, Fergusson DA, Tinmouth A, Cook DJ, Marshall JC, et al. Age of transfused blood in critically ill adults. N Engl J Med. 2015;372(15):1410-8. 45. Green RS, Erdogan M, Lacroix J, Hebert PC, Tinmouth AT, Sabri E, et al. Age of transfused blood in critically ill adult trauma patients: a prespecified nested analysis of the Age of Blood Evaluation randomized trial. Transfusion. 2018;58(8):1846-54. 46. Fergusson DA, Hebert P, Hogan DL, LeBel L, Rouvinez-Bouali N, Smyth JA, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA. 2012;308(14):1443-51. 47. Chai-Adisaksopha C, Alexander PE, Guyatt G, Crowther MA, Heddle NM, Devereaux PJ, et al. Mortality outcomes in patients transfused with fresher versus older red blood cells: a meta-analysis. Vox Sang. 2017;112(3):268-78. 48. Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, et al. Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA. 2016;316(19):2025-35. 49. Cook RJ, Heddle NM, Lee KA, Arnold DM, Crowther MA, Devereaux PJ, et al. Red blood cell storage and in-hospital mortality: a secondary analysis of the INFORM randomised controlled trial. Lancet Haematol. 2017;4(11):e544-e52. 50. Halmin M, Rostgaard K, Lee BK, Wikman A, Norda R, Nielsen KR, et al. Length of Storage of Red Blood Cells and Patient Survival After Blood Transfusion: A Binational Cohort Study. Ann Intern Med. 2017;166(4):248-56. 51. Shah A, Brunskill SJ, Desborough MJ, Doree C, Trivella M, Stanworth SJ. Transfusion of red blood cells stored for shorter versus longer duration for all conditions. Cochrane Database Syst Rev. 2018;12:CD010801. 52. Fernandes da Cunha DH, Nunes Dos Santos AM, Kopelman BI, Areco KN, Guinsburg R, de Araujo Peres C, et al. Transfusions of CPDA-1 red blood cells stored for up to 28 days decrease donor exposures in very low-birth-weight premature infants. Transfus Med. 2005;15(6):467-73. 53. Retter A, Wyncoll D, Pearse R, Carson D, McKechnie S, Stanworth S, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol. 2013;160(4):445-64. 54. Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172(2):187-207. 55. Pirenne F, Bartolucci P, Habibi A. Management of delayed hemolytic transfusion reaction in sickle cell disease: Prevention, diagnosis, treatment. Transfus Clin Biol. 2017;24(3):227-31. 56. Karafin MS, Tan S, Tormey CA, Spencer BR, Hauser RG, Norris PJ, et al. Prevalence and risk factors for RBC alloantibodies in blood donors in the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). Transfusion. 2019;59(1):217-25. 57. Karafin MS, Westlake M, Hauser RG, Tormey CA, Norris PJ, Roubinian NH, et al. Risk factors for red blood cell alloimmunization in the Recipient Epidemiology and Donor Evaluation Study (REDSIII) database. Br J Haematol. 2018;181(5):672-81. 58. Nahirniak S, Slichter SJ, Tanael S, Rebulla P, Pavenski K, Vassallo R, et al. Guidance on platelet transfusion for patients with hypoproliferative thrombocytopenia. Transfus Med Rev. 2015;29(1):3-13. 59. Schiffer CA, Bohlke K, Delaney M, Hume H, Magdalinski AJ, McCullough JJ, et al. Platelet Transfusion for Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2018;36(3):283-99. 60. Strauss RG. Role of granulocyte/neutrophil transfusions for haematology/oncology patients in the modern era. Br J Haematol. 2012;158(3):299-306. 61. Erony SM, Marshall CE, Gehrie EA, Boyd JS, Ness PM, Tobian AAR, et al. The epidemiology of bacterial culture-positive and septic transfusion reactions at a large tertiary academic center: 2009 to 2016. Transfusion. 2018;58(8):1933-9.
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62. Horth RZ, Jones JM, Kim JJ, Lopansri BK, Ilstrup SJ, Fridey J, et al. Fatal Sepsis Associated with Bacterial Contamination of Platelets - Utah and California, August 2017. MMWR Morb Mortal Wkly Rep. 2018;67(25):718-22. 63. Bacterial Detection Testing by Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion. US Food and Drug Administration;https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator yInformation/Guidances/Blood/UCM627407.pdf. 64. Blajchman MA, Slichter SJ, Heddle NM, Murphy MF. New strategies for the optimal use of platelet transfusions. Hematology Am Soc Hematol Educ Program. 2008:198-204. 65. Cooling L. ABO and platelet transfusion therapy. Immunohematology. 2007;23(1):20-33. 66. Kaufman RM. Platelet ABO matters. Transfusion. 2009;49(1):5-7. 67. Stanworth SJ, Estcourt LJ, Powter G, Kahan BC, Dyer C, Choo L, et al. A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med. 2013;368(19):1771-80. 68. Wandt H, Schaefer-Eckart K, Wendelin K, Pilz B, Wilhelm M, Thalheimer M, et al. Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet. 2012;380(9850):1309-16. 69. Crighton GL, Estcourt LJ, Wood EM, Trivella M, Doree C, Stanworth S. A therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. Cochrane Database Syst Rev. 2015(9):CD010981. 70. Estcourt LJ, Desborough M, Hopewell S, Trivella M, Doree C, Stanworth S. Comparison of different platelet transfusion thresholds prior to insertion of central lines in patients with thrombocytopenia. Cochrane Database Syst Rev. 2015;2015(6). 71. Estcourt LJ, Malouf R, Doree C, Trivella M, Hopewell S, Birchall J. Prophylactic platelet transfusions prior to surgery for people with a low platelet count. Cochrane Database Syst Rev. 2018;9:CD012779. 72. Estcourt LJ, Malouf R, Hopewell S, Doree C, Van Veen J. Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia. Cochrane Database Syst Rev. 2018;4:CD011980. 73. Malouf R, Ashraf A, Hadjinicolaou AV, Doree C, Hopewell S, Estcourt LJ. Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders. Cochrane Database Syst Rev. 2018;5:CD012342. 74. Crighton GL, Estcourt LJ, Wood EM, Stanworth SJ. Platelet Transfusions in Patients with Hypoproliferative Thrombocytopenia: Conclusions from Clinical Trials and Current Controversies. Hematol Oncol Clin North Am. 2016;30(3):541-60. 75. Stanworth SJ, Estcourt LJ, Llewelyn CA, Murphy MF, Wood EM, Investigators TS. Impact of prophylactic platelet transfusions on bleeding events in patients with hematologic malignancies: a subgroup analysis of a randomized trial. Transfusion. 2014;54(10):2385-93. 76. Estcourt LJ, Stanworth S, Doree C, Trivella M, Hopewell S, Blanco P, et al. Different doses of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. Cochrane Database Syst Rev. 2015(10):CD010984. 77. Slichter SJ, Kaufman RM, Assmann SF, McCullough J, Triulzi DJ, Strauss RG, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med. 2010;362(7):600-13. 78. Estcourt LJ, Stanworth SJ, Doree C, Hopewell S, Trivella M, Murphy MF. Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. Cochrane Database Syst Rev. 2015(11):CD010983. 79. Weil IA, Kumar P, Seicean S, Neuhauser D, Seicean A. Platelet count abnormalities and perioperative outcomes in adults undergoing elective, non-cardiac surgery. PLoS One. 2019;14(2):e0212191.
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80. Estcourt LJ, Birchall J, Allard S, Bassey SJ, Hersey P, Kerr JP, et al. Guidelines for the use of platelet transfusions. Br J Haematol. 2017;176(3):365-94. 81. Kaufman RM, Djulbegovic B, Gernsheimer T, Kleinman S, Tinmouth AT, Capocelli KE, et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2015;162(3):205-13. 82. Whitlock R, Crowther MA, Ng HJ. Bleeding in cardiac surgery: its prevention and treatment--an evidence-based review. Crit Care Clin. 2005;21(3):589-610. 83. Wandt H, Schafer-Eckart K, Greinacher A. Platelet transfusion in hematology, oncology and surgery. Dtsch Arztebl Int. 2014;111(48):809-15. 84. Arnold DM, Lauzier F, Albert M, Williamson D, Li N, Zarychanski R, et al. The association between platelet transfusions and bleeding in critically ill patients with thrombocytopenia. Res Pract Thromb Haemost. 2017;1(1):103-11. 85. Lieberman L, Bercovitz RS, Sholapur NS, Heddle NM, Stanworth SJ, Arnold DM. Platelet transfusions for critically ill patients with thrombocytopenia. Blood. 2014;123(8):1146-51; quiz 280. 86. Busch MP, Bloch EM, Kleinman S. Prevention of transfusion-transmitted infections. Blood. 2019;133(17):1854-64. 87. Kaufman RM, Assmann SF, Triulzi DJ, Strauss RG, Ness P, Granger S, et al. Transfusion-related adverse events in the Platelet Dose study. Transfusion. 2015;55(1):144-53. 88. King KE, Shirey RS, Thoman SK, Bensen-Kennedy D, Tanz WS, Ness PM. Universal leukoreduction decreases the incidence of febrile nonhemolytic transfusion reactions to RBCs. Transfusion. 2004;44(1):25-9. 89. Semple JW, Rebetz J, Kapur R. Transfusion-associated circulatory overload and transfusionrelated acute lung injury. Blood. 2019. 90. Schmidt AE, Henrichs KF, Kirkley SA, Refaai MA, Blumberg N. Prophylactic Preprocedure Platelet Transfusion Is Associated With Increased Risk of Thrombosis and Mortality. Am J Clin Pathol. 2017;149(1):87-94. 91. Zakko L, Rustagi T, Douglas M, Laine L. No Benefit From Platelet Transfusion for Gastrointestinal Bleeding in Patients Taking Antiplatelet Agents. Clin Gastroenterol Hepatol. 2017;15(1):46-52. 92. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387(10038):2605-13. 93. Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh V, Hudson C, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. N Engl J Med. 2019;380(3):242-51. 94. Warner MA, Woodrum D, Hanson A, Schroeder DR, Wilson G, Kor DJ. Preprocedural platelet transfusion for patients with thrombocytopenia undergoing interventional radiology procedures is not associated with reduced bleeding complications. Transfusion. 2017;57(4):890-8. 95. McGrath T, Koch CG, Xu M, Li L, Mihaljevic T, Figueroa P, et al. Platelet transfusion in cardiac surgery does not confer increased risk for adverse morbid outcomes. Ann Thorac Surg. 2008;86(2):54353. 96. Ninkovic S, McQuilten Z, Gotmaker R, Newcomb AE, Cole-Sinclair MF. Platelet transfusion is not associated with increased mortality or morbidity in patients undergoing cardiac surgery. Transfusion. 2018;58(5):1218-27. 97. Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G, Italian Society of Transfusion M, et al. Recommendations for the transfusion of plasma and platelets. Blood Transfus. 2009;7(2):13250. 98. Neisser-Svae A, Trawnicek L, Heger A, Mehta T, Triulzi D. Five-day stability of thawed plasma: solvent/detergent-treated plasma comparable with fresh-frozen plasma and plasma frozen within 24 hours. Transfusion. 2016;56(2):404-9. 99. Yazer MH, Cortese-Hassett A, Triulzi DJ. Coagulation factor levels in plasma frozen within 24 hours of phlebotomy over 5 days of storage at 1 to 6 degrees C. Transfusion. 2008;48(12):2525-30.
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100. O'Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004;126(1):11-28. 101. Tinmouth A. Assessing the Rationale and Effectiveness of Frozen Plasma Transfusions: An Evidence-based Review. Hematol Oncol Clin North Am. 2016;30(3):561-72. 102. Stanworth SJ, Grant-Casey J, Lowe D, Laffan M, New H, Murphy MF, et al. The use of freshfrozen plasma in England: high levels of inappropriate use in adults and children. Transfusion. 2011;51(1):62-70. 103. Stanworth SJ, Walsh TS, Prescott RJ, Lee RJ, Watson DM, Wyncoll D, et al. A national study of plasma use in critical care: clinical indications, dose and effect on prothrombin time. Crit Care. 2011;15(2):R108. 104. Holland L, Sarode R. Should plasma be transfused prophylactically before invasive procedures? Curr Opin Hematol. 2006;13(6):447-51. 105. Segal JB, Dzik WH, Transfusion Medicine/Hemostasis Clinical Trials N. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion. 2005;45(9):1413-25. 106. Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion. 2006;46(8):1279-85. 107. Karam O, Tucci M, Combescure C, Lacroix J, Rimensberger PC. Plasma transfusion strategies for critically ill patients. Cochrane Database Syst Rev. 2013(12):CD010654. 108. Yang L, Stanworth S, Hopewell S, Doree C, Murphy M. Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials. Transfusion. 2012;52(8):1673-86; quiz 109. Warner MA, Chandran A, Jenkins G, Kor DJ. Prophylactic Plasma Transfusion Is Not Associated With Decreased Red Blood Cell Requirements in Critically Ill Patients. Anesth Analg. 2017;124(5):163643. 110. Warner MA, Frank RD, Weister TJ, Smith MM, Stubbs JR, Kor DJ. Higher intraoperative plasma transfusion volumes are associated with inferior perioperative outcomes. Transfusion. 2019;59(1):112-24. 111. Warner MA, Woodrum DA, Hanson AC, Schroeder DR, Wilson GA, Kor DJ. Prophylactic Plasma Transfusion Before Interventional Radiology Procedures Is Not Associated With Reduced Bleeding Complications. Mayo Clin Proc. 2016;91(8):1045-55. 112. Green L, Bolton-Maggs P, Beattie C, Cardigan R, Kallis Y, Stanworth SJ, et al. British Society of Haematology Guidelines on the spectrum of fresh frozen plasma and cryoprecipitate products: their handling and use in various patient groups in the absence of major bleeding. Br J Haematol. 2018;181(1):54-67. 113. Roback JD, Caldwell S, Carson J, Davenport R, Drew MJ, Eder A, et al. Evidence-based practice guidelines for plasma transfusion. Transfusion. 2010;50(6):1227-39. 114. Jia Q, Brown MJ, Clifford L, Wilson GA, Truty MJ, Stubbs JR, et al. Prophylactic plasma transfusion for surgical patients with abnormal preoperative coagulation tests: a single-institution propensity-adjusted cohort study. Lancet Haematol. 2016;3(3):e139-48. 115. Murad MH, Stubbs JR, Gandhi MJ, Wang AT, Paul A, Erwin PJ, et al. The effect of plasma transfusion on morbidity and mortality: a systematic review and meta-analysis. Transfusion. 2010;50(6):1370-83. 116. Nascimento B, Callum J, Tien H, Peng H, Rizoli S, Karanicolas P, et al. Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial. Br J Anaesth. 2016;117(6):775-82. 117. Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth. 2014;113(6):922-34. 118. Levy JH, Goodnough LT. How I use fibrinogen replacement therapy in acquired bleeding. Blood. 2015;125(9):1387-93.
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119. Gillissen A, van den Akker T, Caram-Deelder C, Henriquez D, Bloemenkamp KWM, de Maat MPM, et al. Coagulation parameters during the course of severe postpartum hemorrhage: a nationwide retrospective cohort study. Blood Adv. 2018;2(19):2433-42. 120. McQuilten ZK, Bailey M, Cameron PA, Stanworth SJ, Venardos K, Wood EM, et al. Fibrinogen concentration and use of fibrinogen supplementation with cryoprecipitate in patients with critical bleeding receiving massive transfusion: a bi-national cohort study. Br J Haematol. 2017;179(1):131-41. 121. McQuilten ZK, Wood EM, Bailey M, Cameron PA, Cooper DJ. Fibrinogen is an independent predictor of mortality in major trauma patients: A five-year statewide cohort study. Injury. 2017;48(5):1074-81. 122. Ranucci M, Pistuddi V, Baryshnikova E, Colella D, Bianchi P. Fibrinogen Levels After Cardiac Surgical Procedures: Association With Postoperative Bleeding, Trigger Values, and Target Values. Ann Thorac Surg. 2016;102(1):78-85. 123. Curry N, Rourke C, Davenport R, Beer S, Pankhurst L, Deary A, et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth. 2015;115(1):76-83. 124. Holcomb JB, Fox EE, Zhang X, White N, Wade CE, Cotton BA, et al. Cryoprecipitate use in the PROMMTT study. J Trauma Acute Care Surg. 2013;75(1 Suppl 1):S31-9. 125. Ciavarella D, Reed RL, Counts RB, Baron L, Pavlin E, Heimbach DM, et al. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol. 1987;67(3):365-8. 126. Ranucci M, Solomon C. Supplementation of fibrinogen in acquired bleeding disorders: experience, evidence, guidelines, and licences. Br J Anaesth. 2012;109(2):135-7. 127. Nascimento B, Rizoli S, Rubenfeld G, Fukushima R, Ahmed N, Nathens A, et al. Cryoprecipitate transfusion: assessing appropriateness and dosing in trauma. Transfus Med. 2011;21(6):394-401. 128. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. Management of bleeding following major trauma: an updated European guideline. Crit Care. 2010;14(2):R52. 129. Sorensen B, Tang M, Larsen OH, Laursen PN, Fenger-Eriksen C, Rea CJ. The role of fibrinogen: a new paradigm in the treatment of coagulopathic bleeding. Thromb Res. 2011;128 Suppl 1:S13-6. 130. Tinegate H, Allard S, Grant-Casey J, Hennem S, Kilner M, Rowley M, et al. Cryoprecipitate for transfusion: which patients receive it and why? A study of patterns of use across three regions in England. Transfus Med. 2012;22(5):356-61. 131. Pavord S, Maybury H. How I treat postpartum hemorrhage. Blood. 2015;125(18):2759-70. 132. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013;17(2):R76. 133. Runyon BA, Aasld. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-3. 134. European Association for the Study of the Liver. Electronic address eee, Clinical practice guidelines p, Wendon J, Panel m, Cordoba J, Dhawan A, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047-81. 135. Burman D, Hodson AK, Wood CB, Brueton NF. Acute anaphylaxis, pulmonary oedema, and intravascular haemolysis due to cryoprecipitate. Arch Dis Child. 1973;48(6):483-5. 136. McVerry BA, Machin SJ. Incidence of allo-immunization and allergic reactions to cryoprecipitate in haemophilia. Vox Sang. 1979;36(2):77-80. 137. Reese EP, Jr., McCullough JJ, Craddock PR. An adverse pulmonary reaction to cryoprecipitate in a hemophiliac. Transfusion. 1975;15(6):583-8. 138. Callum JL, Karkouti K, Lin Y. Cryoprecipitate: the current state of knowledge. Transfus Med Rev. 2009;23(3):177-88. 139. Bolton-Maggs PH. SHOT conference report 2016: serious hazards of transfusion - human factors continue to cause most transfusion-related incidents. Transfus Med. 2016;26(6):401-5.
ACCEPTED MANUSCRIPT
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140. West KA, Gea-Banacloche J, Stroncek D, Kadri SS. Granulocyte transfusions in the management of invasive fungal infections. Br J Haematol. 2017;177(3):357-74. 141. Price TH, Boeckh M, Harrison RW, McCullough J, Ness PM, Strauss RG, et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood. 2015;126(18):2153-61. 142. Seidel MG, Peters C, Wacker A, Northoff H, Moog R, Boehme A, et al. Randomized phase III study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant. 2008;42(10):679-84. 143. Estcourt LJ, Stanworth SJ, Hopewell S, Doree C, Trivella M, Massey E. Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2016;4:CD005339. 144. Valentini CG, Farina F, Pagano L, Teofili L. Granulocyte Transfusions: A Critical Reappraisal. Biol Blood Marrow Transplant. 2017;23(12):2034-41. 145. Netelenbos T, Massey E, de Wreede LC, Harding K, Hamblin A, Sekhar M, et al. The burden of invasive infections in neutropenic patients: incidence, outcomes, and use of granulocyte transfusions. Transfusion. 2019;59(1):160-8. 146. Strauss RG. Therapeutic granulocyte transfusions: neutropenic patients with acute leukemia continue to need them - why are definitive evidence-based practice guidelines elusive? Transfusion. 2019;59(1):6-8. 147. A Open Label, Post Marketing Surveillance Study Following Transfusion of INTERCEPT Platelet Components (PIPER). 2015 ongoing;https://clinicaltrials.gov/ct2/show/NCT02549222?term=cerus. 148. Paglino JC, Pomper GJ, Fisch GS, Champion MH, Snyder EL. Reduction of febrile but not allergic reactions to RBCs and platelets after conversion to universal prestorage leukoreduction. Transfusion. 2004;44(1):16-24. 149. Yazer MH, Podlosky L, Clarke G, Nahirniak SM. The effect of prestorage WBC reduction on the rates of febrile nonhemolytic transfusion reactions to platelet concentrates and RBC. Transfusion. 2004;44(1):10-5. 150. Trial to Reduce Alloimmunization to Platelets Study G. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med. 1997;337(26):1861-9. 151. Bowden RA, Slichter SJ, Sayers M, Weisdorf D, Cays M, Schoch G, et al. A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood. 1995;86(9):3598-603. 152. Preiksaitis JK. The cytomegalovirus-"safe" blood product: is leukoreduction equivalent to antibody screening? Transfus Med Rev. 2000;14(2):112-36. 153. Mintz PD. Febrile reactions to platelet transfusions. Am J Clin Pathol. 1991;95(5):609-12. 154. Heddle NM, Klama L, Meyer R, Walker I, Boshkov L, Roberts R, et al. A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets. Transfusion. 1999;39(3):231-8. 155. Zantek ND, Parker RI, van de Watering LM, Josephson CD, Bateman ST, Valentine SL, et al. Recommendations on Selection and Processing of RBC Components for Pediatric Patients From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med. 2018;19(9S Suppl 1):S163-S9. 156. Tobian AA, Savage WJ, Tisch DJ, Thoman S, King KE, Ness PM. Prevention of allergic transfusion reactions to platelets and red blood cells through plasma reduction. Transfusion. 2011;51(8):1676-83. 157. Heddle NM, Blajchman MA, Meyer RM, Lipton JH, Walker IR, Sher GD, et al. A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets. Transfusion. 2002;42(5):556-66. 158. Heddle NM, Klama L, Singer J, Richards C, Fedak P, Walker I, et al. The role of the plasma from platelet concentrates in transfusion reactions. N Engl J Med. 1994;331(10):625-8.
ACCEPTED MANUSCRIPT
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159. Cohn CS, Stubbs J, Schwartz J, Francis R, Goss C, Cushing M, et al. A comparison of adverse reaction rates for PAS C versus plasma platelet units. Transfusion. 2014;54(8):1927-34. 160. Tobian AA, Fuller AK, Uglik K, Tisch DJ, Borge PD, Benjamin RJ, et al. The impact of platelet additive solution apheresis platelets on allergic transfusion reactions and corrected count increment (CME). Transfusion. 2014;54(6):1523-9; quiz 2. 161. van Hout FMA, van der Meer PF, Wiersum-Osselton JC, Middelburg RA, Schipperus MR, van der Bom JG, et al. Transfusion reactions after transfusion of platelets stored in PAS-B, PAS-C, or plasma: a nationwide comparison. Transfusion. 2018;58(4):1021-7. 162. Hauser L, Roque-Afonso AM, Beyloune A, Simonet M, Deau Fischer B, Burin des Roziers N, et al. Hepatitis E transmission by transfusion of Intercept blood system-treated plasma. Blood. 2014;123(5):796-7. 163. Liu Y, Bewersdorf JP, Stahl M, Zeidan AM. Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: The dawn of a new era? Blood Rev. 2019;34:67-83. 164. Assi R, Kantarjian H, Ravandi F, Daver N. Immune therapies in acute myeloid leukemia: a focus on monoclonal antibodies and immune checkpoint inhibitors. Curr Opin Hematol. 2018;25(2):136-45. 165. Velliquette RW, Aeschlimann J, Kirkegaard J, Shakarian G, Lomas-Francis C, Westhoff CM. Monoclonal anti-CD47 interference in red cell and platelet testing. Transfusion. 2019;59(2):730-7. 166. Organization WH. Metrics: Disability-Adjusted Life Year (DALY) - Quantifying the Burden of Disease from mortality and morbidity 2018 [cited 2018 1/2/2018]. Available from: http://www.who.int/healthinfo/global_burden_disease/metrics_daly/en/. 167. Cushing MM, DeSimone RA, Goel R, Hsu YS, Parra P, Racine-Brzostek SE, et al. The impact of Daratumumab on transfusion service costs. Transfusion. 2019. 168. Anani WQ, Marchan MG, Bensing KM, Schanen M, Piefer C, Gottschall JL, et al. Practical approaches and costs for provisioning safe transfusions during anti-CD38 therapy. Transfusion. 2017;57(6):1470-9. 169. Oostendorp M, Lammerts van Bueren JJ, Doshi P, Khan I, Ahmadi T, Parren PW, et al. When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. Transfusion. 2015;55(6 Pt 2):1555-62. 170. Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion. 2015;55(6 Pt 2):1545-54. 171. Deneys V, Thiry C, Frelik A, Debry C, Martin B, Doyen C. Daratumumab: Therapeutic asset, biological trap! Transfus Clin Biol. 2018;25(1):2-7. 172. Quach H, Benson S, Haysom H, Wilkes AM, Zacher N, Cole-Sinclair M, et al. Considerations for pre-transfusion immunohaematology testing in patients receiving the anti-CD38 monoclonal antibody daratumumab for the treatment of multiple myeloma. Intern Med J. 2018;48(2):210-20. 173. Chinoca Ziza KN, Paiva TA, Mota SR, Dezan MR, Schmidt LC, Brunetta DM, et al. A blockage monoclonal antibody protocol as an alternative strategy to avoid anti-CD38 interference in immunohematological testing. Transfusion. 2019. 174. Hosokawa M, Kashiwagi H, Nakayama K, Sakuragi M, Nakao M, Morikawa T, et al. Distinct effects of daratumumab on indirect and direct antiglobulin tests: a new method employing 0.01 mol/L dithiothreitol for negating the daratumumab interference with preserving K antigenicity (Osaka method). Transfusion. 2018;58(12):3003-13. 175. Lancman G, Arinsburg S, Jhang J, Cho HJ, Jagannath S, Madduri D, et al. Blood Transfusion Management for Patients Treated With Anti-CD38 Monoclonal Antibodies. Front Immunol. 2018;9:2616. 176. Folkes AS, Feng M, Zain JM, Abdulla F, Rosen ST, Querfeld C. Targeting CD47 as a cancer therapeutic strategy: the cutaneous T-cell lymphoma experience. Curr Opin Oncol. 2018;30(5):332-7. 177. Russ A, Hua AB, Montfort WR, Rahman B, Riaz IB, Khalid MU, et al. Blocking "don't eat me" signal of CD47-SIRPalpha in hematological malignancies, an in-depth review. Blood Rev. 2018;32(6):480-9. 178. Acker JP, Marks DC, Sheffield WP. Quality Assessment of Established and Emerging Blood Components for Transfusion. J Blood Transfus. 2016;2016:4860284.
ACCEPTED MANUSCRIPT
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179. Ness PM, Gehrie EA. Blood products for resuscitation: moving forward by going backward. Transfusion. 2019;59(S1):834-6. 180. Spinella PC, Pidcoke HF, Strandenes G, Hervig T, Fisher A, Jenkins D, et al. Whole blood for hemostatic resuscitation of major bleeding. Transfusion. 2016;56 Suppl 2:S190-202. 181. Seheult JN, Anto V, Alarcon LH, Sperry JL, Triulzi DJ, Yazer MH. Clinical outcomes among low-titer group O whole blood recipients compared to recipients of conventional components in civilian trauma resuscitation. Transfusion. 2018;58(8):1838-45. 182. Reddoch-Cardenas KM, Bynum JA, Meledeo MA, Nair PM, Wu X, Darlington DN, et al. Coldstored platelets: A product with function optimized for hemorrhage control. Transfus Apher Sci. 2019;58(1):16-22. 183. Strandenes G. ATO, et al. https://rdcr.org/wp-content/uploads/2018/07/07-Apelseth-Strandenes180619.BFF-Cold-stored-platelet-program.-TOA_GS.pdf. 184. Milford EM, Reade MC. Comprehensive review of platelet storage methods for use in the treatment of active hemorrhage. Transfusion. 2016;56 Suppl 2:S140-8. 185. Bux J, Dickhorner D, Scheel E. Quality of freeze-dried (lyophilized) quarantined single-donor plasma. Transfusion. 2013;53(12):3203-9. 186. Van PY, Holcomb JB, Schreiber MA. Novel concepts for damage control resuscitation in trauma. Curr Opin Crit Care. 2017;23(6):498-502. 187. Wood EM, Ang AL, Bisht A, Bolton-Maggs PH, Bokhorst AG, Flesland O, et al. International haemovigilance: what have we learned and what do we need to do next? Transfus Med. 2019. 188. Harris JC, Crookston KP. Blood Product Safety. StatPearls. Treasure Island (FL)2019. 189. Research CfBEa. Fatalities Reported to FDA Following Blood Collection and Transfusion. In: Administration UFaD, editor. Silver Spring, MD. 190. Narayan S (Ed), Poles D, et al. on behalf of the Serious Hazards of Transfusion (SHOT) Steering group. The 2018 Annual SHOT Report (2019). Available from: https://www.shotuk.org/shot-reports/ 191. Promotion DoHQ. National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol. In: Diseases NCfEaZI, editor. Atlanta, GA: Centers for Disease Control and Prevention 2018. 192. Bakitas M, Lyons KD, Hegel MT, Balan S, Brokaw FC, Seville J, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial. JAMA. 2009;302(7):741-9. 193. Ferrell BR, Temel JS, Temin S, Alesi ER, Balboni TA, Basch EM, et al. Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017;35(1):96-112. 194. Sexauer A, Cheng MJ, Knight L, Riley AW, King L, Smith TJ. Patterns of hospice use in patients dying from hematologic malignancies. J Palliat Med. 2014;17(2):195-9. 195. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-42. 196. LeBlanc TW, Abernethy AP, Casarett DJ. What is different about patients with hematologic malignancies? A retrospective cohort study of cancer patients referred to a hospice research network. J Pain Symptom Manage. 2015;49(3):505-12. 197. Button E, Chan R, Chambers S, Butler J, Yates P. Signs, Symptoms, and Characteristics Associated With End of Life in People With a Hematologic Malignancy: A Review of the Literature. Oncol Nurs Forum. 2016;43(5):E178-87. 198. LeBlanc TW. Palliative care and hematologic malignancies: old dog, new tricks? J Oncol Pract. 2014;10(6):e404-7. 199. Odejide OO, Cronin AM, Condron NB, Fletcher SA, Earle CC, Tulsky JA, et al. Barriers to Quality End-of-Life Care for Patients With Blood Cancers. J Clin Oncol. 2016;34(26):3126-32. 200. LeBlanc TW, Egan PC, Olszewski AJ. Transfusion dependence, use of hospice services, and quality of end-of-life care in leukemia. Blood. 2018;132(7):717-26.
ACCEPTED MANUSCRIPT
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201. To THM, LeBlanc TW, Eastman P, Neoh K, Agar MR, To LB, et al. The Prospective Evaluation of the Net Effect of Red Blood Cell Transfusions in Routine Provision of Palliative Care. J Palliat Med. 2017;20(10):1152-7. 202. Preston NJ, Hurlow A, Brine J, Bennett MI. Blood transfusions for anaemia in patients with advanced cancer. Cochrane Database Syst Rev. 2012(2):CD009007. 203. Elyan B, Hayes S, Day R, Johny A, Perkins P. Blood transfusions in a day hospice setting. Palliat Med. 2012;26(6):862-3. 204. Rabiner SF, Telfer MC, Fajardo R. Home transfusions of hemophiliacs. JAMA. 1972;221(8):8857. 205. Thompson HW, McKelvey J. Home blood transfusion therapy: a home health agency's 5-year experience. Transfusion. 1995;35(5):453. 206. Rutman R, Kakaiya R, Miller WV. Home transfusion for the cancer patient. Semin Oncol Nurs. 1990;6(2):163-7. 207. Idri S, Catoni MP, Si Ali H, Patte R, Briere J, Baudelot J, et al. [Transfusion at home? An alternative to the day hospital]. Transfus Clin Biol. 1996;3(4):235-9. 208. Ademokun A, Kaznica S, Deas S. Home blood transfusion: a necessary service development. Transfus Med. 2005;15(3):219-22. 209. Charron J, Gouezec H, Bajeux E. [Home blood transfusion in France: Benefits and development terms]. Transfus Clin Biol. 2018. 210. Trueman P, Drummond M, Hutton J. Developing guidance for budget impact analysis. Pharmacoeconomics. 2001;19(6):609-21. 211. Custer B, Hoch JS. Cost-effectiveness analysis: what it really means for transfusion medicine decision making. Transfus Med Rev. 2009;23(1):1-12. 212. Russell WA, Stramer SL, Busch MP, Custer B. Screening the Blood Supply for Zika Virus in the 50 U.S. States and Puerto Rico: A Cost-Effectiveness Analysis. Ann Intern Med. 2019. 213. Excellence NIfHaC. Technology appraisal guidance 2017 [cited 2017 12/30/2017]. Available from: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-technologyappraisal-guidance. 214. Staginnus U, Corash L. Economics of pathogen inactivation technology for platelet concentrates in Japan. Int J Hematol. 2004;80(4):317-24. 215. Moeremans K, Warie H, Annemans L. Assessment of the economic value of the INTERCEPT blood system in Belgium. Transfus Med. 2006;16(1):17-30. 216. Bell CE, Botteman MF, Gao X, Weissfeld JL, Postma MJ, Pashos CL, et al. Cost-effectiveness of transfusion of platelet components prepared with pathogen inactivation treatment in the United States. Clin Ther. 2003;25(9):2464-86. 217. Girona-Llobera E, Jimenez-Marco T, Galmes-Trueba A, Muncunill J, Serret C, Serra N, et al. Reducing the financial impact of pathogen inactivation technology for platelet components: our experience. Transfusion. 2014;54(1):158-68. 218. McCullough J, Goldfinger D, Gorlin J, Riley WJ, Sandhu H, Stowell C, et al. Cost implications of implementation of pathogen-inactivated platelets. Transfusion. 2015;55(10):2312-20. 219. Basora M, Pereira A, Coca M, Tio M, Lozano L. Cost-effectiveness analysis of ferric carboxymaltose in pre-operative haemoglobin optimisation in patients undergoing primary knee arthroplasty. Blood Transfus. 2018;16(5):438-42. 220. Kleineruschkamp A, Meybohm P, Straub N, Zacharowski K, Choorapoikayil S. A model-based cost-effectiveness analysis of Patient Blood Management. Blood Transfus. 2019;17(1):16-26. 221. McLoughlin C, Roberts TE, Jackson LJ, Moore P, Wilson M, Hooper R, et al. Cost-effectiveness of cell salvage and donor blood transfusion during caesarean section: results from a randomised controlled trial. BMJ Open. 2019;9(2):e022352. 222. Walsh TS, Stanworth S, Boyd J, Hope D, Hemmatapour S, Burrows H, et al. The Age of BLood Evaluation (ABLE) randomised controlled trial: description of the UK-funded arm of the international trial, the UK cost-utility analysis and secondary analyses exploring factors associated with health-related
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quality of life and health-care costs during the 12-month follow-up. Health Technol Assess. 2017;21(62):1-118. 223. Wu Y, Zeng Y, Hu Q, Li M, Bao X, Zhong J, et al. Blood loss and cost-effectiveness of oral vs intravenous tranexamic acid in primary total hip arthroplasty: A randomized clinical trial. Thromb Res. 2018;171:143-8. 224. Kramer K, Zaaijer HL, Verweij MF. The Precautionary Principle and the Tolerability of Blood Transfusion Risks. Am J Bioeth. 2017;17(3):32-43. 225. Leach Bennett J, Blajchman MA, Delage G, Fearon M, Devine D. Proceedings of a consensus conference: Risk-Based Decision Making for Blood Safety. Transfus Med Rev. 2011;25(4):267-92. 226. Stein J, Besley J, Brook C, Hamill M, Klein E, Krewski D, et al. Risk-based decision-making for blood safety: preliminary report of a consensus conference. Vox Sang. 2011;101(4):277-81. 227. Leach Bennett J, Devine DV. Risk-based decision making in transfusion medicine. Vox Sang. 2018;113(8):737-49. 228. Ward SJ, Stramer SL, Szczepiorkowski ZM. Assessing the risk of Babesia to the United States blood supply using a risk-based decision-making approach: Report of AABB's Ad Hoc Babesia Policy Working Group (original report). Transfusion. 2018;58(8):1916-23. 229. Styles CE, Seed CR, Hoad VC, Gaudieri S, Keller AJ. Reconsideration of blood donation testing strategy for human T-cell lymphotropic virus in Australia. Vox Sang. 2017;112(8):723-32. 230. O'Brien SF, Ward S, Gallian P, Fabra C, Pillonel J, Kitchen AD, et al. Malaria blood safety policy in five non-endemic countries: a retrospective comparison through the lens of the ABO risk-based decision-making framework. Blood Transfus. 2019. 231. Jacobs MR, Good CE, Lazarus HM, Yomtovian RA. Relationship between bacterial load, species virulence, and transfusion reaction with transfusion of bacterially contaminated platelets. Clin Infect Dis. 2008;46(8):1214-20. 232. Yomtovian R, Tomasulo P, Jacobs MR. Platelet bacterial contamination: assessing progress and identifying quandaries in a rapidly evolving field. Transfusion. 2007;47(8):1340-6. 233. Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS)--explanation and elaboration: a report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force. Value Health. 2013;16(2):231-50. 234. Haass K SM, Savinkina A, Kuehnert M, Basavaraju. S. Transfusion-transmitted infections reported to the National Healthcare Safety Network Hemovigilance Module. Transfusion Medicine Reviews. 2019;doi:10.1016/j.tmrv.2019.01.001. 235. Hong H, Xiao W, Lazarus HM, Good CE, Maitta RW, Jacobs MR. Detection of septic transfusion reactions to platelet transfusions by active and passive surveillance. Blood. 2016;127(4):496502. 236. McDonald C, Allen J, Brailsford S, Roy A, Ball J, Moule R, et al. Bacterial screening of platelet components by National Health Service Blood and Transplant, an effective risk reduction measure. Transfusion. 2017;57(5):1122-31.
Emily K. Storch, Brian S. Custer, Michael R. Jacobs, Jay E. Menitove, Paul D. Mintz PII: DOI: Article Number: Reference:
S0268-960X(19)30062-1 https://doi.org/10.1016/j.blre.2019.100593 100593 YBLRE 100593
To appear in:
Blood Reviews
Please cite this article as: E.K. Storch, B.S. Custer, M.R. Jacobs, et al., Review of current transfusion therapy and blood banking practices, Blood Reviews, https://doi.org/10.1016/ j.blre.2019.100593
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ACCEPTED MANUSCRIPT Review of current transfusion therapy and blood banking practices 1
Emily K. Storch1,* [email protected], Brian S. Custer2 [email protected], Michael R. Jacobs3 [email protected], Jay E. Menitove4
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[email protected], Paul D. Mintz5 [email protected]
Food and Drug Administration
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Blood Systems Research Institute; UCSF Department of Laboratory Medicine
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Department of Pathology, Case Western Reserve University, Department of Clinical
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Microbiology, University Hospitals Cleveland Medical Center
Clinical Professor, Department of Pathology and Laboratory Medicine, University of
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Kansas Medical Center Verax Biomedical Incorporated
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Corresponding author.
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This article reflects the views of the author and should not be construed to represent FDA’s views or policies.
ACCEPTED MANUSCRIPT Abstract
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Transfusion Medicine is a dynamically evolving field. Recent high-quality research has reshaped the paradigms guiding blood transfusion. As increasing evidence supports the benefit of limiting transfusion, guidelines have been developed and disseminated into clinical practice governing optimal transfusion of red cells, platelets, plasma and cryoprecipitate. Concepts ranging from transfusion thresholds to prophylactic use to maximal storage time are addressed in guidelines. Patient blood management programs have developed to implement principles of patient safety through limiting transfusion in clinical practice. Data from National Hemovigilance Surveys showing dramatic declines in blood utilization over the past decade demonstrate the practical uptake of current principles guiding patient safety. In parallel with decreasing use of traditional blood products, the development of new technologies for blood transfusion such as freeze drying and cold storage has accelerated. Approaches to policy decision making to augment blood safety have also changed. Drivers of these changes include a deeper understanding of emerging threats and adverse events based on hemovigilance, and an increasing healthcare system expectation to align blood safety decision making with approaches used in other healthcare disciplines.
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Keywords: blood transfusion; red blood cells; platelets; plasma; cryoprecipitate; patient blood management; hemovigilance; cold stored platelets; lyophilized plasma; pathogen reduction.
ACCEPTED MANUSCRIPT 1. Introduction Blood transfusion constitutes an integral component of patient care, with up to 10% of hospitalized patients transfused, depending on the patient
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population.[2] [3] Recognition of the importance of transfusion dates back to
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the 17th century when the first human blood transfusions were performed in
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Paris by Jean Denis in 1667.[4] Modern blood transfusion originated with
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the identification of the major blood groups in 1901 by Karl Landsteiner and the subsequent introduction of pre-transfusion compatibility testing using
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agglutination techniques in 1907.[5, 6] Despite the long history of blood
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transfusion, until recently evidence guiding optimal transfusion practices has
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been limited. Clinical decision making was instead empirically based,
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relying on such paradigms as the “10/30” rule, informed by limited underlying scientific evidence from the 1940s to improve outcomes in
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surgical patients.[7] [8] [9] [10, 11] The past decade has witnessed the
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emergence of strong evidence-based clinical practice guidelines for transfusion of blood and blood components, which has begun to influence clinical medicine,[12] although practice continues to lag behind evidence based recommendations in key metrics such as transfusion of plasma given to non-bleeding patients to correct minimally elevated INRs.[13] [14] It has been suggested that this discrepancy is based at least in part on lack of
ACCEPTED MANUSCRIPT exposure to transfusion medicine knowledge in medical education. [15] [14] This review will highlight key evidence-based guidelines and practice points in clinical transfusion practice, as well as present current and emerging
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concepts in the field of transfusion medicine, including novel blood and
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blood-derived products for transfusion.
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2. Red blood cells
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Red blood cells (RBCs) are derived either from Whole Blood (WB)
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donations or collected by apheresis technology. The volume of an average unit of WB RBCs following plasma removal ranges from 200 to 350 mL,
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and has a hematocrit of 55% to 80%. Depending on the anticoagulant or
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additive solution utilized, the shelf life of a RBC unit ranges from 21 to 42
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days. The average storage age of a transfused RBC unit in the U.S. is 19 days, with 79% of RBCs transfused between day 1 and day 35. [13, 16] One unit of RBC is expected to raise the hemoglobin of an adult patient by 1 g/dL or hematocrit by approximately 3%.[17, 18]
ACCEPTED MANUSCRIPT 2.1.
Indications & current practice
RBCs function to provide oxygen delivery to tissues, and as such are standard treatment for patients who require an increase in oxygen carrying
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capacity and red cell mass. Indications for red cell transfusion include
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patients with symptomatic anemia, decreased bone marrow function (e.g.
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aplastic anemia, chemotherapy), defective red cell production (e.g.
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thalassemia), decreased red cell survival (e.g. hemolytic anemia), acute
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bleeding, those undergoing invasive procedures, and red cell exchange transfusion. Common clinical scenarios requiring RBC transfusion include
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orthopedic surgery, critical care, gastrointestinal bleeding, cardiac surgery
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and acute coronary syndromes. [17] RBCs are the most frequently transfused
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blood product, with approximately 11 million red cells transfused annually. [1] [3]
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While RBC transfusion is common practice to avoid compromised
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peripheral tissue oxygenation, minor decreases in Hgb don’t necessarily indicate poor oxygen delivery (DO 2) or consumption (VO 2) due to compensatory physiologic mechanisms, such as increased cardiac output or altered oxygen extraction by tissues in hypoxemic states. [9] The limits of compensation at which patients are able to tolerate low hemoglobin levels vary by multiple factors including patient co-morbidities, age, baseline
ACCEPTED MANUSCRIPT metabolic function, erythropoietin levels, and nutritional status, therefore complicating the determination of a static ‘transfusion trigger’ across all patient populations and clinical situations. [9, 19]
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Multiple randomized controlled trials (RCTs) evaluating indications and
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outcomes of transfusion have been performed in recent years, providing
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evidence for transfusion strategies in adult patients. [20] [17] [21-23] [24,
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25] [26] [27] A large meta-analysis of 31 trials comparing restrictive (7 to 8 g/dL) to liberal transfusion thresholds (9 to 10 g/dL) including over 12,000
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patients found a similar 30-day mortality between the two groups (risk ratio
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0.97; 95% CI 0.81 to 1.16). [10] Secondary outcomes including risk of
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pneumonia, stroke, myocardial infarction (MI) and thromboembolism were also similar between groups. However the results cannot be generalized to
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all populations, due to variation in study design, including inconsistent
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transfusion thresholds across patient populations. [17] For example, in
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patients with underlying cardiovascular disease in whom compensatory physiological mechanisms to maintain adequate DO 2 are compromised, [9] a threshold of 7 g/dL as opposed to 8 g/dL could impart harm. [9] While the overall results demonstrated that a restrictive vs a liberal transfusion strategy did not impact risk of mortality and adverse outcomes, there were insufficient data to provide recommendations for specific patient subgroups
ACCEPTED MANUSCRIPT including those with acute coronary syndrome, myocardial infarction, stroke, neurological injury and hematological malignancies. An important caveat is that certain subgroups, in particular those with
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underlying cardiovascular disease, have shown benefit from a higher
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transfusion threshold. A trial of over 2000 cardiac surgery patients (TITRe2)
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demonstrated a higher 90-day mortality risk in the subjects receiving a
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restrictive transfusion strategy, although other outcomes including 30-day mortality did not differ between groups. [23] In addition, a meta-analysis of
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trials in patients with cardiovascular disease demonstrated an increased risk
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ratio of 1.78 for myocardial infarction, cardiac arrest or acute coronary
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syndrome (95% CI, 1.18 to 2.70) with a restrictive transfusion strategy. [28] While the other large study in cardiac surgery patients (TRICS III) did not
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show increased mortality from restrictive transfusion, at the time of the
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meta-analysis, longer-term data were not yet available. Of note, an updated
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analysis of the TRICS III trial has recently been published, [29] showing no difference in six-month mortality rates (odds ratio, 0.95; 95% CI, 0.75 to 1.21) with restrictive versus liberal transfusion. In addition, no significant differences were seen between the groups in the primary composite outcome (death from any cause, myocardial infarction, stroke, or new onset renal failure requiring dialysis), or in secondary outcomes (including emergency
ACCEPTED MANUSCRIPT department visits, hospital readmission, or coronary revascularization within 6 months). In order to address these questions, a recently published update of the
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meta-analysis focused on trials of transfusion thresholds in patients with
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cardiovascular disease. [20] The updated meta-analysis included 37 trials
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with over 19,000 patients. No difference was seen between a restrictive and
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a liberal strategy in 30-day mortality in patients undergoing cardiac surgery (risk ratio 0.99; 95% CI, 0.74 to 1.33) or in overall 30-day mortality among
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26 trials (risk ratio, 1.00; 95% CI, 0.86 to 1.16). However two trials[21, 30]
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(n = 154) showed an increased risk of 30-day mortality in patients with acute
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myocardial infarction from the restrictive compared to the liberal strategy group (RR 3.88; 95% CI, 0.83 to 18.13). Given the lack of benefit seen with
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a liberal strategy, and to avoid the potential risks posed by unnecessary
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blood exposure, the authors recommend use of a restrictive transfusion
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strategy of 7 to 8 g/dL in most patient populations, including those undergoing cardiac surgery. However, they were unable to determine whether a restrictive or a liberal strategy is preferable in patients with underlying coronary artery disease or congestive heart failure due to lack of currently available evidence. A recent retrospective cohort of RBC transfusion in patients with moderate anemia (defined as Hgb levels between
ACCEPTED MANUSCRIPT 7 and 10 g/dL) added support to these paradigms. The study showed that following implementation of patient blood management programs, inpatient transfusion of RBC decreased from 31% in 2010 to 23% in 2014 (p <0.001),
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while the adjusted prevalence of rehospitalization within 6 months decreased
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over the same timeframe from 36.5% to 32.8% (P <0.001). Similarly,
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adjusted prevalence of mortality within 6 months decreased from 16.1% to
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15.6% (P=0.004). However the proportion of patients with resolution of moderate anemia decreased from 42% to 34% (P <0.001). [31] These
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findings however are complicated by data showing a severity-dependent
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association between severity of anemia and frequency of 30-day hospital
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readmissions. A recent retrospective study of 152,757 hospitalizations comparing anemia at discharge with hospital readmission showed a
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significant increase in odds of 30-day readmission. For mild anemia (defined
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as Hgb 11-12 g/dL in women, 11-13 g/dL in men) the odds ratio was 1.74
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(95% CI 1.65 to 1.82); 2.76 (95% CI 2.64 to 2.89) for moderate anemia (Hgb 9-11 g/dL); and 3.47 (95% CI 3.30 to 3.65) for severe anemia (Hgb ≤9 g/dL), P <0.001. [32] The efficacy and safety of restrictive versus liberal RBC transfusion for patients with hematological malignancies undergoing intensive treatment or hematopoietic stem cell transplant (HSCT) was recently examined in a meta-
ACCEPTED MANUSCRIPT analysis. [33] Only six studies were deemed eligible for inclusion, of which four were completed (3 randomized controlled trials, 1 non-randomized study), for a total of 240 participants. The restrictive strategy ranged from 7
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to 9 g/dL compared to a range of 8 to 12 g/dL in the liberal strategy. The
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study demonstrated low-quality evidence that a restrictive RBC transfusion
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policy has little effect on 30- or 100-day mortality, bleeding or hospital stay,
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and may decrease the number of RBC transfusions received per patient. A continuing area of investigation in transfusion medicine is the
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appropriate storage age of red cells for transfusion. Storage of red blood
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cells results in physiologic changes measured by in vitro parameters,
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including impaired nitric oxide metabolism,[34] accumulation of lactic acid, decreased pH, ATP, 2,3-DPG, release of inflammatory mediators, and
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increased red cell membrane rigidity, which may reduce oxygen delivery.
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[35] Collectively these changes are referred to as the ‘storage lesion’, [36]
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[37] which may contribute to impaired oxygen uptake and delivery. [18] [38-40]
While in vitro results might suggest that increased storage would impair the quality of red blood cells, multiple randomized controlled trials have failed to demonstrate clinical benefit from transfusing fresher blood (generally stored for fewer than 10 days) compared to blood stored for
ACCEPTED MANUSCRIPT longer periods. [24, 41-43] [44] [45] [46] (See Table 1) [47] While most trials have demonstrated no benefit from transfusion of fresher blood, there is variation amongst the trials in the storage duration of both fresher and
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standard-issue RBC. In a systematic review, the mean storage age for fresher
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RBCs was 12.1 days compared to 19 days for standard issue RBCs in adults.
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[48] In addition, most trials of RBC storage have not assessed the longest-
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term storage, approaching the 42-day expiration date, although this question has been recently addressed, as described below.
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Two trials evaluating storage age of RBCs in adult patients have recently
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been published, likewise finding no benefit of transfusing fresher blood. [24,
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42] The INFORM[42] trial randomized 31,497 subjects at sites in Canada, the United States and Australia and Israel. The primary analysis included
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20,858 subjects who received fresher blood versus standard-issue blood
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(mean storage age 13.0 ± 7.6 days vs 23.6 ± 8.9 days respectively). In-
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hospital mortality was 9.1% in the fresher arm versus 8.7% in the standardissue arm (OR 1.05; 95% CI, 0.95 to 1.16, p = 0.34). The authors concluded that transfusion of fresher blood did not improve in-hospital mortality compared to standard-issue blood. The TRANSFUSE trial[24] randomized 4994 patients in Australia, New Zealand, Ireland, Finland and Saudi Arabia to compare the effect of storage time on 90-day mortality. The primary
ACCEPTED MANUSCRIPT analysis included 4919 adult ICU patients who received the freshest blood in inventory compared to standard-issue blood (mean storage age 11.8 ± 5.3 days vs 22.4 ± 7.5 days respectively). The mortality rate was 24.8% vs
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24.1% in the fresher vs standard-issue arms respectively (OR 1.04; 95% CI,
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0.91 to 1.18, p = 0.57). The authors concluded that transfusion of fresher
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blood did not affect the outcome of 90-day mortality in critically ill patients.
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A meta-analysis including the results of the INFORM and TRANSFUSE trials determined a relative risk of 1.04 (95% CI, 0.98 to 1.10) from
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transfusion of fresher compared to stored blood. [47]
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Two recent studies have evaluated the issue of blood stored to the end of
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the storage period (36-42 days). [49, 50] A secondary analysis of data from the INFORM trial compared patients who received fresher blood to those
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who received a minimum of one unit of end-of-storage blood (i.e. 36-42
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days). [49] No increase in mortality was seen among those receiving the
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oldest blood (HR 0.94, 95% CI, 0.73 to 1.20, p = 0.60). A study using the SCANDAT2 observational database evaluated 30-day and 1-year mortality among 854,862 transfusion recipients in Sweden and Denmark. [50] No difference in mortality in either time frame was seen between patients receiving older blood (stored 30 to 42 days) compared to patients receiving fresher blood (stored 10 to 19 days). The hazard ratio of 30-day and 1-year
ACCEPTED MANUSCRIPT mortality was 0.99 (95% CI, 0.95 to 1.02) and 1.00 (95% CI, 0.98 to 1.02), respectively. Additional analysis of a subset of patients who received over six units of RBC stored for more than 30 days compared to those who
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received fresher blood similarly demonstrated no association between RBC
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storage and mortality.
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A recently published Cochrane review included 22 trials that evaluated
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the effect of storage duration on transfusion outcomes in all patient populations. [51] No difference in the primary outcome of mortality was
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detected between study groups at any of the time points evaluated. Although
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there was heterogeneity among the trials and not all reported on predefined
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secondary outcomes (e.g. incidence of infection, adverse reactions, length of stay), analysis of the available data revealed no significant differences
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between the study groups.
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Table 1. Duration of red blood cell storage and clinical outcome Reference Study population RBC storage duration in Primary days outcome INFORM General population Mean (SD) Mortality Heddle et al., of hospitalized Fresh - 13 (7.6) Fresh – 9.1% NEJM 2016 patients Older – 23.6 (8.9) Older – 8.7% Total patients in Odds ratio 1.05 primary analysis, N (95% CI 0.95 to = 20,858 1.16) Fresh, N = 6936 P = 0.34 Older, N = 13,922 ABLE Critically ill adult Mean (SD) Mortality
ACCEPTED MANUSCRIPT ICU patients Fresh - 6.1 (4.9) Total patients in Standard - 22 (8.4) primary analysis, N = 2412 Fresh, N = 1206 Standard, N = 1206
Fresh – 37% Standard – 35.3% ARD 1.7, (95% CI -2.1 to 5.5)
RECESS Steiner et al., NEJM 2015
Patients 12 years Mean (SD) Fresh - 7.8 (4.8) of age undergoing Older - 28.3 (6.7) complex cardiac surgery Total patients in primary analysis, N = 1098 Fresh, N = 538 Standard, N = 560
Change in the 7day Multiple Organ Dysfunction Score (MODS; range 0-24) Fresh – 8.5±3.6 Older – 8.7±3.6 Estimated treatment effect -0.2 (95% CI 0.6 to 0.3) P = 0.44
TOTAL Dhabangi et al., JAMA 2015
Children aged 6-60 Median (IQR) months with Fresh - 8 (7, 9) malaria or sickle Older - 32 (30, 34) cell disease Total patients in primary analysis, N = 286 Fresh, N = 143 Standard, N = 143
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M ED
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Lacroix et al., NEJM 2015
Premature infants with birth weights <1250 g in the neonatal ICU
Mean (SD) Fresh – 5.1 (2) Standard – 14.6 (8.3)
Lactate level 3 mmol/L Fresh – 83/143 (58%) Older – 87/143 (61%) Between group difference 0.03 (95% CI, -0.07 to ) P = < .001 Composite measure of major neonatal morbidities as
ACCEPTED MANUSCRIPT
Critically ill adult Mean (SD) patients in the ICU Fresh – 11.8 (5.3) Total patients in Standard – 22.4 (7.5) primary analysis, N = 4919 Fresh, N = 2457 Standard, N = 2462
INFORM, 2° analysis Cook et al., Lancet Haematol, 2018
General population of hospitalized patients Total patients in primary analysis, N = 24,736 Fresh, N = 1392 Standard, N = 18,854 Oldest, N = 4480 All transfusion recipients in Sweden and Denmark N = 854,862 Fresh, N = 278,207 Oldest, N = 46,474
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TRANSFUSE Cooper et al., NEJM 2017
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Halmin et al., AIM, 2017 SCANDAT data
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Fresh: ≤ 7 d Oldest: > 35 d
well as death Fresh – 52.7% Standard – 52.9% Relative risk 1.01 (95% CI 0.90 to 1.12) 90-day all-cause mortality Fresh – 24.8% Standard – 24.1% Odds ratio 1.04 (95% CI 0.91 to 1.18) P = 0.57 Mortality Fresh to Oldest Hazard ratio 0.91 (95% CI 0.72 to 1.14) P = 0.40
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Total patients in primary analysis, N = 377 Fresh, N =188 Standard, N = 189
Fresh (ref): 10-19 d Oldest: 30 – 42 d
Mortality 30-day hazard ratio: 0.99 (95% CI, 0.95 to 1.02) 1 year hazard ratio: 1.00 (95% CI, 0.98 to 1.02)
ACCEPTED MANUSCRIPT 2.2.
Guidelines
Multiple evidence-based guidelines have been published on transfusion of red cells in the last five to ten years across a variety of disciplines ranging
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from transfusion medicine to anesthesiology to nephrology. [41, 52] Based
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on evidence from high-quality randomized trials as detailed above, most of
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the guidelines recommend a restrictive transfusion strategy of 7 to 8 g/dL. A
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common theme among the guidelines is that transfusion should not be based strictly on laboratory parameters such as hemoglobin levels, but the clinical
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condition and circumstances of the individual patient should be considered.
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[48, 53] [41, 52] [54]
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Importantly among such guidelines, in 2016 AABB published “Clinical
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Practice Guidelines: Red Blood Cell Transfusion Thresholds and Storage. [48] The recommendations are based on evaluation of 31 randomized
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controlled trials including 12,587 subjects. The guidelines recommend
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withholding transfusion until the hemoglobin level is 7 g/dL or below in hemodynamically stable hospitalized patients, including the critically ill, as opposed to a level of 10 g/dL. For patients undergoing orthopedic surgery, cardiac surgery, and with preexisting cardiovascular disease, a restrictive transfusion level of 8 g/dL is recommended. Recommendations are not provided for patients with acute coronary syndrome,
ACCEPTED MANUSCRIPT hematological/oncological patients with severe thrombocytopenia at risk of bleeding or chronic transfusion-dependent anemia patients due to lack of evidence in these populations. The AABB guidelines also address the issue
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of RBC storage age. Based on evaluation of 13 RCTs (n = 5515) showing no
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benefit from fresher blood, the guidelines recommend that all patients
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Adverse effects
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2.3.
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including neonates, should be transfused with standard-issue blood.
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Adverse effects of red cell transfusion include transfusion associated circulatory overload (TACO) and transfusion related acute lung injury
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(TRALI), transfusion transmitted infection, febrile non-hemolytic
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transfusion reactions (FNHTR), allergic/anaphylactic reactions, transfusion
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associated graft versus host disease (TA-GVHD), and alloimmunization. In addition, RBC transfusions are frequently implicated in hemolytic reactions, both acute hemolytic transfusion reactions (AHTRs) and delayed hemolytic transfusion reactions (DHTRs). In certain patients, most commonly sickle cell disease patients, a complication of delayed hemolytic reactions can lead to potentially lethal complications of hyperhemolysis. [55]
ACCEPTED MANUSCRIPT Alloimmunization is implicated in hemolytic transfusion reactions when clinically significant antibodies are involved. Recipient data collected from 2013 to 2016 from the Recipient Epidemiology and Donor Evaluation
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Study-III (REDS-III) database showed 2% of 319,177 patients had a positive
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antibody screen with at least one clinically significant antibody. Statistically
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significant risk factors for RBC alloimmunization included female sex,
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white race, age, and RhD-negative status. Clinical diagnoses including sickle cell disease or trait, systemic lupus erythematosus, rheumatoid arthritis and
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myelodysplastic syndrome were also significantly associated with increased
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risk of alloimmunization. In contrast, diagnoses of leukemia, solid tumors,
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or solid organ transplant were significantly associated with decreased risk of
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3. Platelets
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developing an alloantibody following RBC transfusion. [56, 57]
Platelet components can be obtained either from single donor apheresis collections or derived from units of WB. A standard adult platelet dose is considered one apheresis unit or a pool of 4 to 6 Whole Blood-derived (WBD) units, [1, 13] and is expected to raise the platelet count by 30,000 to 50,000/µL. Approximately 2 million platelet components are transfused in
ACCEPTED MANUSCRIPT the US annually, of which the majority (~92%) are apheresis platelets. [1] For most indications, WBD and apheresis platelets are considered equally efficacious, as assessed by metrics including hemostatic efficacy, post-
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transfusion increments, and risk of adverse events. [58, 59] Platelets are
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stored at room temperature (20 to 24 C) for 5 to 7 days. Room temperature
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storage limits the shelf-life of platelets compared to other blood products due
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to the risk of bacterial contamination which can result in fatal septic transfusion reactions. [60] [61, 62] To address the risk of platelet
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contamination, testing for bacterial contamination or photochemical
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pathogen inactivation system are used to reduce the risk of transfusion-
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Indications/current practice
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3.1.
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transmitted infection, including sepsis. (see section 7.7.) [63]
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Indications for platelet transfusions can be categorized into prophylactic versus therapeutic therapy. [64] Prophylactic indications for platelet transfusion include prevention of bleeding in patients with treatmentinduced hypoproliferative thrombocytopenia, congenital or acquired platelet dysfunction, and those undergoing invasive procedures. Therapeutic platelet transfusions are given to treat acute hemorrhage. If feasible, platelets should
ACCEPTED MANUSCRIPT be ABO plasma compatible (if not screened for high titer anti-A and anti-B). [65, 66] Decisions governing prophylactic versus therapeutic treatment, appropriate dosage, and optimal thresholds at which to transfuse remain
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topics of continuing interest in Transfusion Medicine. Recent randomized
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controlled trials [67, 68] and systematic reviews [69-73] have addressed
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these questions in various patient population settings, as detailed below.
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3.1.1. Congenital and acquired bone marrow failure
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A recent Cochrane review aimed to evaluate a therapeutic-only versus
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prophylactic platelet transfusion policy in patients with congenital or acquired bone marrow failure disorders, e.g. myelodysplastic syndrome
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(MDS). [73] Eligible study subjects included patients with bone marrow
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failure disorders requiring long-term platelet transfusions, not actively
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treated with a stem cell transplant or intensive chemotherapy. Only one RCT was identified as eligible for inclusion in the review and the study was discontinued due to poor participant recruitment after enrolling only 9 subjects. No study data were reported, and therefore no analysis performed. While no conclusions could be drawn, the review highlights the need for well-designed studies to determine appropriate transfusion policy in patients
ACCEPTED MANUSCRIPT with bone marrow failure, a population exposed to repeated platelet transfusions.
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3.1.2. Prior to surgery
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A 2018 Cochrane review evaluated prophylactic platelet transfusions prior to
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surgery in thrombocytopenic patients. [71] Of five RCTs identified, three small trials (n = 180) were assessed as eligible for inclusion. One trial
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randomized thrombocytopenic patients in the intensive care unit (ICU) to
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receive prophylactic platelet transfusions versus no transfusion. The other
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two trials evaluated prophylactic platelet transfusion compared to alternative therapies, desmopressin and thrombopoietin mimetics
PT
(romiplostim/eltrombopag) respectively, in patients with liver disease. There
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was insufficient evidence to determine if administering a platelet transfusion
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prior to surgery had an effect on all-cause mortality within 30 days or provided benefit in reducing major or minor bleeding compared to no transfusion or alternative treatment. Likewise, there was insufficient evidence to ascertain a difference in transfusion-related adverse events between groups. The authors concluded that due to the lack of evidence that
ACCEPTED MANUSCRIPT transfusion reduced post-operative bleeding or all-cause mortality, they were unable to recommend prophylactic platelet transfusions in this setting.
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3.1.3. Hematologic malignancy
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Patients with hematologic malignancies represent the patient population in
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which the question of prophylactic versus therapeutic transfusion has been most extensively evaluated and for which the most definitive evidence is
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available. Multiple RCTs and meta-analyses have addressed this question
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and demonstrated that prophylactic platelet transfusion reduces World
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Health Organization (WHO) Grade 2 or greater bleeding in patients with hematological malignancies receiving chemotherapy or allogeneic HSCT.
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[74] [69] [67, 68]
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A 2015 Cochrane review [69] analyzed six RCTs comparing a
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therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with hematological disorders after myelosuppressive chemotherapy or stem cell transplantation. The trials evaluated for the review were conducted between 1978 and 2013 and comprised a total of 1195 subjects. Notable findings comparing the therapeutic-only strategy to the prophylactic strategy included an increased
ACCEPTED MANUSCRIPT number of days with a clinically significant bleeding event (one RCT, 600 participants; mean difference 0.50; 95% CI, 0.10 to 0.90; moderate-quality evidence); shorter time to first bleeding episode (2 RCTs, 801 participants);
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and no difference in the frequency of adverse events (two RCTs, 991
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participants; RR, 1.02; 95% CI, 0.62 to 1.68). There was insufficient
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evidence to determine a difference in the number of subjects with
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severe/life-threatening bleeding or all-cause mortality. The benefit of prophylactic transfusions did not extend to patients receiving autologous
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HSCT. [67, 68, 75] The therapeutic strategy was associated with a
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significant reduction in transfused units. The authors concluded that a
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therapeutic-only strategy compared to a prophylactic platelet transfusion policy is associated with an increased risk of bleeding in hematology
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patients with thrombocytopenia due to myelosuppressive therapy or HSCT),
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and therefore prophylactic platelet transfusions are beneficial in this
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population.
Dosage and thresholds for prophylactic platelet transfusions have also been studied in this population. A 2015 Cochrane review[76] evaluated different doses of prophylactic platelet transfusion in patients with hematologic malignancies undergoing myelosuppressive chemotherapy or HSCT. The review included seven RCTs (n = 1814) in thrombocytopenic
ACCEPTED MANUSCRIPT patients with hematologic malignancies who received low-dose (1.1 x1011/m2 ±25%), standard-dose (2.2 x1011/m2 ±25%), or high-dose (4.4 x1011/m2 ±25%) prophylactic platelet transfusion. There was no difference in
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the number of participants with a clinically significant bleeding event,
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number of days of bleeding, severe/life-threatening bleeding between the
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groups, time to first bleeding episode or all-cause mortality between the
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three treatment arms. A low-dose strategy resulted in an increased median number of platelet transfusions compared to a standard-dose strategy (five
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versus three in the largest study)[77], and a shorter interval between
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transfusions, however, overall the number of platelets transfused was lower.
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A high-dose strategy did not decrease the number of transfusions compared to a standard-dose strategy. A higher rate of transfusion-related adverse
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events was associated with a high-dose strategy. The authors concluded that
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in patients with hematologic disorders who were thrombocytopenic due to
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chemotherapy or HSCT, there was no evidence to suggest that a low-dose transfusion strategy was associated with an increased risk of bleeding compared to higher doses and recommended a change in practice of preferentially using low-dose platelets in hospitalized patients with hematologic malignancies and avoiding high-dose platelet transfusions.
ACCEPTED MANUSCRIPT Different platelet transfusion thresholds for prophylactic platelet transfusion to prevent bleeding in patients with hematologic malignancies after myelosuppressive chemotherapy or HSCT were evaluated in a 2015 systematic review.(See Table 2) [78] Three RCTs (n = 499) comparing a
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standard trigger (10 x 109/L) to a higher trigger (20 x 109/L or 30 x 109/L)
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were included in the review. There was no difference in the number of
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subjects with a clinically significant bleeding episode within 30 days of the start of the study between the standard and the higher trigger groups (3
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studies, n = 499; risk ratio (RR) 1.35, 95% CI, 0.95 to 1.90). There was no
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difference in the number of days of bleeding between the standard and the
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higher trigger groups (one study, n = 255; RR 1.71; 95% CI, 0.84 to 3.48, p = 0.162). In two studies reporting the number of subjects with severe or life-
PT
threatening bleeding, there was no difference between the standard and the
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higher trigger groups (n = 421; RR 0.99, 95% CI, 0.52 to 1.88). Overall, no
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difference was seen between the standard and higher trigger groups in risk of any degree of bleeding, including severe/life-threatening, risk of adverse events, or 30-day mortality. A significant reduction was seen in the number of platelet transfusions per participant in the standard trigger group. The authors concluded that based on low-quality evidence, there was no increase in risk of bleeding associated with a standard trigger (10 x 109/L) compared
ACCEPTED MANUSCRIPT to a higher trigger (20 x 109/L or 30 x 109/L), and a standard trigger was associated with a decrease in the number of transfusion episodes compared to a higher trigger.
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Table 2. Platelet transfusion threshold and risk of bleeding Reference Study population Platelet transfusion threshold Wandt et Adult patients with Prophylactic: ≤10 x al., Lancet hematological 109/L 2012 malignancies Therapeutic: at onset undergoing of bleeding chemotherapy or HSCT Total patients in primary analysis, N = 391 Prophylactic, N = 194 Therapeutic, N = 197
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Adult patients with hematological malignancies undergoing chemotherapy or HSCT Total patients in primary analysis, N = 598 Prophylactic, N = 298 Therapeutic, N = 300
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Stanworth et al., NEJM 2013
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Primary/secondary endpoints Risk of Grade 2 or higher bleeding Prophylactic – 19% Therapeutic – 42% P <0.0001 Risk of Grade 4 or higher bleeding Prophylactic – 1% Therapeutic – 5% P = 0.0159
Prophylactic: ≤10 x 109/L No prophylaxis
Risk of Grade 2 or higher bleeding Prophylactic – 43% Therapeutic – 50% Adj diff in proportions – 8.4 percentage points (90% CI, 1.7 – 15.2) P = 0.06 for non-inferiority
ACCEPTED MANUSCRIPT
While significant heterogeneity remains in clinical practice, [79] these RCTs and systematic reviews have provided the foundation for the development of recent evidence-based guidelines, as discussed below. The
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guidelines focus on the main topics addressed in the studies: prophylactic
Guidelines
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3.2.
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transfusion and efficacious platelet dose.
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versus therapeutic platelet transfusion, appropriate threshold for platelet
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Various guidelines addressing the appropriate transfusion of platelets across
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various populations have recently been published, addressing questions of
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prophylactic versus therapeutic platelet transfusion, appropriate thresholds
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for platelet transfusion and efficacious platelet dose. [58] [59] [80] [54, 81] The AABB Clinical Practice Guidelines for platelet transfusion are
AC
frequently referenced. [81] The guidelines strongly recommend prophylactically transfusing adult hospitalized patients with therapy-induced hypoproliferative thrombocytopenia at a platelet count <10 x 109/L with up to a single apheresis unit or an equivalent dose of WBD platelets. Other guidelines similarly recommend a threshold of <10 x 109/L in patients with hematologic malignancies undergoing treatment. [59] [80] The AABB
ACCEPTED MANUSCRIPT guidelines recommend prophylactic platelet transfusion at a platelet count <20,000/µL for elective central venous catheter (CVC) placement, <50,000/µL for elective diagnostic lumbar puncture, and <50,000/µL for
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major elective nonneuraxial surgery. AABB recommends against routine
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prophylactic platelet transfusion in patients without thrombocytopenia
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undergoing cardiac surgery with cardiopulmonary bypass, as platelet
US
transfusion has been shown to be an independent predictor of adverse outcomes in such situations, including mortality. However platelet
AN
transfusion is recommended if these patients develop perioperative bleeding
M
or signs of platelet dysfunction, findings which can develop due to exposure
ED
to the cardiopulmonary bypass circuit. [82] In patients with intracranial hemorrhage taking antiplatelet agents, AABB is unable to recommend for or
PT
against platelet transfusion due to insufficient evidence.
CE
Recently published guidelines from the American Society of Clinical
AC
Oncology (ASCO) provide updated recommendations for platelet transfusion strategies in patients with cancer. [59] For patients undergoing allogeneic HSCT or those receiving therapy for hematologic malignancies, prophylactic platelet transfusion at a threshold of <10 x 109/L is recommended. Based on extrapolation from studies in hematology patients, prophylactic platelet transfusion at a threshold of <10 x 109/L is also
ACCEPTED MANUSCRIPT recommended in patients with solid tumors. The guidelines recommend consideration of transfusion at higher levels in certain circumstances, such as patients exhibiting signs of hemorrhage or sepsis. In adult recipients of
T
autologous HSCT and patients with chronic, stable, severe
IP
thrombocytopenia not receiving active treatment, a therapeutic platelet
CR
transfusion strategy is recommended, in which transfusions are administered
US
only for episodes of clinically significant bleeding. For patients undergoing invasive procedures, the ASCO guidelines recommend similar thresholds as
AN
AABB of 40,000/µL to 50,000/µL for major procedures and ≥20,000/µL for
M
less invasive procedures, e.g. bone marrow biopsies or CVC insertion. In
ED
addition, the guidelines recommend providing leukocyte-reduced RBCs and platelets to prevent alloimmunization, in particular to patients with AML
PT
undergoing induction chemotherapy.
CE
Various international guidelines also provide recommendations for
AC
platelet transfusion strategies, in general alignment with the AABB and ASCO guidelines. [83] [58, 80]. Common recommendations across the guidelines include providing prophylactic platelet transfusions to thrombocytopenic patients receiving intensive therapy at a threshold of <10 x 109/L, routinely using only one standard adult dose for prophylactic transfusions, withholding prophylactic treatment in patients with autologous
ACCEPTED MANUSCRIPT HSCT or with asymptomatic thrombocytopenia due to chronic bone marrow failure, and increasing the platelet transfusion threshold based on patientspecific risk factors for bleeding. General consensus among both U.S. and
T
international guidelines emphasizes avoiding the risk of unnecessary
Adverse events
AN
3.3.
US
CR
and patient-specific risk factors. [84] [80, 85]
IP
transfusions, and to guide patient care primarily based on clinical judgment
M
Adverse events associated with platelet transfusion include infectious and
ED
non-infectious etiologies. Transfusion transmitted infection can be caused by viruses, (e.g. HBV, HIV, West Nile Virus), parasites (e.g. Babesia, malaria),
PT
bacterial contamination, [60] [61, 62], prion diseases (e.g. variant
CE
Creutzfeld-Jakob disease), and emerging infectious diseases. [86] Common
AC
non-infectious etiologies due to platelet transfusion include allergic/anaphylactic reactions[87], FNHTRs [88], TRALI and TACO, [89] platelet alloimmunization and hemolytic reactions. [80] Receiving platelet transfusions prior to invasive procedures has been associated with increased risk in multiple observational studies. Prophylactic pre-procedure platelet transfusion was associated with an increased risk of
ACCEPTED MANUSCRIPT thrombosis and mortality in hospitalized patients in a prospective observational trial. [90]. A retrospective cohort study of patients with gastrointestinal (GI) bleeding on antiplatelet medications who received
T
platelet transfusions showed a 5.57 increased odds ratio of death compared
IP
to controls. [91] A randomized trial of platelet transfusion in adults with
CR
acute intracerebral hemorrhage associated with antiplatelet therapy
US
demonstrated increased odds of death and dependence in patients receiving platelet transfusions compared to standard care (OR, 2.05; 95% CI 1.18 to
AN
3.56, p = 0.0114). [92] Similarly, a randomized trial of 660 neonates
M
compared a threshold of less than 50 x 109/L to a threshold less than 25 x
ED
109/L. The primary outcome was death or major bleeding up to and including day 28. New major bleeding episodes occurred in 14% of infants
PT
in the high-threshold group compared to 11% in the low threshold group
CE
(HR 1.32; 95% CI 1.00 to 1.74). The primary outcome of death or a new
AC
major bleeding episode occurred in 26% of infants in the high-threshold group compared to 19% in the low-threshold group (adj OR 1.57; 95% CI, 1.06 to 2.32; P=0.02). Death occurred in 15% of the high-threshold group compared to 10% in the low-threshold group (OR 1.56; 95% CI, 0.95 to 2.55), although this did not reach statistical significance. Ninety percent of patients in the high-threshold group received a platelet transfusion compared
ACCEPTED MANUSCRIPT to 53% in the low-threshold group (HR 2.75; 95% CI, 2.36 to 3.21). [93] A study of prophylactic platelet transfusion prior to interventional radiology procedures demonstrated an association of platelet transfusion with
T
increased rates of ICU admission (OR, 1.57; p = .022). [94] However,
IP
studies of other populations undergoing invasive procedures, including
CR
cardiac surgery have failed to show an association between platelet
AN
US
transfusion and increased mortality or morbidity. [95, 96]
ED
M
4. Plasma
Plasma constitutes over half of the total blood volume, and contains multiple
PT
coagulation factors, immunoglobulins, albumin and other proteins. Plasma
CE
can be processed by the separation of a WB donation or collected by
AC
apheresis. The average volume of a plasma unit derived from WB is approximately 250 mL, although apheresis collections can range from 400 to 600 mL.
Plasma products can be frozen following collection and later thawed prior to use, or maintained in a liquid state. Plasma products for transfusion include frozen plasma, liquid plasma, thawed plasma, cryoprecipitate-
ACCEPTED MANUSCRIPT reduced plasma, Solvent/detergent (S/D) plasma and pathogen-reduced plasma. Fresh-frozen plasma (FFP) is separated from RBCs or collected by apheresis and frozen at -18°C or colder within 8 hours of collection. FFP
T
contains normal levels of coagulation factors, albumin and
IP
immunoglobulins. [97] When frozen at -18°C or colder, FFP has a shelf life
CR
of 12 months. Plasma frozen within 24 hours after phlebotomy (FP24) is
US
processed similarly to FFP but frozen within 24 hours of collection. While plasma for transfusion is generally referred to as FFP, frozen within 8 hours
AN
of collection, in practice the majority of plasma is FP24, frozen anytime up
M
to 24 hours following collection. FFP and FP24 are generally used
ED
interchangeably, however, FP24 is not indicated to treat deficiencies of labile coagulation factors, e.g. Factors V and VIII. Once thawed, plasma has
PT
a shelf life of 24 hours, stored at 1 to 6°C. Although not an FDA-recognized
CE
product, thawed plasma stored longer than 24 hours can be relabeled as
AC
Thawed Plasma and stored up to 5 days. Thawed Plasma is used as a source of nonlabile plasma proteins. Clinical differences between frozen and thawed plasma products have not been demonstrated and Thawed Plasma has been reported to reduce product outdating in hospitals. [98] [99-101] Cryoprecipitate-reduced plasma is prepared by thawing and centrifuging FFP, followed by removal of the cryoprecipitate. The remaining product is
ACCEPTED MANUSCRIPT deficient in fibrinogen, Factor VIII, Factor XIII, von Willebrand Factor (vWF) and fibronectin. It is indicated for transfusion or plasma exchange in patients with thrombotic thrombocytopenic purpura (TTP) or reversal of
Indications/current practice
US
CR
4.1.
IP
T
warfarin coagulopathy (if other therapies are not employed).
Accepted indications for plasma transfusion include as prophylaxis prior to
AN
performing invasive procedures, to treat bleeding in patients with multiple
M
coagulation factor deficiencies, e.g. disseminated intravascular coagulation
ED
(DIC) or liver disease, in patients undergoing massive transfusion who have dilutional coagulopathy, to manage specific coagulation factor deficiencies
PT
for which a licensed coagulation factor concentrate is not available, for
CE
warfarin reversal and plasma exchange. [101]
AC
Inappropriate uses include as a primary means for the expansion of circulatory volume, hypoproteinemia, and correction of congenital or acquired deficiencies of clotting in the absence of bleeding. [102, 103] [97] [101] Importantly, plasma transfusions should not be given to correct minor coagulation test abnormalities in non-bleeding patients, e.g. slightly elevated prothrombin time/international normalized ratio (PT/INR) or activated
ACCEPTED MANUSCRIPT partial thromboplastin time (aPTT). This practice is discouraged because mild to moderate elevations in commonly used coagulation tests such as the PT/INR correlate poorly with bleeding propensity, [104, 105] moderate
T
increases in the INR are not corrected by plasma transfusion, [14, 106] and
IP
multiple randomized and observational studies have shown that prophylactic
CR
plasma transfusions do not improve bleeding outcomes, [107, 108] but may
US
in fact adversely affect clinical outcome. [109] [110, 111] A recent study found that plasma transfusions continue to be administered typically in two-
AN
unit doses for modest elevations in INR, that two-unit transfusions had very
M
little effect on the patient’s INR (median decrease 0.4), and in 20% of
ED
patients, the indication for transfusion was prophylactic preprocedural INR correction in stable non-bleeding patients. [14, 15] In such situations, plasma
PT
transfusion is not expected to affect either the INR or reduce surgical
CE
bleeding risk, but instead exposes the patient to transfusion associated risks
AC
including TACO, TRALI, anaphylaxis and transfusion-transmitted infection (TTI).
4.2.
Guidelines
ACCEPTED MANUSCRIPT Recent guidelines from the British Society of Hematology address the use of plasma and cryoprecipitate products in various patient groups in the absence of major bleeding. [112] Key practice points emphasize that abnormal
T
coagulation tests (PT/aPTT) are poor predictors of bleeding risks in non-
IP
bleeding patients prior to an invasive procedure; a detailed clinical history
CR
should be routinely assessed on a patient-specific basis prior to undergoing a
US
procedure; and the impact of commonly used doses of FFP to correct clotting results or to reduce bleeding risk is very limited for a PT/INR
AN
between 1.5 to 1.9. For patients with prolonged PT likely due to acquired
M
vitamin K deficiency, administration of vitamin K is recommended. The
ED
guidelines cite insufficient evidence on which to base a recommendation for the optimal dose of FFP for patients with abnormal coagulation tests
PT
undergoing a procedure. The guidelines recommend providing ABO-
CE
identical products, or low-titer anti-A or anti-B plasma if only ABO non-
AC
identical plasma is available. In 2010 the AABB published Evidence-Based Practice Guidelines for Plasma Transfusion[113] including recommendations that plasma be transfused to patients requiring massive transfusion and to patients with warfarin therapy-related intracranial hemorrhage. The panel found insufficient evidence to recommend for or against transfusion of plasma at a
ACCEPTED MANUSCRIPT plasma:red blood cell ratio of 1:3 or more (indicating more plasma per red cell) during massive transfusion, plasma transfusion in patients undergoing surgery in the absence of massive transfusion, or transfusion of plasma to
T
reverse warfarin in patients without intracranial hemorrhage. The guidelines
IP
recommend against plasma transfusion for other groups of patients, (e.g. in
CR
the absence of massive transfusion, surgery, bleeding or over-
US
anticoagulation), such as patients with acute pancreatitis, organophosphate poisoning, coagulopathy, or acetaminophen poisoning. In these
AN
heterogeneous populations, the available evidence indicated that the adverse
Adverse effects
PT
4.3.
ED
M
effects of plasma transfusion outweighed any potential benefit.
CE
Transfusion of plasma is associated with TRALI, TACO, FNHTRs, allergic
AC
or anaphylactic reactions, and transfusion transmitted infection. The risk of TRALI from plasma transfusion has decreased in recent years since implementation of policies requiring plasma to be selected from primarily male or never-pregnant female donors. [112] [113] Recent evidence suggests that plasma transfusion in surgical procedures may be associated with adverse outcomes. [110] Several studies have
ACCEPTED MANUSCRIPT demonstrated increased rates of bleeding complications in patients receiving prophylactic plasma transfusions to correct preprocedural abnormal coagulation tests in the absence of clinical bleeding. [109, 111, 114] A
T
recent retrospective cohort study showed an association between higher
IP
intraoperative plasma transfusion volumes and inferior perioperative clinical
CR
outcomes, including increased odds of peri-operative and post-operative
US
RBC transfusion, higher mortality, and fewer hospital and ICU-free days. [14] A meta-analysis of surgical studies showed that transfusion of plasma
AN
was associated with a trend of increased risk of death (OR 1.22; 95% CI,
ED
M
0.73 to 2.03). [115]
CE
PT
5. Cryoprecipitated Antihemophilic Factor (AHF)
AC
Cryoprecipitated Antihemophilic Factor (AHF) (cryoprecipitate) contains fibrinogen, Factor VIII, Factor XIII, vWF, and fibronectin. It is prepared by thawing and centrifuging WB-derived or apheresis FFP, followed by removal of the supernatant plasma. [116, 117] The cold-insoluble precipitate is suspended in a small amount of plasma (~15 mL) and refrozen at -18°C or colder within one hour, which permits a shelf-life of one year. FDA and
ACCEPTED MANUSCRIPT AABB Standards require that each unit of cryoprecipitate contain ≥80 IU of Factor VIII and ≥150 mg of fibrinogen, although in practice the average fibrinogen content per unit is significantly higher, in the range of 200 to 250
Indications/current practice
US
CR
5.1.
IP
T
mg. [118]
Although the use of most blood components has been decreasing steadily
AN
over the past decade, the use of cryoprecipitate has increased, both in the
M
U.S. and internationally. [1, 112] The reasons for the increase are unclear,
ED
although recent studies in obstetrics, cardiac surgery and trauma showing that acquired hypofibrinogenemia is associated with worse outcomes and
PT
risk of bleeding is a possible factor. [119-122] While cryoprecipitate is
CE
widely used, there is limited evidence to support its efficacy. [118] [117]
AC
[123, 124] Current practice likely still continues to be guided by historical reports suggesting hemostatic insufficiency occurs at fibrinogen levels <1 g/L[125] although this metric has been drawn into question. [126-130] Cryoprecipitate is recommended for fibrinogen replacement in diseases of acquired hypofibrinogenemia, such as liver transplantation, cardiovascular surgery and obstetric hemorrhage. [118, 131] Although
ACCEPTED MANUSCRIPT historically cryoprecipitate was also used to treat Factor VIII deficiency, Factor XIII deficiency, and vWF deficiency, due to the availability of coagulation factor concentrates, it is now used almost exclusively for
T
fibrinogen replacement. Newly developed coagulation factor concentrates
IP
are currently considered the standard of care in Factor VIII deficiency,
CR
congenital fibrinogen deficiency (including hypofibrinogenemia and
US
afibrinogenemia), and von Willebrand disease. A Factor XIII concentrate derived from human plasma is also available. However currently licensed
AN
fibrinogen concentrates in the U.S. are not indicated for acquired
Guidelines
PT
5.2.
ED
M
hypofibrinogenemia, which remains treated with cryoprecipitate.
CE
Due to the lack of evidence from randomized trials evaluating fibrinogen
AC
replacement, guidelines on the use of cryoprecipitate are mostly based on consensus and vary substantially. [120, 126] [132] The recent British Society of Hematology guidelines[112] found insufficient evidence to recommend a specific threshold at which cryoprecipitate should be transfused or the appropriate dose necessary for prophylaxis in non-bleeding patients undergoing invasive procedures. The guidelines suggest that
ACCEPTED MANUSCRIPT cryoprecipitate can be used in non-bleeding patients with low fibrinogen levels (e.g. <1 g/L) undergoing invasive procedures, however note this recommendation is not evidence-based. In accordance with American
T
Association for the Study of Liver Diseases and European Association for
IP
the Study of the Liver recommendations[133, 134], the guidelines
CR
recommend against prophylactic transfusion of FFP and cryoprecipitate in
AN
Adverse effects
M
5.3.
US
low bleeding risk procedures, such as paracentesis.
ED
While the risks of cryoprecipitate transfusion are in theory similar to those of FFP (e.g. allergic reactions, FNHTRs and TTI), reported adverse
PT
reactions due to cryoprecipitate transfusion are infrequent. [117] While
CE
cryoprecipitate has been associated with adverse reactions of hemolysis due
AC
to transfused isohemagglutinins, thrombosis, and respiratory distress, such reports are rare and mostly limited to case reports or small case series. [135138] Cryoprecipitate has been implicated in rare cases of TRALI. [139] However, this risk has been mitigated since the implementation of policies for collection of plasma for transfusion primarily from male or never-
ACCEPTED MANUSCRIPT pregnant female donors. Large volumes of transfused cryoprecipitate should
T
be ABO-plasma compatible.
CR
IP
6. Granulocytes
US
Granulocyte components are collected by cytapheresis from donors stimulated with corticosteroids and/or granulocyte colony-stimulating factor
AN
(G-CSF). Hydroxyethyl starch, a red cell sedimenting agent, is typically
M
used in granulocyte collection to facilitate the separation of granulocytes
ED
from red blood cells. Each unit contains ≥1.0 x 1010 granulocytes and up to 50 mL RBCs as well as small amounts of lymphocytes and platelets. Due to
PT
the RBC content, granulocyte components are ABO matched to the recipient
CE
to avoid hemolytic reactions. Cytomegalovirus (CMV)-seronegative
AC
granulocyte components should be provided if available, particularly to immunosuppressed CMV-seronegative patients. [140] Granulocytes are stored at room temperature, often irradiated, and administered within 24 hours of collection. Although stimulation with G-CSF can produce higher yields of granulocytes than corticosteroid stimulation, due to logistical considerations such as recruiting eligible donors within 24 hours, and
ACCEPTED MANUSCRIPT increased donor adverse side effects such as bone pain and myalgias, many facilities collect granulocytes without G-CSF stimulation.[141]
Indications/current practice
IP
T
6.1.
CR
Granulocytes are indicated in patients with life-threatening bacterial and
US
fungal infections who have severe neutropenia (ANC <500/µL), are unresponsive to appropriate therapy following a reasonable period of
AN
treatment, and have a reasonable prospect of recovery. [141] Granulocyte
M
transfusions are also indicated in patients with congenital disorders of
ED
neutrophil function, such as chronic granulomatous disease. However, the clinical efficacy of granulocyte transfusions remains unproven. [140] [142,
PT
143] In clinical practice, granulocytes are prescribed inconsistently and it
CE
has been reported that as few as 25% of eligible patients receive them. [144-
AC
146] When administered, higher doses are more likely to provide therapeutic benefit, [141] although may pose a higher risk of adverse effects such as lung injury.
6.2.
Guidelines
ACCEPTED MANUSCRIPT Although granulocyte transfusions have long been used to treat patients with invasive infections, studies have failed to demonstrate a conclusive survival benefit. [60, 141, 142] Due to the lack of definitive evidence and a paucity
T
of well-designed trials, many of which have been underpowered, [141,
IP
142]clinical practice guidelines have yet to be developed. For example, a
CR
Cochrane review evaluating 10 RCTs found no difference in 30-day
US
mortality between patients with neutropenia who received granulocyte transfusions compared to a control group who did not (RR 0.75, 95% CI
AN
0.54 to 1.04). Nor was a difference seen in reversal of infection between the
M
two groups (RR 0.98, 95% CI 0.81 to 1.19). However, a subgroup analysis
ED
showed fewer infections in the group receiving intermediate-dose granulocyte transfusions (1.0 to 4.0 x 1010 granulocytes) In conclusion, the
PT
authors reported that there was insufficient evidence to determine whether
CE
granulocyte transfusions affect all-cause or infection-related mortality but
AC
acknowledged that the quality of the evidence was very low to low. [143] The lack of consistent evidence has been suggested to result from difficulty in obtaining a sufficient number of granulocytes to provide efficacy and from low enrollment resulting in under-powered studies. For example, the Resolving Infection in Neutropenia with Granulocytes (RING) trial, which studied the efficacy of G-CSF/dexamethasone-mobilized granulocyte
ACCEPTED MANUSCRIPT transfusion in neutropenic patients on chemotherapy with infection, noted no difference in outcome between the treatment group compared to the control group. However, a secondary analysis showed that patients receiving higher
T
doses (0.6 x 109/kg) had a statistically significant better outcome in terms
IP
of clinical course and survival, although the study was statistically
CR
underpowered. [141] A recent review also notes these concerns, concluding
US
that despite conclusive evidence of improvement in clinical outcomes following granulocyte transfusion, this is largely due to low clinical trial
AN
enrollment, and concludes granulocyte transfusions are critical in supporting
M
neutropenic patients with life-threatening bacterial or fungal infections.
ED
[144] Similarly a review by West et al. of granulocyte transfusions in
PT
neutropenic patients recognizes the potential benefit of granulocyte transfusions in select circumstances however recommends against routine
CE
granulocyte transfusions in neutropenic patients with localized fungal
AC
infection due to the significant risk posed to patients. [140]
6.3.
Adverse effects
Adverse effects from granulocyte transfusions include febrile reactions, severe pulmonary complications, hypoxia, hypertension, and HLA
ACCEPTED MANUSCRIPT alloimmunization. Granulocyte transfusions also pose a risk of TTI, with
T
CMV transmission of particular concern in immunosuppressed populations.
CR
IP
7. Further processing
US
Blood products are frequently modified to prevent adverse transfusion reactions. Common processing steps of products for transfusion include
AN
leukocyte reduction, irradiation and washing. New technologies to prevent
M
pathogen transmission including solvent-detergent treatment and pathogen
ED
inactivation technologies have been developed, however safety and efficacy
CE
Leukocyte reduction
AC
7.1.
PT
considerations remain and surveillance is ongoing. [147]
Leukocyte reduction involves the removal of white blood cells (WBC) from blood components though filtration or during apheresis collection. The purpose of leukocyte reduction is to prevent adverse effects of leukocytes in transfused blood components. The majority (>90%) of RBCs and platelets in the U.S. are leukocyte reduced. [12] Established clinical benefits of
ACCEPTED MANUSCRIPT leukocyte reduction include decreasing FNHTRs [88, 148, 149], preventing HLA alloimmunization[150], and reducing CMV transmission. [151] As CMV is a highly cell-associated virus, removing the WBCs in blood
T
components helps prevent transfusion transmission. [152] Similarly, as HLA
IP
antigens are found on leukocytes, decreasing the concentration of WBCs
CR
reduces the likelihood of HLA alloimmunization. [150] The proposed
US
principal mechanisms for FNHTRs include immune (antibody-mediated) and non-immune etiologies (biologic response mediators). The immune
AN
mechanism involves recipient anti-HLA or anti-HNA reacting with donor
M
WBCs leading to an antigen-antibody reaction accompanied by release of
ED
inflammatory molecules.(see Figure 1) [153] The non-immune mechanism is caused by buildup of cytokines released from WBCs during storage which
PT
act on the hypothalamus to induce febrile symptoms. [153,
CE
154]Leukoreduced components, therefore, cause FNHTRs much less often
AC
than non-leukoreduced components. Leukocyte reduction is not indicated for prevention of TA-GVHD.
7.2.
Irradiation
ACCEPTED MANUSCRIPT Irradiation of cellular blood components delivers 2500 cGy to the product which prevents proliferation of viable T-lymphocytes by causing DNA damage and preventing replication. Irradiation is indicated for the prevention
T
of TA-GVHD. [18, 155] Populations at risk of TA-GVHD include
IP
immunosuppressed patients (due to HSCT or various drug regimens),
CR
recipients of neonatal exchange or intrauterine transfusions, and recipients of
US
blood components from blood relatives or in a population with limited HLA diversity. [155] Accordingly, irradiation of cellular blood components is
AN
indicated for recipients of allogeneic HSCT, transfusion between blood
M
relatives, immunosuppressed patients, intrauterine transfusions and
PT
Washing
CE
7.3.
ED
premature neonates.
AC
Washing of cellular blood components removes the majority of plasma proteins, electrolytes and antibodies, which can be implicated in transfusion reactions, notably allergic/anaphylactic reactions. Washing of cellular products is indicated in patients with repeated and/or severe allergic reactions, those at risk of hyperkalemia, and patients with documented IgA deficiency if blood components from an IgA deficient donor are unavailable.
ACCEPTED MANUSCRIPT [18, 155] While washing is a very effective strategy for preventing allergic reactions with up to a 95% reduction in incidence of allergic reactions to platelet components, [156] a disadvantage is that it can result in substantial
Volume reduction
US
CR
7.4.
IP
T
loss of product.
Volume reduction removes plasma and additive solutions by centrifugation.
AN
It is indicated to manage volume in recipients at risk of transfusion-
M
associated circulatory overload, such as patients with cardiac dysfunction. It
ED
also reduces exposure to plasma proteins which can prevent adverse transfusion events such as allergic reactions, FNHTRs and ABO
CE
PT
incompatibilities. [157, 158]
AC
7.5. Platelet Additive Solution (PAS)
Apheresis platelets can be stored in Platelet Additive Solution (PAS), an isotonic solution composed of varying electrolyte composition (see table 3). There are two approved PAS solutions in the U.S., InterSol® and IsoplateTM. Storage in PAS reduces 65% of the plasma used to store apheresis platelets.
ACCEPTED MANUSCRIPT Allergic transfusion reactions are thought to be due to allergenic proteins in plasma, therefore reduction of plasma volume should decrease allergic reactions. [159] [156] Storage in PAS presents an alternative to 100%
T
plasma storage. Similar to the reduction in transfusion reactions seen with
IP
plasma reduction by washing or volume, storage in PAS has been shown to
CR
reduce allergic reactions[159, 160] and in some studies, febrile reactions,
US
[159, 161] although this has not been seen in all studies. [160] Table 3. Composition of various platelet additive solutions PAS-D Citrate Acetate Magnesium Potassium Gluconate
PAS-E Citrate Phosphate Acetate Magnesium Potassium
AN
PAS-C* Citrate Phosphate Acetate
M
PAS-B Citrate Acetate
ED
PAS-A Citrate Phosphate Potassium
PAS-F† Acetate Magnesium Potassium Gluconate
PAS-G Citrate Phosphate Acetate Magnesium Potassium Glucose
CE
PT
* Approved in the US as Intersol® † Approved in the US as Isoplate TM
Partly based on: Ringwald J, Zimmermann R, Eckstein R. The new generation of platelet additive
AC
solution for storage at 22 degrees C: development and current experience. Transfus Med Rev. 2006;20:158-64.
7.6.
Solvent-Detergent treatment
Solvent-detergent (S/D) treatment (Octaplas, Pooled Plasma, Octapharma USA) [161] is a method used in the manufacture of plasma derivatives that
ACCEPTED MANUSCRIPT inactivates lipid-enveloped pathogens by disrupting cellular membranes and inhibiting DNA replication. Octaplas is manufactured from a pool of 630 to 1520 individual donors of a single ABO blood group (A, B, AB, or O). The
T
pooled product is treated with S/D reagents [1% tri-n-butyl phosphate
IP
(TNBP) and 1% octoxynol] for 1 to 1.5 hours at 30°C to inactivate
CR
enveloped viruses. Octaplas treatment is not effective against non-enveloped
US
viruses such as human parvovirus B19 and hepatitis E, therefore the manufacturing plasma pool is tested for these pathogens. Octaplas contains
AN
comparable levels of coagulation factors to healthy blood donors except
M
protein S and alpha-2-antiplasmin, which are decreased due to the solvent
ED
detergent treatment. It is indicated for the replacement of multiple coagulation factors in patients with acquired deficiency due to liver disease
PT
and those undergoing cardiac surgery or liver transplant, and for plasma
CE
exchange in patients with TTP. Studies in these patient populations have
AC
demonstrated comparable hemostatic and coagulation parameters as conventional plasma products. It is contraindicated in patients with IgA deficiency or severe deficiency of Protein S. Transfusion reactions can occur with ABO group mismatches, therefore the product should be ABO compatible with the patient.
ACCEPTED MANUSCRIPT 7.7.
Pathogen reduction
An FDA approved pathogen inactivation method available in the U.S. for platelets and plasma is Amotosalen (S-59, psoralen derivative) and
T
photoactivation by UVA light (INTERCEPT blood system, Cerus
IP
Corporation). [156] INTERCEPT treatment is a photochemical process in
CR
which amotosalen (S-59), a chemical that binds nucleic acids, is added to the
US
platelet or plasma component; subsequent UVA illumination results in covalent cross-linking of amotosalen-bound nucleic acids, preventing
AN
replication. The Intercept blood system for plasma is intended to reduce the
M
risk of transfusion-transmitted infection (TTI) in Whole Blood-derived or
ED
apheresis plasma or apheresis platelets. Non-enveloped viruses (e.g. hepatitis A, Hepatitis E, Parvovirus B19, poliovirus) and Bacillus cereus spores are
PT
resistant to INTERCEPT treatment. Two cases of hepatitis E transmission by
CE
INTERCEPT-treated plasma have been reported. [162] These components
AC
are contraindicated in patients with hypersensitivity to amotosalen or other psoralens or neonates treated with phototherapy devices emitting certain wavelengths. [156] Other pathogen inactivation technologies such as riboflavin plus UV light are available and used internationally but are not currently approved in the U.S.
ACCEPTED MANUSCRIPT 8. Blood bank laboratory testing
The blood bank performs pretransfusion testing to determine serologic
T
compatibility between the recipient and the donor. Pretransfusion testing of
IP
patients receiving allogeneic blood includes typing for ABO and Rh and
CR
performing an antibody screen to detect unexpected antibodies to red cell
US
antigens. The ABO group is determined by testing red cells with anti-A and anti-B reagents and testing the serum or plasma with A1 and B reagent red
AN
cells. Rh type is determined using anti-D reagent. The antibody screen is an
M
indirect antiglobulin test (IAT) comprised of commercial red blood cells
ED
from two to three type O donors who in sum express the most common clinically significant red cell antigens. When clinically significant antibodies
PT
are detected, further evaluation is required for antibody identification.
CE
Antibody identification is performed using commercial kits consisting of
AC
panels of phenotyped donor cells. The final step to ensure compatibility is a crossmatch, performed by direct agglutination (“immediate spin”) in the absence of clinically significant antibodies, or by the antiglobulin technique in the presence of a positive antibody screen.
8.1.
Interference with serological testing
ACCEPTED MANUSCRIPT
Recent innovative immunotherapies, while providing revolutionary advances in patient care, have led to complications in blood bank testing. Immunotherapy involves the use of humanized monoclonal antibodies to
IP
T
target malignant cells for destruction in coordination with the patient’s
CR
immune system. [163] [164, 165] Monoclonal antibodies can cause
US
interference in ABO and Rh typing, antibody detection and identification. Daratumumab (DARZALEX, Janssen Biotech, Inc.) is a human IgG1k
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monoclonal antibody directed against the CD38 antigen expressed on the
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surface of hematopoietic cells, particularly malignant myeloma cells and
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plasma cells. [166, 167] Daratumumab also targets CD38 expressed on RBCs, resulting in a false positive IAT that affects antibody screens,
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antibody identification panels and IAT crossmatch. The interference can last
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up to 6 months and can prevent antibody detection. ABO/Rh testing
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however is not affected. [168, 169] [170] Denaturing of CD38 with dithiothreitol (DTT) has been shown to successfully allow for subsequent antibody testing. [169-171] Trypsintreated reagent RBCs or CD38-negative RBCs can also be used. [172] Additional mitigation strategies are currently under investigation. [172-174]
ACCEPTED MANUSCRIPT Future CD38 antibody therapies are in development, which may require ongoing evaluation and adjustments in blood bank testing. [169, 175] Anti-CD47 (Hu5F9-G4) is a recently developed monoclonal IgG4
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antibody undergoing clinical trials for treatment of both hematologic and
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solid malignancies. CD47 is a glycoprotein expressed on all cells which
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prevents phagocytosis through interactions with the macrophage receptor
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SIRP. Anti-CD47 can block this signal, allowing for the destruction of certain cancer cells, such as leukemic blasts. [176, 177] A recent study
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investigated the interference of anti-CD47 in pre-transfusion serological
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testing using samples from four patients on anti-CD47 therapy[165] and
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showed that anti-CD47 interfered with all phases of pretransfusion antibody
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screening and crossmatch, including ABO reverse typing. The interference could not be mitigated with DTT or other commonly used denaturing
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enzymatic agents. The most effective solution was to perform multiple RBC
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alloadsorptions with papain-treated RBCs and use monoclonal Gammaclone (Immucor) anti-IgG (which does not detect IgG4 subclass antibodies) in IAT testing. This testing strategy is labor-intensive and not cost effective, and therefore further investigation will be required into feasible testing strategies for patients on anti-CD47 therapy. As monoclonal antibody therapies continue to emerge as transformative therapeutic agents, blood
ACCEPTED MANUSCRIPT bank testing paradigms will face an evolving challenge requiring novel approaches.
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9. New and re-emerging products for transfusion
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Since the late 1900s, blood component therapy has been the standard of care
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in transfusion medicine and the driving principle behind the operation of laboratory blood banks. [178] [179] Innovations in refrigerated storage of
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blood components, improved design of blood bags and storage containers,
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preservative and anticoagulation solutions, in concert with product screening
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and donor testing have driven the widespread implementation of component therapy and improved product quality. However, the most common blood
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components for transfusion, (e.g. RBCs, platelets and plasma), require
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specific storage conditions and have limited shelf lives. Processing steps
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may include freezing and thawing for products such as plasma or cryoprecipitate, potentially leading to delays in providing blood for patients requiring urgent transfusions, while platelets require storage at room temperature which shortens the shelf-life to 5-7 days due to concerns of bacterial contamination. These limitations are particularly pronounced on the
ACCEPTED MANUSCRIPT battlefield where urgently needed blood products have to be transported and short product shelf-lives are prohibitive. [180] In consideration of the limitations of currently available products for
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transfusion, recent attention has focused on new products and strategies for
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transfusion. There has been a resurgence of interest in the use of WB for
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trauma resuscitation, a commonly transfused product from World War I until
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the 1970s. [180] Proponents of WB cite benefits of immediate availability, balanced resuscitation without the dilutional factors of anticoagulant
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preservative solutions, increased storage, and hemostatic efficacy.
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Observational studies of civilian patients receiving cold stored low
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isohemagglutinin titer group O Whole Blood (LTOWB) have shown no differences in clinical outcomes in patients receiving conventional
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component therapy compared to LTOWB, with a trend toward lower
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mortality in the LTOWB group. [181]
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With the recognition of the hemostatic efficacy of cold-stored platelets (CSP) contained in WB, platelets stored at 4°C have emerged as a potentially beneficial product. CSP were used commonly until 1969, when data showed they were more rapidly cleared from circulation than room temperature platelets, at which time room temperature platelets became more widely used, although CSP use continued until the early 1980s . [178]
ACCEPTED MANUSCRIPT Although CSP have documented lower recovery and survival, lower yields, and morphologic changes, they have an activated profile, which may result in greater hemostatic efficacy as compared to room temperature platelets,
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especially in acutely bleeding platelets. [182] CSP can also potentially be
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stored for longer periods and have decreased risk of bacterial contamination.
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A Norwegian study of transfusion of 4°C-stored platelets stored for up to 7
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days compared to room temperature platelets stored for up to 7 days in patients undergoing cardiothoracic surgery found no difference in mortality,
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number of thromboembolic events, or length of stay in the ICU, with
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decreased bleeding in the CSP group. [183]
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In addition to CSP, other novel products under development include lyophilized and cryopreserved platelets, [97, 184]freeze dried (lyophilized)
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plasma[185], and hemoglobin substitutes. [186] Although pre-clinical trials
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show promising results, large clinical trials are needed to provide evidence
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of safety and efficacy.
10. Special topics
10.1.
Vein-to-Vein Hemovigilance
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Hemovigilance has been defined as “a set of surveillance procedures covering the whole transfusion chain (from the collection of blood and its
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components to the follow-up of recipients), intended to collect and assess
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information on unexpected or undesirable effects resulting from the
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therapeutic use of labile blood products, and to prevent their occurrence or
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recurrence”.[187] The objective of hemovigilance is to monitor the entire
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vein-to-vein process of transfusion from the selection of donors to posttransfusion outcomes in patients.[188] Hemovigilance programs collect a
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range of transfusion-related outcomes data which can be broadly grouped
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into blood collection, preparation for transfusion, and post-transfusion
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monitoring. In blood collection, the focus is on donors and includes monitoring infectious disease marker rates, adverse events during and after
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collection, and longer-term monitoring of donor health status, such as iron
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depletion. The focus of preparation for transfusion is on use of proper patient and unit identification procedures and laboratory testing for typing and cross-matching, where process mistakes such as labeling errors can lead to “wrong blood in tube” and other preventable errors that present serious and potentially fatal risks to transfusion recipients. In post-transfusion monitoring, the focus is on proper infusion of each component and
ACCEPTED MANUSCRIPT monitoring for signs of potential transfusion reactions that can range from mild to severe, including mortality. When adverse events occur during the transfusion chain, investigations are triggered to establish the degree to
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which causality can be linked to transfusion using imputability criteria. In
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the U.S., donor and recipient fatalities are required to be reported to the
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FDA. Categories from the FDA fatality reporting classification system
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include: definite/certain, probable/likely, possible,
doubtful/unlikely/improbable, ruled out/excluded, or not
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determined/assessable/evaluable. In fiscal year 2016, of the 67 potential
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transfusion-associated fatality reports in the U.S., 43 (64%) were classified
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as either definite/certain, probable/likely or possible, 17 (25%) were classified as either doubtful/unlikely/improbable or not
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determined/assessable/evaluable, and 7 (11%) were classified as ruled
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out/excluded.[189] Causes of fatalities were distributed among allergic
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reactions/anaphylaxis, transfusion associated circulatory overload (TACO), transfusion related acute lung injury (TRALI), ABO-incompatible hemolytic transfusion reactions (HTR), and transfusion-transmitted infections. However, in the U.S. and some other countries reporting of non-fatal adverse events to surveillance and regulatory agencies may be voluntary, raising the important concern of underreporting. Fatalities are known to be
ACCEPTED MANUSCRIPT the proverbial tip of the iceberg with morbidity and near misses thought to be at least two orders of magnitude more common. Hemovigilance programs are implemented in a range of data
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collection approaches in different jurisdictions. The most intensive program
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is active surveillance of transfusion recipients for any sign of risk and
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clinical outcome. Active hemovigilance programs are uncommon because of
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the expense of implementing such programs. However, they provide the highest quality evidence on adverse event rates, due to the collection of data
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on all patients, including those who do and do not experience adverse
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events. Passive hemovigilance programs similarly seek to assess patient risk
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but do so by relying on the reporting of transfusion-related events only in those patients where an adverse event was identified. These data are then
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related back to the overall transfused population to establish rates of adverse
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events. As adverse event reporting is highly variable, passive surveillance is
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less accurate than active surveillance. The serious hazards of transfusion (SHOT) program in the UK provides data showing both preparation for transfusion, and post-transfusion monitoring demonstrate continued need to reduce patient risks. These data consistently show near misses, errors, and adverse events throughout the entire transfusion chain.[139, 190] In the U.S. about 6% of transfusing facilities participate in the National Healthcare
ACCEPTED MANUSCRIPT Safety Network hemovigilance program which has established a common protocol for assessing events.[191] The low participation of acute care facilities indicates that the overall system representation remains
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Palliative transfusion of blood products
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10.2.
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insufficient.
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Despite reports of improvement in survival associated with palliative care, as few as 2% of patients with hematologic malignancies use hospice, [192-195]
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and when they do get referred to hospice, the referral often comes within
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days of death. [194] [196] In a review of over 48,000 cancer patients
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admitted to hospice, those patients with hematological malignancies were more likely to die within 24 hours of hospice enrollment (10.9% vs 6.8%,
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odds ratio 1.66, p<0.001) or within 7 days (36% vs 25.1%, odds ratio 1.68,
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p<0.001) compared to solid tumor patients. [193, 196] As noted in the recent American Society of Hematology survey, lack of transfusion capability was the major barrier to referral of these patients leading to delayed enrollment in hospice. [197-199] The standard practice of hospice services requiring revocation of blood transfusions upon enrollment in this largely transfusion dependent population has created a system that prevents referral of patients
ACCEPTED MANUSCRIPT with hematologic malignancies from receiving palliative care/hospice care in the home. [198, 200] Review of available literature shows transfusions can improve symptoms [201] and provide palliative benefits to these patients,
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hence improving their quality of life despite poor prognosis. [198] Twelve
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before- and after-transfusion studies showed subjective response rates in the
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30-70% range. [202] In a recent study, approximately 80% of patients
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derived symptomatic benefit from symptoms such as fatigue, breathlessness, generalized weakness and dizziness. [201] Patients identify benefit from
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transfusions through home hospice or hospital based systems. [203]
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Increasingly, hematologists have identified that increased access to hospice
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care is necessary for good patient care in patients with hematologic malignancies. Moreover, more than half of hematologist-oncologists are
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likely to increase utilization of hospice for these patients if blood and
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platelet transfusions are provided.
Further barriers to transfusions exist with both cost and logistics of transfusions on hospice. While technically covered by the Medicare hospice benefit, in reality many hospices do not provide transfusions because of lack of adequate reimbursement and logistical capability of in-home transfusions or transporting patients to clinics. Data for safety of in-home transfusions
ACCEPTED MANUSCRIPT exists and is surprisingly long. Transfusion of products for patients with hemophilia [204] dates back to 1972, whereas home-based transfusion strategies of blood products for cancer patients have been safely employed
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by home health agencies in the U.S. since the 1980s. Reactions are noted to
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be minimal with only 1 in 1060 transfused products with a home health
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agency over 5 years, [205] and 1 in 415 in one center’s experience in cancer
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patients. [206] France set forth a dedicated study to evaluate transfusion risk in home-based settings as well as the economic and global health benefits to
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the healthcare system in providing care in the home. It was noted that
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minimal reactions were found, with only 3 mild transfusion related reactions
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in one group of 757 infusions, [207] and in another group only one transfusion event in 148 transfusions. [208] All studies identified that
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structural systems needed to be in place to provide for home-based
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transfusions, but once in place, could safely provide care. [205, 206, 209]
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Transfusion support has the potential to improve the quality of life in patients with terminal malignancies once data for the logistic and safety considerations are adequately embraced by the hematology community.
10.3.
Health economics/cost effectiveness
ACCEPTED MANUSCRIPT The role of health economics in transfusion medicine is controversial because of the complex issues related to society’s expectation that blood products are safe for recipients coupled with the fact that all safety measures
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cannot be implemented due to budget constraints. While no resolution of this
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controversy is expected in the immediate future, health economics is an
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important part of the overall evidence base for blood safety and transfusion
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medicine interventions. Healthcare policy decision makers must consider two broad objectives related to economics. The first is to remain within
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available finances or budgets and the second is to maximize health benefits
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at attainable costs.[210] These two objectives do not necessarily lead to
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consistent decisions or policy. Decision making that stays within the available budget may not maximize health benefits to the transfused
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population. Whereas alternately, attempting to maximize health benefits at
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attainable costs requires making difficult choices between interventions,
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including not selecting options that may be most effective and forgoing the health benefits that could be achieved. Budget impact analysis provides information in a balance-sheet format
of costs and cost savings for the implementation or maintenance of a healthcare intervention over a time period of usually one to five years. Costeffectiveness is an assessment of the ratio of costs to benefits, comparing at
ACCEPTED MANUSCRIPT least two different interventions. [211] Results are often reported as cost per quality-adjusted life year (QALY). Blood safety measures have been shown to exceed traditional thresholds of acceptable costs when compared to other
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interventions in health and medicine. A standard threshold is $50,000-
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$100,000-per quality adjusted life year (QALY) gained. In blood safety,
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cost-effectiveness of adopted interventions frequently exceeds thresholds of
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$1,000,000/QALY. Some have proposed that the adoption of Zika virus testing of donations in 2016 represents an example of inefficient use of
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resources because the risk of transfusion-transmitted Zika virus in the U.S.
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was small and subsequently has further decreased;[212] however at the time
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it was unknown how rapidly the epidemic might spread or potential modes of transmission. Due to these factors and the extreme devastation of
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infection, particularly in neonates, policy was implemented to avert such
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consequences. This policy has subsequently been reconsidered in light of
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recent epidemiologic data. [213] Cost-effectiveness analyses of newer interventions, e.g. pathogen
inactivation, have been applied to assess the economic value of such interventions in different patient populations.[214-216] The health economics of pathogen inactivation for platelets and plasma in the U.S. continues to be one of the barriers to broader adoption. Budget impact
ACCEPTED MANUSCRIPT analyses focused on the cost offsets that can be achieved are being published and such analyses are expected to increase in the near future. [217, 218] The totality of the evidence suggests that shifts in the approach to reimbursement
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for use of pathogen inactivation may be necessary before wider adoption is
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possible.
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Within the domain of patient transfusion, assessment of adopted
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interventions tends to better conform to the standard threshold. Many different analyses have been conducted, for example, the health economics
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of adopting patient blood management programs and the use of cell salvage
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or tranexamic acid to reduce allogeneic blood exposure.[219-223] Studies
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have defined the totality of costs that accrue in the transfusion chain and how alternative approaches may achieve additional health benefits at
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reduced total cost of care and reduced blood exposure. However, studies
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defining the cost-effectiveness of commonly transfused components (RBC,
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platelets, FFP/FP24, etc.) derived from donated blood are limited because of the challenge of completing such studies for the range of indications for which patients are transfused.
11. New safety considerations
ACCEPTED MANUSCRIPT 11.1.
Risk Based Decision Management (RBDM)
The paradigm for system-level decision making in blood safety has received
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scrutiny in the past decade. The concept of the precautionary principle, its
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meaning, and how it defines or mischaracterizes risk tolerability has been
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the source of significant debate in transfusion medicine.[224] An
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international consensus conference held in 2010 to define a Risk-Based Decision Making (RBDM) framework was borne out of the objective to
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provide a structured, consistent process for evaluating and making blood
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safety decisions.[225, 226] The framework is a comprehensive tool that
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links separate lines of evidence together to help decision makers choose proportionate responses to different blood safety threats. The concept of
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proportionate response requires the acceptance that all risks cannot be
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prevented and approaches can be used to define the tolerability of each
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separate risk. RBDM is based on four policy foundations: risk management principles, risk communication and stakeholder participation, assessment principles, and risk tolerability.[227] Ways in which these foundations are defined and how they are incorporated into the process will vary among jurisdictions.
ACCEPTED MANUSCRIPT The framework segments the process into six steps: preparation, problem formulation, participation strategy, assessments, evaluation, and decision. Each step has defined activities, expectations for information that is
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generated, and recommended methods. Preparation and problem formulation
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are not considered trivial, and the careful definition of the exact problem or
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decision that is being faced is a critical part of process. As part of each
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RBDM assessment, specific analytical approaches are recommended in the domains of risk, health economics and outcomes, and social concern. These
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findings are then used to evaluate and choose a course of action for threat or
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problem. Uptake of the RBDM framework has expanded and several
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jurisdictions have published assessments covering a range of topics initially focused on infectious threats in transfusion, including Babesia, malaria and
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HTLV.[228-230] The use of the framework in patient safety considerations
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beyond infectious threats is possible, but to date examples of the use of the
11.2.
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framework beyond infectious threats have not been published.
Bacterial testing of platelets
Room temperature storage of platelets allows initial small bacterial loads to increase to very high inocula, which has limited storage time to 5-7 days and
ACCEPTED MANUSCRIPT necessitated testing for bacterial contamination or use of pathogen reduction technology. [63] Bacterial species associated with contaminated platelets include Gram negative species (e.g., Pseudomonas aeruginosa and
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Enterobacteriaceae) and Gram positive species (e.g., Staphylococcus aureus,
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other Staphylococcus species, Bacillus species and Streptococcus species).
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STR are predominantly associated with transfusion of platelets contaminated
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with bacterial loads above 105 CFU/mL, with more virulent bacterial species (Gram negatives and Staphylococcus aureus) also associated with more
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severe STR. [231]
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In the US testing for bacterial contamination was mandated by AABB in
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2004 and was generally implemented by culture of products 24-36 hours after collection using BacT/ALERT or eBDS systems. [232] Under 21 CFR
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606.145(a), effective March 23, 2016, blood collection establishments and
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transfusion services must assure that the risk of bacterial contamination of
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platelets is adequately controlled using FDA approved or cleared devices, or other adequate and appropriate methods found acceptable for this purpose by FDA. [233]This requirement currently can be met with either bacterial testing or pathogen reduction performed with an FDA-approved pathogen reduction device. [63] As noted above, pathogen reduction of apheresis platelets using amotosalen was approved for use in the US in 2014, and this
ACCEPTED MANUSCRIPT process is increasingly being used. [63] [154] However, despite use of culture since 2004, STR and fatalities, while reduced, continued to occur. Ten fatalities from bacterial contamination of platelet products during the 5-
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year period 2012-2016 were reported to FDA (a rate of approximately 1 per
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million platelet transfusions), 8 associated with apheresis and 2 with pooled
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platelets. [60] Thirty STR from bacterial contamination of platelet products
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during the 7-year period 2010-2016 were reported by the NHSN Hemovigilance Module from 308 facilities (a rate of 19.5 per million platelet
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transfusions), with 26 associated with apheresis and 4 with WB platelets
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(rates of 24 and 8.6 per million, respectively). [234] Considerably higher
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rates of STR have been reported from active surveillance programs: 97 per million by active bacterial surveillance during 2007-2013[235] and 38 per
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million by active clinical surveillance during 2009-2016. [61]
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Various solutions to enhance the safety and availability of platelets for
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transfusion and further reduce STR have been proposed. These solutions include methods to allow platelet storage for up to 5 days or 7 days. Proposed methods for 5-day storage include primary culture followed by secondary culture or secondary rapid testing and pathogen reduction technology. Pathogen reduction technology is not currently approved for 7day storage. For 7-day storage, proposed methods similarly include primary
ACCEPTED MANUSCRIPT culture followed by secondary culture or rapid testing as well as a large volume delayed sampling protocol. [236]
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12. Summary and future considerations
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Transfusion of blood products constitutes a critical component of medical
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care, and is among the most common procedures in hospitalized patients. [3]
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The current era of transfusion medicine is built on a robust historical legacy, which has facilitated its continuing evolution and advancement. [4] Recent
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innovations in transfusion medicine research have redefined the paradigms
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guiding transfusion practice, moving away from standard laboratory triggers
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as the basis for transfusion towards a wholistic consideration of patientspecific factors. While blood transfusion continues to be recognized as a
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life-saving and crucial therapy, increasing evidence points to the benefit of
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limiting unnecessary transfusions, both for avoidance of adverse outcomes and from a cost perspective. The development of patient blood management programs, which focus on patient safety, adherence to guidelines, and consideration of transfusion alternatives, has facilitated the implementation of recommended preventive measures to improve patient safety. New developments in transfusion medicine focus on innovative blood products
ACCEPTED MANUSCRIPT such as cryopreserved platelets and lyophilized plasma that can overcome the limitations of currently available therapies to provide greater
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accessibility and improved quality and availability.
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Practice points * Unnecessary transfusions should be avoided
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* Platelets should be provided prophylactically at a transfusion threshold of <10 x 109/L in patients at risk of bleeding
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* Therapeutic platelet transfusion strategies should be used in non-bleeding patients not at high risk of bleeding
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* Plasma should not be transfused to correct minor abnormalities in coagulation tests as a preventive measure. Plasma should not be transfused for an INR ≤ 2
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* Patient blood management programs can improve patient safety, reduce unnecessary transfusions and provide cost savings
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* Structured evaluation approaches for blood and patient safety are being adopted to facilitate enhanced use of evidence-based practice in transfusion
Research agenda * Studies of hemoglobin thresholds in additional patient subgroups, such as pediatric and neonatal patients, patients on extracorporeal support, and patients with myocardial infarction and acute coronary syndrome to
ACCEPTED MANUSCRIPT determine conclusively if there is an adverse effect of a restrictive RBC transfusion strategy in these populations * Development of new technologies to refine the decision making process for RBC transfusion, such as non-invasive methods of directly assessing tissue oxygenation
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* Investigation of the effects of storage on RBCs and the appropriate storage age for transfusion, as well as possible mitigation of the deleterious effects of storage
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*Development of a viable oxygen therapeutic to replace human RBC transfusion
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* Continuing research into appropriate transfusion parameters for all blood components particularly cryoprecipitate for which there is less available information in order to formulate guidelines
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* Transfusion approach to hemorrhagic shock and massive trauma
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* Further evaluation of a possible association between donor characteristics, (e.g. age, sex, prior pregnancy), and recipient transfusion outcomes
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* Development of a robust in vitro test that will accurately and reliably predict post-transfusion platelet recovery and survival
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* Continuing studies into new products such as cold stored platelets, freezedried plasma and lyophilized plasma to evaluate safety and efficacy * Development of new and advancing technologies, such as pathogen inactivation of whole blood to protect against emerging infectious diseases * Further analysis of health economics and cost-effectiveness in relation to blood safety and availability with consideration of approaches such as patient blood management and reduced RBC exposure that may achieve health benefits at lower cost
ACCEPTED MANUSCRIPT
Conflict of interest The author has no conflicts of interest to disclose.
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Acknowledgements We would like to acknowledge the contributions of Jennifer Holter-Chakrabarty, MD, University of Oklahoma, Rachel Cook, MD, MS, Oregon Health & Sciences University, and Sarah Holstein, MD, PhD, University of Nebraska on behalf of the ASH Government Affairs and Palliative Care Committee.
ACCEPTED MANUSCRIPT References
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1. Ellingson KD, Sapiano MRP, Haass KA, Savinkina AA, Baker ML, Chung KW, et al. Continued decline in blood collection and transfusion in the United States-2015. Transfusion. 2017;57 Suppl 2:158898. 2. Karafin MS, Bruhn R, Westlake M, Sullivan MT, Bialkowski W, Edgren G, et al. Demographic and epidemiologic characterization of transfusion recipients from four US regions: evidence from the REDS-III recipient database. Transfusion. 2017;57(12):2903-13. 3. Di Minno G, Navarro D, Perno CF, Canaro M, Gurtler L, Ironside JW, et al. Pathogen reduction/inactivation of products for the treatment of bleeding disorders: what are the processes and what should we say to patients? Ann Hematol. 2017;96(8):1253-70. 4. Farr AD. The first human blood transfusion. Med Hist. 1980;24(2):143-62. 5. Farr AD. Blood group serology--the first four decades (1900--1939). Med Hist. 1979;23(2):21526. 6. Landsteiner K. On agglutination of normal human blood. Transfusion. 1961;1:5-8. 7. Adams RC, Lundy, J.S. Anesthesia in cases of poor surgical risk. Some suggestions for decreasing the risk. Surg Gynecol Obstet. 1942;74:1011-19. 8. Madjdpour C, Spahn DR. Allogeneic red blood cell transfusions: efficacy, risks, alternatives and indications. Br J Anaesth. 2005;95(1):33-42. 9. Wang JK, Klein HG. Red blood cell transfusion in the treatment and management of anaemia: the search for the elusive transfusion trigger. Vox Sang. 2010;98(1):2-11. 10. Carson JL, Stanworth SJ, Roubinian N, Fergusson DA, Triulzi D, Doree C, et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2016;10:CD002042. 11. Roubinian N, Carson JL. Red Blood Cell Transfusion Strategies in Adult and Pediatric Patients with Malignancy. Hematol Oncol Clin North Am. 2016;30(3):529-40. 12. Whitaker BI, Kamani N. Surveys of blood collection and utilization. Transfusion. 2018;58(2):541-2. 13. Sapiano MRP, Savinkina AA, Ellingson KD, Haass KA, Baker ML, Henry RA, et al. Supplemental findings from the National Blood Collection and Utilization Surveys, 2013 and 2015. Transfusion. 2017;57 Suppl 2:1599-624. 14. Warner MA, Hanson AC, Weister TJ, Higgins AA, Madde NR, Schroeder DR, et al. Changes in International Normalized Ratios After Plasma Transfusion of Varying Doses in Unique Clinical Environments. Anesth Analg. 2018;127(2):349-57. 15. Waters JH, Yazer MH. The Mythology of Plasma Transfusion. Anesth Analg. 2018;127(2):338-9. 16. Whitaker B, Rajbhandary S, Kleinman S, Harris A, Kamani N. Trends in United States blood collection and transfusion: results from the 2013 AABB Blood Collection, Utilization, and Patient Blood Management Survey. Transfusion. 2016;56(9):2173-83. 17. Carson JL, Triulzi DJ, Ness PM. Indications for and Adverse Effects of Red-Cell Transfusion. N Engl J Med. 2017;377(13):1261-72. 18. Klein HG, Spahn DR, Carson JL. Red blood cell transfusion in clinical practice. Lancet. 2007;370(9585):415-26. 19. Friedman BA, Burns TL, Schork MA. An analysis of blood transfusion of surgical patients by sex: a question for the transfusion trigger. Transfusion. 1980;20(2):179-88. 20. Carson JL, Stanworth SJ, Alexander JH, Roubinian N, Fergusson DA, Triulzi DJ, et al. Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease. Am Heart J. 2018;200:96-101. 21. Cooper HA, Rao SV, Greenberg MD, Rumsey MP, McKenzie M, Alcorn KW, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol. 2011;108(8):1108-11.
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22. Lacroix J, Hebert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356(16):1609-19. 23. Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA, Angelini GD, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372(11):997-1008. 24. Cooper DJ, McQuilten ZK, Nichol A, Ady B, Aubron C, Bailey M, et al. Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults. N Engl J Med. 2017;377(19):1858-67. 25. Shehata N, Mistry N, da Costa BR, Pereira TV, Whitlock R, Curley GF, et al. Restrictive compared with liberal red cell transfusion strategies in cardiac surgery: a meta-analysis. Eur Heart J. 2018. 26. Villanueva C, Colomo A, Bosch A, Concepcion M, Hernandez-Gea V, Aracil C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11-21. 27. Mazer CD, Whitlock RP, Fergusson DA, Hall J, Belley-Cote E, Connolly K, et al. Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med. 2017;377(22):2133-44. 28. Docherty AB, O'Donnell R, Brunskill S, Trivella M, Doree C, Holst L, et al. Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis. BMJ. 2016;352:i1351. 29. Mazer CD, Whitlock RP, Fergusson DA, Belley-Cote E, Connolly K, Khanykin B, et al. SixMonth Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery. N Engl J Med. 2018;379(13):1224-33. 30. Carson JL, Brooks MM, Abbott JD, Chaitman B, Kelsey SF, Triulzi DJ, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. 2013;165(6):964-71 e1. 31. Roubinian NH, Murphy EL, Mark DG, Triulzi DJ, Carson JL, Lee C, et al. Long-Term Outcomes Among Patients Discharged From the Hospital With Moderate Anemia: A Retrospective Cohort Study. Ann Intern Med. 2018. 32. Koch CG, Li L, Sun Z, Hixson ED, Tang A, Chagin K, et al. Magnitude of Anemia at Discharge Increases 30-Day Hospital Readmissions. J Patient Saf. 2017;13(4):202-6. 33. Estcourt LJ, Malouf R, Trivella M, Fergusson DA, Hopewell S, Murphy MF. Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support. Cochrane Database Syst Rev. 2017;1:CD011305. 34. Stapley R, Owusu BY, Brandon A, Cusick M, Rodriguez C, Marques MB, et al. Erythrocyte storage increases rates of NO and nitrite scavenging: implications for transfusion-related toxicity. Biochem J. 2012;446(3):499-508. 35. Hess JR. Red cell changes during storage. Transfus Apher Sci. 2010;43(1):51-9. 36. Glynn SA. The red blood cell storage lesion: a method to the madness. Transfusion. 2010;50(6):1164-9. 37. D'Alessandro A, Liumbruno G, Grazzini G, Zolla L. Red blood cell storage: the story so far. Blood Transfus. 2010;8(2):82-8. 38. Roback JD. Vascular effects of the red blood cell storage lesion. Hematology Am Soc Hematol Educ Program. 2011;2011:475-9. 39. Roback JD, Neuman RB, Quyyumi A, Sutliff R. Insufficient nitric oxide bioavailability: a hypothesis to explain adverse effects of red blood cell transfusion. Transfusion. 2011;51(4):859-66. 40. Tinmouth A, Fergusson D, Yee IC, Hebert PC, Investigators A, Canadian Critical Care Trials G. Clinical consequences of red cell storage in the critically ill. Transfusion. 2006;46(11):2014-27. 41. Dhabangi A, Ainomugisha B, Cserti-Gazdewich C, Ddungu H, Kyeyune D, Musisi E, et al. Effect of Transfusion of Red Blood Cells With Longer vs Shorter Storage Duration on Elevated Blood Lactate Levels in Children With Severe Anemia: The TOTAL Randomized Clinical Trial. JAMA. 2015;314(23):2514-23. 42. Heddle NM, Cook RJ, Arnold DM, Liu Y, Barty R, Crowther MA, et al. Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion. N Engl J Med. 2016;375(20):1937-45.
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43. Steiner ME, Ness PM, Assmann SF, Triulzi DJ, Sloan SR, Delaney M, et al. Effects of red-cell storage duration on patients undergoing cardiac surgery. N Engl J Med. 2015;372(15):1419-29. 44. Lacroix J, Hebert PC, Fergusson DA, Tinmouth A, Cook DJ, Marshall JC, et al. Age of transfused blood in critically ill adults. N Engl J Med. 2015;372(15):1410-8. 45. Green RS, Erdogan M, Lacroix J, Hebert PC, Tinmouth AT, Sabri E, et al. Age of transfused blood in critically ill adult trauma patients: a prespecified nested analysis of the Age of Blood Evaluation randomized trial. Transfusion. 2018;58(8):1846-54. 46. Fergusson DA, Hebert P, Hogan DL, LeBel L, Rouvinez-Bouali N, Smyth JA, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA. 2012;308(14):1443-51. 47. Chai-Adisaksopha C, Alexander PE, Guyatt G, Crowther MA, Heddle NM, Devereaux PJ, et al. Mortality outcomes in patients transfused with fresher versus older red blood cells: a meta-analysis. Vox Sang. 2017;112(3):268-78. 48. Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, et al. Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA. 2016;316(19):2025-35. 49. Cook RJ, Heddle NM, Lee KA, Arnold DM, Crowther MA, Devereaux PJ, et al. Red blood cell storage and in-hospital mortality: a secondary analysis of the INFORM randomised controlled trial. Lancet Haematol. 2017;4(11):e544-e52. 50. Halmin M, Rostgaard K, Lee BK, Wikman A, Norda R, Nielsen KR, et al. Length of Storage of Red Blood Cells and Patient Survival After Blood Transfusion: A Binational Cohort Study. Ann Intern Med. 2017;166(4):248-56. 51. Shah A, Brunskill SJ, Desborough MJ, Doree C, Trivella M, Stanworth SJ. Transfusion of red blood cells stored for shorter versus longer duration for all conditions. Cochrane Database Syst Rev. 2018;12:CD010801. 52. Fernandes da Cunha DH, Nunes Dos Santos AM, Kopelman BI, Areco KN, Guinsburg R, de Araujo Peres C, et al. Transfusions of CPDA-1 red blood cells stored for up to 28 days decrease donor exposures in very low-birth-weight premature infants. Transfus Med. 2005;15(6):467-73. 53. Retter A, Wyncoll D, Pearse R, Carson D, McKechnie S, Stanworth S, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol. 2013;160(4):445-64. 54. Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172(2):187-207. 55. Pirenne F, Bartolucci P, Habibi A. Management of delayed hemolytic transfusion reaction in sickle cell disease: Prevention, diagnosis, treatment. Transfus Clin Biol. 2017;24(3):227-31. 56. Karafin MS, Tan S, Tormey CA, Spencer BR, Hauser RG, Norris PJ, et al. Prevalence and risk factors for RBC alloantibodies in blood donors in the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). Transfusion. 2019;59(1):217-25. 57. Karafin MS, Westlake M, Hauser RG, Tormey CA, Norris PJ, Roubinian NH, et al. Risk factors for red blood cell alloimmunization in the Recipient Epidemiology and Donor Evaluation Study (REDSIII) database. Br J Haematol. 2018;181(5):672-81. 58. Nahirniak S, Slichter SJ, Tanael S, Rebulla P, Pavenski K, Vassallo R, et al. Guidance on platelet transfusion for patients with hypoproliferative thrombocytopenia. Transfus Med Rev. 2015;29(1):3-13. 59. Schiffer CA, Bohlke K, Delaney M, Hume H, Magdalinski AJ, McCullough JJ, et al. Platelet Transfusion for Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2018;36(3):283-99. 60. Strauss RG. Role of granulocyte/neutrophil transfusions for haematology/oncology patients in the modern era. Br J Haematol. 2012;158(3):299-306. 61. Erony SM, Marshall CE, Gehrie EA, Boyd JS, Ness PM, Tobian AAR, et al. The epidemiology of bacterial culture-positive and septic transfusion reactions at a large tertiary academic center: 2009 to 2016. Transfusion. 2018;58(8):1933-9.
ACCEPTED MANUSCRIPT
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62. Horth RZ, Jones JM, Kim JJ, Lopansri BK, Ilstrup SJ, Fridey J, et al. Fatal Sepsis Associated with Bacterial Contamination of Platelets - Utah and California, August 2017. MMWR Morb Mortal Wkly Rep. 2018;67(25):718-22. 63. Bacterial Detection Testing by Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion. US Food and Drug Administration;https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator yInformation/Guidances/Blood/UCM627407.pdf. 64. Blajchman MA, Slichter SJ, Heddle NM, Murphy MF. New strategies for the optimal use of platelet transfusions. Hematology Am Soc Hematol Educ Program. 2008:198-204. 65. Cooling L. ABO and platelet transfusion therapy. Immunohematology. 2007;23(1):20-33. 66. Kaufman RM. Platelet ABO matters. Transfusion. 2009;49(1):5-7. 67. Stanworth SJ, Estcourt LJ, Powter G, Kahan BC, Dyer C, Choo L, et al. A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med. 2013;368(19):1771-80. 68. Wandt H, Schaefer-Eckart K, Wendelin K, Pilz B, Wilhelm M, Thalheimer M, et al. Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet. 2012;380(9850):1309-16. 69. Crighton GL, Estcourt LJ, Wood EM, Trivella M, Doree C, Stanworth S. A therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. Cochrane Database Syst Rev. 2015(9):CD010981. 70. Estcourt LJ, Desborough M, Hopewell S, Trivella M, Doree C, Stanworth S. Comparison of different platelet transfusion thresholds prior to insertion of central lines in patients with thrombocytopenia. Cochrane Database Syst Rev. 2015;2015(6). 71. Estcourt LJ, Malouf R, Doree C, Trivella M, Hopewell S, Birchall J. Prophylactic platelet transfusions prior to surgery for people with a low platelet count. Cochrane Database Syst Rev. 2018;9:CD012779. 72. Estcourt LJ, Malouf R, Hopewell S, Doree C, Van Veen J. Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia. Cochrane Database Syst Rev. 2018;4:CD011980. 73. Malouf R, Ashraf A, Hadjinicolaou AV, Doree C, Hopewell S, Estcourt LJ. Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders. Cochrane Database Syst Rev. 2018;5:CD012342. 74. Crighton GL, Estcourt LJ, Wood EM, Stanworth SJ. Platelet Transfusions in Patients with Hypoproliferative Thrombocytopenia: Conclusions from Clinical Trials and Current Controversies. Hematol Oncol Clin North Am. 2016;30(3):541-60. 75. Stanworth SJ, Estcourt LJ, Llewelyn CA, Murphy MF, Wood EM, Investigators TS. Impact of prophylactic platelet transfusions on bleeding events in patients with hematologic malignancies: a subgroup analysis of a randomized trial. Transfusion. 2014;54(10):2385-93. 76. Estcourt LJ, Stanworth S, Doree C, Trivella M, Hopewell S, Blanco P, et al. Different doses of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. Cochrane Database Syst Rev. 2015(10):CD010984. 77. Slichter SJ, Kaufman RM, Assmann SF, McCullough J, Triulzi DJ, Strauss RG, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med. 2010;362(7):600-13. 78. Estcourt LJ, Stanworth SJ, Doree C, Hopewell S, Trivella M, Murphy MF. Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. Cochrane Database Syst Rev. 2015(11):CD010983. 79. Weil IA, Kumar P, Seicean S, Neuhauser D, Seicean A. Platelet count abnormalities and perioperative outcomes in adults undergoing elective, non-cardiac surgery. PLoS One. 2019;14(2):e0212191.
ACCEPTED MANUSCRIPT
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80. Estcourt LJ, Birchall J, Allard S, Bassey SJ, Hersey P, Kerr JP, et al. Guidelines for the use of platelet transfusions. Br J Haematol. 2017;176(3):365-94. 81. Kaufman RM, Djulbegovic B, Gernsheimer T, Kleinman S, Tinmouth AT, Capocelli KE, et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2015;162(3):205-13. 82. Whitlock R, Crowther MA, Ng HJ. Bleeding in cardiac surgery: its prevention and treatment--an evidence-based review. Crit Care Clin. 2005;21(3):589-610. 83. Wandt H, Schafer-Eckart K, Greinacher A. Platelet transfusion in hematology, oncology and surgery. Dtsch Arztebl Int. 2014;111(48):809-15. 84. Arnold DM, Lauzier F, Albert M, Williamson D, Li N, Zarychanski R, et al. The association between platelet transfusions and bleeding in critically ill patients with thrombocytopenia. Res Pract Thromb Haemost. 2017;1(1):103-11. 85. Lieberman L, Bercovitz RS, Sholapur NS, Heddle NM, Stanworth SJ, Arnold DM. Platelet transfusions for critically ill patients with thrombocytopenia. Blood. 2014;123(8):1146-51; quiz 280. 86. Busch MP, Bloch EM, Kleinman S. Prevention of transfusion-transmitted infections. Blood. 2019;133(17):1854-64. 87. Kaufman RM, Assmann SF, Triulzi DJ, Strauss RG, Ness P, Granger S, et al. Transfusion-related adverse events in the Platelet Dose study. Transfusion. 2015;55(1):144-53. 88. King KE, Shirey RS, Thoman SK, Bensen-Kennedy D, Tanz WS, Ness PM. Universal leukoreduction decreases the incidence of febrile nonhemolytic transfusion reactions to RBCs. Transfusion. 2004;44(1):25-9. 89. Semple JW, Rebetz J, Kapur R. Transfusion-associated circulatory overload and transfusionrelated acute lung injury. Blood. 2019. 90. Schmidt AE, Henrichs KF, Kirkley SA, Refaai MA, Blumberg N. Prophylactic Preprocedure Platelet Transfusion Is Associated With Increased Risk of Thrombosis and Mortality. Am J Clin Pathol. 2017;149(1):87-94. 91. Zakko L, Rustagi T, Douglas M, Laine L. No Benefit From Platelet Transfusion for Gastrointestinal Bleeding in Patients Taking Antiplatelet Agents. Clin Gastroenterol Hepatol. 2017;15(1):46-52. 92. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387(10038):2605-13. 93. Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh V, Hudson C, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. N Engl J Med. 2019;380(3):242-51. 94. Warner MA, Woodrum D, Hanson A, Schroeder DR, Wilson G, Kor DJ. Preprocedural platelet transfusion for patients with thrombocytopenia undergoing interventional radiology procedures is not associated with reduced bleeding complications. Transfusion. 2017;57(4):890-8. 95. McGrath T, Koch CG, Xu M, Li L, Mihaljevic T, Figueroa P, et al. Platelet transfusion in cardiac surgery does not confer increased risk for adverse morbid outcomes. Ann Thorac Surg. 2008;86(2):54353. 96. Ninkovic S, McQuilten Z, Gotmaker R, Newcomb AE, Cole-Sinclair MF. Platelet transfusion is not associated with increased mortality or morbidity in patients undergoing cardiac surgery. Transfusion. 2018;58(5):1218-27. 97. Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G, Italian Society of Transfusion M, et al. Recommendations for the transfusion of plasma and platelets. Blood Transfus. 2009;7(2):13250. 98. Neisser-Svae A, Trawnicek L, Heger A, Mehta T, Triulzi D. Five-day stability of thawed plasma: solvent/detergent-treated plasma comparable with fresh-frozen plasma and plasma frozen within 24 hours. Transfusion. 2016;56(2):404-9. 99. Yazer MH, Cortese-Hassett A, Triulzi DJ. Coagulation factor levels in plasma frozen within 24 hours of phlebotomy over 5 days of storage at 1 to 6 degrees C. Transfusion. 2008;48(12):2525-30.
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100. O'Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004;126(1):11-28. 101. Tinmouth A. Assessing the Rationale and Effectiveness of Frozen Plasma Transfusions: An Evidence-based Review. Hematol Oncol Clin North Am. 2016;30(3):561-72. 102. Stanworth SJ, Grant-Casey J, Lowe D, Laffan M, New H, Murphy MF, et al. The use of freshfrozen plasma in England: high levels of inappropriate use in adults and children. Transfusion. 2011;51(1):62-70. 103. Stanworth SJ, Walsh TS, Prescott RJ, Lee RJ, Watson DM, Wyncoll D, et al. A national study of plasma use in critical care: clinical indications, dose and effect on prothrombin time. Crit Care. 2011;15(2):R108. 104. Holland L, Sarode R. Should plasma be transfused prophylactically before invasive procedures? Curr Opin Hematol. 2006;13(6):447-51. 105. Segal JB, Dzik WH, Transfusion Medicine/Hemostasis Clinical Trials N. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion. 2005;45(9):1413-25. 106. Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion. 2006;46(8):1279-85. 107. Karam O, Tucci M, Combescure C, Lacroix J, Rimensberger PC. Plasma transfusion strategies for critically ill patients. Cochrane Database Syst Rev. 2013(12):CD010654. 108. Yang L, Stanworth S, Hopewell S, Doree C, Murphy M. Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials. Transfusion. 2012;52(8):1673-86; quiz 109. Warner MA, Chandran A, Jenkins G, Kor DJ. Prophylactic Plasma Transfusion Is Not Associated With Decreased Red Blood Cell Requirements in Critically Ill Patients. Anesth Analg. 2017;124(5):163643. 110. Warner MA, Frank RD, Weister TJ, Smith MM, Stubbs JR, Kor DJ. Higher intraoperative plasma transfusion volumes are associated with inferior perioperative outcomes. Transfusion. 2019;59(1):112-24. 111. Warner MA, Woodrum DA, Hanson AC, Schroeder DR, Wilson GA, Kor DJ. Prophylactic Plasma Transfusion Before Interventional Radiology Procedures Is Not Associated With Reduced Bleeding Complications. Mayo Clin Proc. 2016;91(8):1045-55. 112. Green L, Bolton-Maggs P, Beattie C, Cardigan R, Kallis Y, Stanworth SJ, et al. British Society of Haematology Guidelines on the spectrum of fresh frozen plasma and cryoprecipitate products: their handling and use in various patient groups in the absence of major bleeding. Br J Haematol. 2018;181(1):54-67. 113. Roback JD, Caldwell S, Carson J, Davenport R, Drew MJ, Eder A, et al. Evidence-based practice guidelines for plasma transfusion. Transfusion. 2010;50(6):1227-39. 114. Jia Q, Brown MJ, Clifford L, Wilson GA, Truty MJ, Stubbs JR, et al. Prophylactic plasma transfusion for surgical patients with abnormal preoperative coagulation tests: a single-institution propensity-adjusted cohort study. Lancet Haematol. 2016;3(3):e139-48. 115. Murad MH, Stubbs JR, Gandhi MJ, Wang AT, Paul A, Erwin PJ, et al. The effect of plasma transfusion on morbidity and mortality: a systematic review and meta-analysis. Transfusion. 2010;50(6):1370-83. 116. Nascimento B, Callum J, Tien H, Peng H, Rizoli S, Karanicolas P, et al. Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial. Br J Anaesth. 2016;117(6):775-82. 117. Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth. 2014;113(6):922-34. 118. Levy JH, Goodnough LT. How I use fibrinogen replacement therapy in acquired bleeding. Blood. 2015;125(9):1387-93.
ACCEPTED MANUSCRIPT
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119. Gillissen A, van den Akker T, Caram-Deelder C, Henriquez D, Bloemenkamp KWM, de Maat MPM, et al. Coagulation parameters during the course of severe postpartum hemorrhage: a nationwide retrospective cohort study. Blood Adv. 2018;2(19):2433-42. 120. McQuilten ZK, Bailey M, Cameron PA, Stanworth SJ, Venardos K, Wood EM, et al. Fibrinogen concentration and use of fibrinogen supplementation with cryoprecipitate in patients with critical bleeding receiving massive transfusion: a bi-national cohort study. Br J Haematol. 2017;179(1):131-41. 121. McQuilten ZK, Wood EM, Bailey M, Cameron PA, Cooper DJ. Fibrinogen is an independent predictor of mortality in major trauma patients: A five-year statewide cohort study. Injury. 2017;48(5):1074-81. 122. Ranucci M, Pistuddi V, Baryshnikova E, Colella D, Bianchi P. Fibrinogen Levels After Cardiac Surgical Procedures: Association With Postoperative Bleeding, Trigger Values, and Target Values. Ann Thorac Surg. 2016;102(1):78-85. 123. Curry N, Rourke C, Davenport R, Beer S, Pankhurst L, Deary A, et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth. 2015;115(1):76-83. 124. Holcomb JB, Fox EE, Zhang X, White N, Wade CE, Cotton BA, et al. Cryoprecipitate use in the PROMMTT study. J Trauma Acute Care Surg. 2013;75(1 Suppl 1):S31-9. 125. Ciavarella D, Reed RL, Counts RB, Baron L, Pavlin E, Heimbach DM, et al. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol. 1987;67(3):365-8. 126. Ranucci M, Solomon C. Supplementation of fibrinogen in acquired bleeding disorders: experience, evidence, guidelines, and licences. Br J Anaesth. 2012;109(2):135-7. 127. Nascimento B, Rizoli S, Rubenfeld G, Fukushima R, Ahmed N, Nathens A, et al. Cryoprecipitate transfusion: assessing appropriateness and dosing in trauma. Transfus Med. 2011;21(6):394-401. 128. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. Management of bleeding following major trauma: an updated European guideline. Crit Care. 2010;14(2):R52. 129. Sorensen B, Tang M, Larsen OH, Laursen PN, Fenger-Eriksen C, Rea CJ. The role of fibrinogen: a new paradigm in the treatment of coagulopathic bleeding. Thromb Res. 2011;128 Suppl 1:S13-6. 130. Tinegate H, Allard S, Grant-Casey J, Hennem S, Kilner M, Rowley M, et al. Cryoprecipitate for transfusion: which patients receive it and why? A study of patterns of use across three regions in England. Transfus Med. 2012;22(5):356-61. 131. Pavord S, Maybury H. How I treat postpartum hemorrhage. Blood. 2015;125(18):2759-70. 132. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013;17(2):R76. 133. Runyon BA, Aasld. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-3. 134. European Association for the Study of the Liver. Electronic address eee, Clinical practice guidelines p, Wendon J, Panel m, Cordoba J, Dhawan A, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047-81. 135. Burman D, Hodson AK, Wood CB, Brueton NF. Acute anaphylaxis, pulmonary oedema, and intravascular haemolysis due to cryoprecipitate. Arch Dis Child. 1973;48(6):483-5. 136. McVerry BA, Machin SJ. Incidence of allo-immunization and allergic reactions to cryoprecipitate in haemophilia. Vox Sang. 1979;36(2):77-80. 137. Reese EP, Jr., McCullough JJ, Craddock PR. An adverse pulmonary reaction to cryoprecipitate in a hemophiliac. Transfusion. 1975;15(6):583-8. 138. Callum JL, Karkouti K, Lin Y. Cryoprecipitate: the current state of knowledge. Transfus Med Rev. 2009;23(3):177-88. 139. Bolton-Maggs PH. SHOT conference report 2016: serious hazards of transfusion - human factors continue to cause most transfusion-related incidents. Transfus Med. 2016;26(6):401-5.
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140. West KA, Gea-Banacloche J, Stroncek D, Kadri SS. Granulocyte transfusions in the management of invasive fungal infections. Br J Haematol. 2017;177(3):357-74. 141. Price TH, Boeckh M, Harrison RW, McCullough J, Ness PM, Strauss RG, et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood. 2015;126(18):2153-61. 142. Seidel MG, Peters C, Wacker A, Northoff H, Moog R, Boehme A, et al. Randomized phase III study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant. 2008;42(10):679-84. 143. Estcourt LJ, Stanworth SJ, Hopewell S, Doree C, Trivella M, Massey E. Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2016;4:CD005339. 144. Valentini CG, Farina F, Pagano L, Teofili L. Granulocyte Transfusions: A Critical Reappraisal. Biol Blood Marrow Transplant. 2017;23(12):2034-41. 145. Netelenbos T, Massey E, de Wreede LC, Harding K, Hamblin A, Sekhar M, et al. The burden of invasive infections in neutropenic patients: incidence, outcomes, and use of granulocyte transfusions. Transfusion. 2019;59(1):160-8. 146. Strauss RG. Therapeutic granulocyte transfusions: neutropenic patients with acute leukemia continue to need them - why are definitive evidence-based practice guidelines elusive? Transfusion. 2019;59(1):6-8. 147. A Open Label, Post Marketing Surveillance Study Following Transfusion of INTERCEPT Platelet Components (PIPER). 2015 ongoing;https://clinicaltrials.gov/ct2/show/NCT02549222?term=cerus. 148. Paglino JC, Pomper GJ, Fisch GS, Champion MH, Snyder EL. Reduction of febrile but not allergic reactions to RBCs and platelets after conversion to universal prestorage leukoreduction. Transfusion. 2004;44(1):16-24. 149. Yazer MH, Podlosky L, Clarke G, Nahirniak SM. The effect of prestorage WBC reduction on the rates of febrile nonhemolytic transfusion reactions to platelet concentrates and RBC. Transfusion. 2004;44(1):10-5. 150. Trial to Reduce Alloimmunization to Platelets Study G. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med. 1997;337(26):1861-9. 151. Bowden RA, Slichter SJ, Sayers M, Weisdorf D, Cays M, Schoch G, et al. A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood. 1995;86(9):3598-603. 152. Preiksaitis JK. The cytomegalovirus-"safe" blood product: is leukoreduction equivalent to antibody screening? Transfus Med Rev. 2000;14(2):112-36. 153. Mintz PD. Febrile reactions to platelet transfusions. Am J Clin Pathol. 1991;95(5):609-12. 154. Heddle NM, Klama L, Meyer R, Walker I, Boshkov L, Roberts R, et al. A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets. Transfusion. 1999;39(3):231-8. 155. Zantek ND, Parker RI, van de Watering LM, Josephson CD, Bateman ST, Valentine SL, et al. Recommendations on Selection and Processing of RBC Components for Pediatric Patients From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med. 2018;19(9S Suppl 1):S163-S9. 156. Tobian AA, Savage WJ, Tisch DJ, Thoman S, King KE, Ness PM. Prevention of allergic transfusion reactions to platelets and red blood cells through plasma reduction. Transfusion. 2011;51(8):1676-83. 157. Heddle NM, Blajchman MA, Meyer RM, Lipton JH, Walker IR, Sher GD, et al. A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets. Transfusion. 2002;42(5):556-66. 158. Heddle NM, Klama L, Singer J, Richards C, Fedak P, Walker I, et al. The role of the plasma from platelet concentrates in transfusion reactions. N Engl J Med. 1994;331(10):625-8.
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
US
CR
IP
T
159. Cohn CS, Stubbs J, Schwartz J, Francis R, Goss C, Cushing M, et al. A comparison of adverse reaction rates for PAS C versus plasma platelet units. Transfusion. 2014;54(8):1927-34. 160. Tobian AA, Fuller AK, Uglik K, Tisch DJ, Borge PD, Benjamin RJ, et al. The impact of platelet additive solution apheresis platelets on allergic transfusion reactions and corrected count increment (CME). Transfusion. 2014;54(6):1523-9; quiz 2. 161. van Hout FMA, van der Meer PF, Wiersum-Osselton JC, Middelburg RA, Schipperus MR, van der Bom JG, et al. Transfusion reactions after transfusion of platelets stored in PAS-B, PAS-C, or plasma: a nationwide comparison. Transfusion. 2018;58(4):1021-7. 162. Hauser L, Roque-Afonso AM, Beyloune A, Simonet M, Deau Fischer B, Burin des Roziers N, et al. Hepatitis E transmission by transfusion of Intercept blood system-treated plasma. Blood. 2014;123(5):796-7. 163. Liu Y, Bewersdorf JP, Stahl M, Zeidan AM. Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: The dawn of a new era? Blood Rev. 2019;34:67-83. 164. Assi R, Kantarjian H, Ravandi F, Daver N. Immune therapies in acute myeloid leukemia: a focus on monoclonal antibodies and immune checkpoint inhibitors. Curr Opin Hematol. 2018;25(2):136-45. 165. Velliquette RW, Aeschlimann J, Kirkegaard J, Shakarian G, Lomas-Francis C, Westhoff CM. Monoclonal anti-CD47 interference in red cell and platelet testing. Transfusion. 2019;59(2):730-7. 166. Organization WH. Metrics: Disability-Adjusted Life Year (DALY) - Quantifying the Burden of Disease from mortality and morbidity 2018 [cited 2018 1/2/2018]. Available from: http://www.who.int/healthinfo/global_burden_disease/metrics_daly/en/. 167. Cushing MM, DeSimone RA, Goel R, Hsu YS, Parra P, Racine-Brzostek SE, et al. The impact of Daratumumab on transfusion service costs. Transfusion. 2019. 168. Anani WQ, Marchan MG, Bensing KM, Schanen M, Piefer C, Gottschall JL, et al. Practical approaches and costs for provisioning safe transfusions during anti-CD38 therapy. Transfusion. 2017;57(6):1470-9. 169. Oostendorp M, Lammerts van Bueren JJ, Doshi P, Khan I, Ahmadi T, Parren PW, et al. When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. Transfusion. 2015;55(6 Pt 2):1555-62. 170. Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion. 2015;55(6 Pt 2):1545-54. 171. Deneys V, Thiry C, Frelik A, Debry C, Martin B, Doyen C. Daratumumab: Therapeutic asset, biological trap! Transfus Clin Biol. 2018;25(1):2-7. 172. Quach H, Benson S, Haysom H, Wilkes AM, Zacher N, Cole-Sinclair M, et al. Considerations for pre-transfusion immunohaematology testing in patients receiving the anti-CD38 monoclonal antibody daratumumab for the treatment of multiple myeloma. Intern Med J. 2018;48(2):210-20. 173. Chinoca Ziza KN, Paiva TA, Mota SR, Dezan MR, Schmidt LC, Brunetta DM, et al. A blockage monoclonal antibody protocol as an alternative strategy to avoid anti-CD38 interference in immunohematological testing. Transfusion. 2019. 174. Hosokawa M, Kashiwagi H, Nakayama K, Sakuragi M, Nakao M, Morikawa T, et al. Distinct effects of daratumumab on indirect and direct antiglobulin tests: a new method employing 0.01 mol/L dithiothreitol for negating the daratumumab interference with preserving K antigenicity (Osaka method). Transfusion. 2018;58(12):3003-13. 175. Lancman G, Arinsburg S, Jhang J, Cho HJ, Jagannath S, Madduri D, et al. Blood Transfusion Management for Patients Treated With Anti-CD38 Monoclonal Antibodies. Front Immunol. 2018;9:2616. 176. Folkes AS, Feng M, Zain JM, Abdulla F, Rosen ST, Querfeld C. Targeting CD47 as a cancer therapeutic strategy: the cutaneous T-cell lymphoma experience. Curr Opin Oncol. 2018;30(5):332-7. 177. Russ A, Hua AB, Montfort WR, Rahman B, Riaz IB, Khalid MU, et al. Blocking "don't eat me" signal of CD47-SIRPalpha in hematological malignancies, an in-depth review. Blood Rev. 2018;32(6):480-9. 178. Acker JP, Marks DC, Sheffield WP. Quality Assessment of Established and Emerging Blood Components for Transfusion. J Blood Transfus. 2016;2016:4860284.
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
US
CR
IP
T
179. Ness PM, Gehrie EA. Blood products for resuscitation: moving forward by going backward. Transfusion. 2019;59(S1):834-6. 180. Spinella PC, Pidcoke HF, Strandenes G, Hervig T, Fisher A, Jenkins D, et al. Whole blood for hemostatic resuscitation of major bleeding. Transfusion. 2016;56 Suppl 2:S190-202. 181. Seheult JN, Anto V, Alarcon LH, Sperry JL, Triulzi DJ, Yazer MH. Clinical outcomes among low-titer group O whole blood recipients compared to recipients of conventional components in civilian trauma resuscitation. Transfusion. 2018;58(8):1838-45. 182. Reddoch-Cardenas KM, Bynum JA, Meledeo MA, Nair PM, Wu X, Darlington DN, et al. Coldstored platelets: A product with function optimized for hemorrhage control. Transfus Apher Sci. 2019;58(1):16-22. 183. Strandenes G. ATO, et al. https://rdcr.org/wp-content/uploads/2018/07/07-Apelseth-Strandenes180619.BFF-Cold-stored-platelet-program.-TOA_GS.pdf. 184. Milford EM, Reade MC. Comprehensive review of platelet storage methods for use in the treatment of active hemorrhage. Transfusion. 2016;56 Suppl 2:S140-8. 185. Bux J, Dickhorner D, Scheel E. Quality of freeze-dried (lyophilized) quarantined single-donor plasma. Transfusion. 2013;53(12):3203-9. 186. Van PY, Holcomb JB, Schreiber MA. Novel concepts for damage control resuscitation in trauma. Curr Opin Crit Care. 2017;23(6):498-502. 187. Wood EM, Ang AL, Bisht A, Bolton-Maggs PH, Bokhorst AG, Flesland O, et al. International haemovigilance: what have we learned and what do we need to do next? Transfus Med. 2019. 188. Harris JC, Crookston KP. Blood Product Safety. StatPearls. Treasure Island (FL)2019. 189. Research CfBEa. Fatalities Reported to FDA Following Blood Collection and Transfusion. In: Administration UFaD, editor. Silver Spring, MD. 190. Narayan S (Ed), Poles D, et al. on behalf of the Serious Hazards of Transfusion (SHOT) Steering group. The 2018 Annual SHOT Report (2019). Available from: https://www.shotuk.org/shot-reports/ 191. Promotion DoHQ. National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol. In: Diseases NCfEaZI, editor. Atlanta, GA: Centers for Disease Control and Prevention 2018. 192. Bakitas M, Lyons KD, Hegel MT, Balan S, Brokaw FC, Seville J, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial. JAMA. 2009;302(7):741-9. 193. Ferrell BR, Temel JS, Temin S, Alesi ER, Balboni TA, Basch EM, et al. Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017;35(1):96-112. 194. Sexauer A, Cheng MJ, Knight L, Riley AW, King L, Smith TJ. Patterns of hospice use in patients dying from hematologic malignancies. J Palliat Med. 2014;17(2):195-9. 195. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-42. 196. LeBlanc TW, Abernethy AP, Casarett DJ. What is different about patients with hematologic malignancies? A retrospective cohort study of cancer patients referred to a hospice research network. J Pain Symptom Manage. 2015;49(3):505-12. 197. Button E, Chan R, Chambers S, Butler J, Yates P. Signs, Symptoms, and Characteristics Associated With End of Life in People With a Hematologic Malignancy: A Review of the Literature. Oncol Nurs Forum. 2016;43(5):E178-87. 198. LeBlanc TW. Palliative care and hematologic malignancies: old dog, new tricks? J Oncol Pract. 2014;10(6):e404-7. 199. Odejide OO, Cronin AM, Condron NB, Fletcher SA, Earle CC, Tulsky JA, et al. Barriers to Quality End-of-Life Care for Patients With Blood Cancers. J Clin Oncol. 2016;34(26):3126-32. 200. LeBlanc TW, Egan PC, Olszewski AJ. Transfusion dependence, use of hospice services, and quality of end-of-life care in leukemia. Blood. 2018;132(7):717-26.
ACCEPTED MANUSCRIPT
AC
CE
PT
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201. To THM, LeBlanc TW, Eastman P, Neoh K, Agar MR, To LB, et al. The Prospective Evaluation of the Net Effect of Red Blood Cell Transfusions in Routine Provision of Palliative Care. J Palliat Med. 2017;20(10):1152-7. 202. Preston NJ, Hurlow A, Brine J, Bennett MI. Blood transfusions for anaemia in patients with advanced cancer. Cochrane Database Syst Rev. 2012(2):CD009007. 203. Elyan B, Hayes S, Day R, Johny A, Perkins P. Blood transfusions in a day hospice setting. Palliat Med. 2012;26(6):862-3. 204. Rabiner SF, Telfer MC, Fajardo R. Home transfusions of hemophiliacs. JAMA. 1972;221(8):8857. 205. Thompson HW, McKelvey J. Home blood transfusion therapy: a home health agency's 5-year experience. Transfusion. 1995;35(5):453. 206. Rutman R, Kakaiya R, Miller WV. Home transfusion for the cancer patient. Semin Oncol Nurs. 1990;6(2):163-7. 207. Idri S, Catoni MP, Si Ali H, Patte R, Briere J, Baudelot J, et al. [Transfusion at home? An alternative to the day hospital]. Transfus Clin Biol. 1996;3(4):235-9. 208. Ademokun A, Kaznica S, Deas S. Home blood transfusion: a necessary service development. Transfus Med. 2005;15(3):219-22. 209. Charron J, Gouezec H, Bajeux E. [Home blood transfusion in France: Benefits and development terms]. Transfus Clin Biol. 2018. 210. Trueman P, Drummond M, Hutton J. Developing guidance for budget impact analysis. Pharmacoeconomics. 2001;19(6):609-21. 211. Custer B, Hoch JS. Cost-effectiveness analysis: what it really means for transfusion medicine decision making. Transfus Med Rev. 2009;23(1):1-12. 212. Russell WA, Stramer SL, Busch MP, Custer B. Screening the Blood Supply for Zika Virus in the 50 U.S. States and Puerto Rico: A Cost-Effectiveness Analysis. Ann Intern Med. 2019. 213. Excellence NIfHaC. Technology appraisal guidance 2017 [cited 2017 12/30/2017]. Available from: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-technologyappraisal-guidance. 214. Staginnus U, Corash L. Economics of pathogen inactivation technology for platelet concentrates in Japan. Int J Hematol. 2004;80(4):317-24. 215. Moeremans K, Warie H, Annemans L. Assessment of the economic value of the INTERCEPT blood system in Belgium. Transfus Med. 2006;16(1):17-30. 216. Bell CE, Botteman MF, Gao X, Weissfeld JL, Postma MJ, Pashos CL, et al. Cost-effectiveness of transfusion of platelet components prepared with pathogen inactivation treatment in the United States. Clin Ther. 2003;25(9):2464-86. 217. Girona-Llobera E, Jimenez-Marco T, Galmes-Trueba A, Muncunill J, Serret C, Serra N, et al. Reducing the financial impact of pathogen inactivation technology for platelet components: our experience. Transfusion. 2014;54(1):158-68. 218. McCullough J, Goldfinger D, Gorlin J, Riley WJ, Sandhu H, Stowell C, et al. Cost implications of implementation of pathogen-inactivated platelets. Transfusion. 2015;55(10):2312-20. 219. Basora M, Pereira A, Coca M, Tio M, Lozano L. Cost-effectiveness analysis of ferric carboxymaltose in pre-operative haemoglobin optimisation in patients undergoing primary knee arthroplasty. Blood Transfus. 2018;16(5):438-42. 220. Kleineruschkamp A, Meybohm P, Straub N, Zacharowski K, Choorapoikayil S. A model-based cost-effectiveness analysis of Patient Blood Management. Blood Transfus. 2019;17(1):16-26. 221. McLoughlin C, Roberts TE, Jackson LJ, Moore P, Wilson M, Hooper R, et al. Cost-effectiveness of cell salvage and donor blood transfusion during caesarean section: results from a randomised controlled trial. BMJ Open. 2019;9(2):e022352. 222. Walsh TS, Stanworth S, Boyd J, Hope D, Hemmatapour S, Burrows H, et al. The Age of BLood Evaluation (ABLE) randomised controlled trial: description of the UK-funded arm of the international trial, the UK cost-utility analysis and secondary analyses exploring factors associated with health-related
ACCEPTED MANUSCRIPT
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quality of life and health-care costs during the 12-month follow-up. Health Technol Assess. 2017;21(62):1-118. 223. Wu Y, Zeng Y, Hu Q, Li M, Bao X, Zhong J, et al. Blood loss and cost-effectiveness of oral vs intravenous tranexamic acid in primary total hip arthroplasty: A randomized clinical trial. Thromb Res. 2018;171:143-8. 224. Kramer K, Zaaijer HL, Verweij MF. The Precautionary Principle and the Tolerability of Blood Transfusion Risks. Am J Bioeth. 2017;17(3):32-43. 225. Leach Bennett J, Blajchman MA, Delage G, Fearon M, Devine D. Proceedings of a consensus conference: Risk-Based Decision Making for Blood Safety. Transfus Med Rev. 2011;25(4):267-92. 226. Stein J, Besley J, Brook C, Hamill M, Klein E, Krewski D, et al. Risk-based decision-making for blood safety: preliminary report of a consensus conference. Vox Sang. 2011;101(4):277-81. 227. Leach Bennett J, Devine DV. Risk-based decision making in transfusion medicine. Vox Sang. 2018;113(8):737-49. 228. Ward SJ, Stramer SL, Szczepiorkowski ZM. Assessing the risk of Babesia to the United States blood supply using a risk-based decision-making approach: Report of AABB's Ad Hoc Babesia Policy Working Group (original report). Transfusion. 2018;58(8):1916-23. 229. Styles CE, Seed CR, Hoad VC, Gaudieri S, Keller AJ. Reconsideration of blood donation testing strategy for human T-cell lymphotropic virus in Australia. Vox Sang. 2017;112(8):723-32. 230. O'Brien SF, Ward S, Gallian P, Fabra C, Pillonel J, Kitchen AD, et al. Malaria blood safety policy in five non-endemic countries: a retrospective comparison through the lens of the ABO risk-based decision-making framework. Blood Transfus. 2019. 231. Jacobs MR, Good CE, Lazarus HM, Yomtovian RA. Relationship between bacterial load, species virulence, and transfusion reaction with transfusion of bacterially contaminated platelets. Clin Infect Dis. 2008;46(8):1214-20. 232. Yomtovian R, Tomasulo P, Jacobs MR. Platelet bacterial contamination: assessing progress and identifying quandaries in a rapidly evolving field. Transfusion. 2007;47(8):1340-6. 233. Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS)--explanation and elaboration: a report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force. Value Health. 2013;16(2):231-50. 234. Haass K SM, Savinkina A, Kuehnert M, Basavaraju. S. Transfusion-transmitted infections reported to the National Healthcare Safety Network Hemovigilance Module. Transfusion Medicine Reviews. 2019;doi:10.1016/j.tmrv.2019.01.001. 235. Hong H, Xiao W, Lazarus HM, Good CE, Maitta RW, Jacobs MR. Detection of septic transfusion reactions to platelet transfusions by active and passive surveillance. Blood. 2016;127(4):496502. 236. McDonald C, Allen J, Brailsford S, Roy A, Ball J, Moule R, et al. Bacterial screening of platelet components by National Health Service Blood and Transplant, an effective risk reduction measure. Transfusion. 2017;57(5):1122-31.