Platelets, Frozen Plasma, and Cryoprecipitate: What is the Clinical Evidence for Their Use in the Neonatal Intensive Care Unit?

Platelets, Frozen Plasma, and Cryoprecipitate: What is the Clinical Evidence for Their Use in the Neonatal Intensive Care Unit? Brandon S. Poterjoy, DO,* and Cassandra D. Josephson, MD† Transfusion of blood components such as platelets, frozen plasma, and cryoprecipitate is a common practice in the neonatal intensive care unit. Although it is intuitive that these components would be transfused in the context of bleeding, their use in neonatology has often been on a prophylactic basis. Due to a lack of consensus guidelines regarding indications for transfusion, however, the neonatologist is left to his/her opinion as to when to transfuse. This article seeks to review the available evidence regarding the use of platelets, frozen plasma, and cryoprecipitate in neonates, as well as the risks associated with the administration of these products. Semin Perinatol 33:66-74 © 2009 Elsevier Inc. All rights reserved. KEYWORDS platelets, fresh frozen plasma, cryoprecipitate, transfusion, neonate

T

he transfusion of plasma-containing products, such as platelets, frozen plasma, and cryoprecipitate, is common practice in the neonatal intensive care unit (NICU), especially among extremely ill neonates. In this setting, neonatologists face complex decisions regarding what product(s) and what dose of a particular product to administer, when to order these products (ie, for therapy versus prophylaxis), and what thresholds should dictate the transfusion. To add to the complexity of these decisions, the neonatal coagulation system is strikingly different from that of adults. Andrew and coworkers examined the development of the coagulation system in full-term and premature infants.1,2 They found that many individual clotting factor levels in healthy full-term and premature infants were approximately 50% of those in healthy adults (ie, the vitamin K-dependent factors II, VII, IX, X, and contact factors XI and XII), whereas others were within normal adult ranges (fibrinogen, factor V, factor VIII, factor XIII, and von Willebrand factor). These investigators also found that neonates had similarly low levels of natural anticoagulants, including antithrombin-III, proteins C & S, and heparin cofactor-II. Tests of global he-

*Division of Neonatal/Perinatal Medicine, Drexel University College of Medicine, St. Christopher’s Hospital for Children, Philadelphia, PA. †Department of Pathology, Emory School of Medicine, Children’s Healthcare of Atlanta, Blood & Tissue Services, Atlanta, GA. Address reprint requests to Cassandra D. Josephson, MD, Emory School of Medicine, Department of Pathology, 1405 Clifton Road NE, Atlanta, GA 30322. E-mail: [email protected]

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0146-0005/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.10.004

mostasis revealed that the result of these mostly low levels of coagulants and anticoagulants was a delicately balanced neonatal hemostatic system, with overall reaction and coagulation times similar to those of adults. Within the first 6 months of life, the infant’s coagulation system matures and all factor levels (except protein C) approach healthy adult values. To aid clinicians with the transfusion of platelet and plasma products,3-8 numerous guidelines were published in the past decade. However, the scientific sources for these guidelines were sparse, which led to recommendations that were mostly based on experience and expert opinion, rather than solid evidence. During the same period, the untoward effects of transfusing plasma-containing products were better recognized and reported, which accentuated the need to optimize transfusion therapy in neonates.4,9-13 The purpose of this manuscript was to review the types of platelets, frozen plasma, and cryoprecipitate products available to the clinician, as well as the basis for current practices (ie, indications, triggers, and dosing of these products) in preterm and term infants. A second goal was to apply a ranking system by Siwek and coworkers14 to rate each reference to neonatal transfusion practices found in the literature in terms of the level of evidence.

Platelets In the U.S., platelet products are available as platelet concentrates (also known as whole-blood-derived platelets or ran-

Platelets, frozen plasma, and cryoprecipitate dom donor platelets) and apheresis platelets (also known as single-donor platelets). Platelet concentrates are derived from a single-donor, whole-blood unit, whereas apheresis platelets are collected via an apheresis machine that returns the remaining constituents of whole blood to the donor. Five to eight platelet concentrates (⬃7 ⫻ 1010 platelets per concentrate) must be pooled together to equate a single apheresis platelet unit dose (containing 3-6 ⫻ 1011 platelets). The process of leukoreduction differentiates the two products as well. The platelet concentrate unit must undergo post-collection leukofiltration for it to be leukoreduced, whereas the process of apheresis itself renders the apheresis unit leukoreduced. Lastly, red blood cell contamination occurs more often in platelet concentrates than in apheresis platelets. Thus, Rh sensitization in an Rh-negative recipient may occur more often when using the former than the latter. Both types of platelets must be stored at room temperature with constant, gentle agitation, and their shelf life is limited to 5 days.7

Indications Thrombocytopenia is a common abnormality in sick neonates, affecting 20% to 35% of those admitted to NICUs.15,16 Approximately 75% of these neonates have mild to moderate thrombocytopenia, defined as a platelet count of 50 to 150 ⫻ 109/L, and 25% have platelet counts ⬍50 ⫻ 109/L, a level thought to significantly increase the bleeding risk. The indications for transfusion of platelets can be divided into prophylactic and therapeutic. Therapeutic transfusions are logical in that they are ordered to treat bleeding, irrespective of the preexisting level of thrombocytopenia. However, most platelet transfusions administered to neonates are given prophylactically, mostly to prevent intraventricular hemorrhage (IVH). In those cases, the threshold to administer platelet transfusions and the appropriate dosing remain controversial. IVH is a major morbidity in preterm neonates, with an incidence of 25% to 31% among very-low-birth-weight (VLBW) infants. A total of 74% of all intraventricular hemorrhages occur in the first 48 hours of life.17-19 Several studies have linked hemostatic abnormalities in neonates to the development of IVH.20-24 However, although it may seem intuitive to administer prophylactic platelet transfusions to prevent IVH or diminish its extension, such intervention has not been shown to reduce the incidence of IVH in preterm infants.25,26 Specifically, only one randomized controlled trial (RCT) to date has compared two platelet transfusion triggers (50 versus 150 ⫻ 109/L) in neonates. This trial, which was limited to VLBW infants in the first week of life and excluded those with platelet counts ⬍50 ⫻ 109/L,25 revealed no significant differences in the frequency or severity of IVH between the two groups. Thus, the investigators concluded that nonbleeding premature infants with platelet counts ⬎50 ⫻ 109/L should not receive prophylactic platelet transfusions. Because all neonates with platelet counts ⬍50 ⫻ 109/L were transfused, this study did not address whether lower platelet counts could be safely tolerated. In response to this question, Murray and coworkers evaluated the outcomes of stable neonates transfused for platelet counts ⬍30 ⫻ 109/L, and of

67 neonates transfused at a platelet count between 30 and 50 ⫻ 109/L because of clinical instability or a previous IVH. In this retrospective review, 51% of neonates with platelet counts ⬍50 ⫻ 109/L were transfused and no major hemorrhage was observed, irrespective of whether platelets were transfused or withheld. These investigators concluded that a prophylactic platelet threshold of ⬍30 ⫻ 109/L most likely represents a safe practice for clinically stable NICU patients, particularly after the first week of life.27 Other studies have revealed the degree of disparity that exists worldwide in the use of platelet transfusions to treat thrombocytopenic neonates.27-29 Specifically, a recent study of transfusion practices in 10 NICUs in the U.S. reported a 10-fold difference in platelet transfusion usage among VLBW infants in the first week of life.30 Perhaps more importantly, this study found no correlation between the platelet transfusion usage and the patients’ severity of illness or the incidence of thrombocytopenia in the different NICUs, suggesting that the observed differences were mostly due to practice variability. Further supporting these findings, our group recently performed a survey among neonatologists in the U.S. and Canada on platelet transfusion practices. This survey revealed significant diversity in platelet transfusion thresholds, product preferences, and component preparation. We speculated that the lack of uniformity in practice is multifactorial, but mostly due to the lack of scientific evidence to inform clinical practice.31 In the absence of clinical studies and scientific data to allow for standardization of practice parameters, numerous experts and consensus groups have published guidelines for platelet administration in neonates (Table 1).27,32-35 Not surprisingly, the recommendations are as diverse as the transfusion practices reported in the literature (Level C, expert opinion).

Dosing A dose of 5 to 10 mL/kg of a platelet concentrate unit has been demonstrated to raise the platelet count in an average full-term newborn by 50,000 to 100,000/␮L.26,36 Based on these observations, most practitioners order 10 mL/kg for each platelet transfusion. Despite lack of corroboration from rigorous testing, the same dosing regimen is implemented for apheresis platelets.

Rate the Evidence There is an absence of Level A studies to inform the practice of transfusing platelets in neonates (Table 2). The decision to transfuse or not to transfuse platelets to infants with platelet counts below 50,000 remains unclear, especially in the context of risk of IVH. Based on the worldwide disparity in transfusion triggers, there is a critical need for randomized, multicenter trials to evaluate the safety of a given platelet count. Until that occurs, based on the recent survey by our group, a platelet count ⬎50,000/␮L seems to be considered “safe” by the majority of U.S. and Canadian neonatologists, and can be used as a “consensus” level, particularly for critically ill infants and for VLBW infants in the first week of life.

B.S. Poterjoy and C.D. Josephson

<100 Not addressed Not addressed <30

<20 <20

Roberts and Murray, 200880

<30 Maintain >50 to >100 if unstable <50 Gibson et al., 200433 Strauss, 200879

Calhoun et al., 200032 Strauss, 200078 Murray, et al., 200227 Roseff et al., 200235

Same as preterm Not addressed

<50 <50 <50 <50 if failure of production <100 if DIC Not addressed <50 Same as preterm <20 <30 <30 <25 <20 <30 <50

<100

Active Bleeding

For stable neonates outside of the high risk period for IVH, a platelet transfusion trigger of 30,000/␮L is used by many neonatologists and is supported by Murray’s study.27 However, this would be considered Level B evidence.

<30 <50

<50 if DIC <100 if falling rapidly <50 <100 <50 <100 Roberts and Murray, 199934

<50 Blanchette et al., 199526

<30

<20 if stable <30 if sick

<50 if failure of production <100 if DIC <50 for minor procedure <100 for major surgery <20 <50 <100 Blanchette et al., 199177

Prior to Invasive Procedure Non-Bleeding Term Non-Bleeding Stable Preterm Non-Bleeding Sick Preterm Author

Table 1 Summary of Platelet Transfusion Triggers Recommended for Neonates

<50 if failure of production <100 if DIC <50 in all cases <100 if DIC Any platelet count if functional disorder <100 if major organ bleeding <50 if minor bleeding Not addressed <100 <100 <50 if stable <100 if sick <50 <50

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Frozen Plasma Plasma consists of many proteins, with albumin being the most abundant. Other plasma proteins include complement, transport molecules, immunoglobulins (gamma-globulins), and coagulation factors, such as fibrinogen, factor XIII, vWF, Factor VIII, and vitamin K-dependent coagulation factors (II, VII, IX, X).7 Plasma products can be produced from whole blood (WB) or through plasmapheresis, but are primarily produced from WB. The “time-after-collection to time-of-freezing” determines whether the product becomes fresh frozen plasma (FFP), ie, frozen within 6 to 8 hours of collection, or F24 plasma, frozen within the first 24 hours after collection.37 Both FFP and F24 can be stored at ⫺18°C or colder, and both products are virtually equivalent, albeit slightly lower factor VIII and factor V levels in F24.7 The term “frozen plasma” (FP) encompasses both of these products.

Indications The practice of plasma transfusions in the NICU is not well established. Several previous studies evaluated the potential usefulness of plasma transfusions in neonates to decrease mortality, to improve long-term neurodevelopmental outcomes, to prevent IVH, as cardiovascular support, to reconstitute blood for extracorporeal bypass/exchange transfusions, and to treat infections and/or support the immune system. Most of these studies, however, did not ultimately provide scientific support for these indications (Table 2). The Northern Neonatal Nursing Initiative (NNNI) Trial38 was designed to test the hypothesis that early volume expansion, and particularly FFP administration, would reduce morbidity and mortality in low-birth-weight (LBW) infants. In that trial, infants born prematurely (⬍32 weeks gestation) were randomized 2 hours after birth to receive one of three therapies: (a) prophylactic FFP (n ⫽ 257), (b) an equal volume of inert gelatin plasma substitute (n ⫽ 261), or (c) an infusion of 10% dextrose (control group, n ⫽ 258). Mortality related to respiratory distress syndrome was similar among all three groups, as was the number of infants with IVH. In the 2-year follow-up study, no significant differences between groups in mortality or severe disability were reported among survivors.39 The results of this large RCT disproved the findings of an earlier, much smaller study,40 which showed a lower incidence of IVH among infants transfused with FFP (14%, n ⫽ 36) compared with controls (41%, n ⫽ 37). To further settle this controversy, in 2004 Osborn and Evans41 performed a meta-analysis of randomized trials of early volume expansion in neonates using different volume expanders (including FFP). This meta-analysis concluded that there were no benefits associated with the early administration of FFP to preterm neonates (Table 2), not in terms of

Platelets, frozen plasma, and cryoprecipitate

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Table 2 Summary of Selected Studies of Platelet, FP, and Cryoprecipitate Study

Design

Component

Andrew et al., 199325

SCRCT

Platelets

Transfuse to Plts >150 k vs. conventional therapy

Murray et al., 200227

RCR

Platelets

Malan and de V Heese, 198081 Gross et al, 198282

SCRCT

FFP

SCRCT

FFP

Beverley et al., 198540

SCRCT

FFP

Emery et al., 199283

SCRCT

FFP

NNNI Trial, 199838

MCRCT

FFP

Plts <30 k vs. history of IVH ⴙ Plts <50 k FFP vs. no therapy for polycythemia FFP ⴙ plts vs. ET vs. control for pts with DIC FFP @ admission & 24 hrs of life vs. control FFP vs. 4.5% and 20% albumin for hypotension FFP @ admission & 24 hrs vs. Gelofusine vs. Control

Supapannachart et al., 199984 Mou et al., 200485

SCRCT

FFP

SCRCT

FFP

Osborn and Evans, 200441 Branson et al., 198345

MA

FFP

CR

FFP & Cryo

Yuen et al., 198644

CR

FFP & Cryo

Bell et al., 198646

CR

FFP & Cryo

Stammers et al., 200043

CR

FFP, Cryo, Plts

Larsen et al., 198747

CS

Plts & Cryo

Mba et al., 199549

CS

pRBC & Cryo

Pomper et al., 200348

CR

Cryo

Tuner et al., 198152

SCT

Prothrombin complex concentrate, cryoprecipitate, or platelet concentrate

Intervention

FFP vs. haemaccel for polycythemia Whole blood vs. reconstituted blood (FFP ⴙ pRBCs) for ECMO circuit priming Early volume expansion with FFP Acute episodes of DIC controlled with FFP & Cryo FFP & Cryo for DIC due to congenital protein C deficiency Transient improvement in pt with Kasabach-Merritt syndrome FFP, Cryo, Plts in pts with DIC Multiple therapies for consumptive coagulopathy in 6 pts with KasabachMerritt Syndrome Pts with hemophilia managed with cryo & pRBCs Cryo prepared from apheresis of 1 donor to treat bleeding in child with vWD

No. Patients

Outcome

Level

Increased plt count; shortened bleeding time; no change in rate of IVH No difference in rate of new IVH

B

B

1

Similar rates of survival; no long-term disability No difference in resolution of DIC or survival Decreased rate of IVH in FFP group No sustained improvement in blood pressure in any group No difference in mortality or cranial ultrasound abnormality Similar rates in decrease of hematocrit Reconstituted blood group has shorter length of stay and less peri-operative fluid overload No impact on mortality, cerebral palsy, hypotension, IVH Pt was stabilized

1

Pt was stabilized

B

1

Pt went to surgery after addition of transexamic acid

B

1

Pt was stabilized with all 3 products Reversal of coagulopathy in all pts

B

152

53 49 33 73 60 776

26 200

2

13 1

Component-directed therapy based on hemostatic defects

B

B B B A

B B

A B

B

B Repeated plasma exchange provided cryo with excellent hemostatic function, even after storage intervals of >1 year Corrected hemostatic defects but did not affect mortality

B

B

Abbreviations: ET, exchange transfusion; MCRT, multicenter, randomized controlled trial; SCRT, single-center, randomized controlled trial; SCT, single center trial; MA, meta-analysis; RCR, retrospective chart review; CR, case report; CS, case series. Level A evidence: high-quality randomized, controlled trial (RCT) that considers all outcomes and meta-analysis (quantitative systematic review) using comprehensive search strategies. Level B evidence: (a) well-designed, nonrandomized trials (a nonquantitative systematic review with appropriate search strategies and well-substantiated conclusions); (b) lower quality RCTs, clinical cohort studies, and case-controlled studies with nonbiased selection of study participants and consistent findings; and (c) other evidence such as high-quality, historical, uncontrolled studies, or well-designed epidemiologic studies with compelling findings. Level C evidence is consensus or expert opinion.

improving blood pressure, decreasing rates or severity of IVH, decreasing mortality, or improving neurodevelopmental outcomes.

Dosing Each milliliter (mL) of undiluted plasma contains 1 international unit (IU) of each coagulation factor. Thus, a dose of 10 to 20 mL/kg of FP is expected to sufficiently correct a factordeficient patient by approximately 30%.7,8

Rate the Evidence With the exceptions of the Osborn and Evans meta-analysis41 and the NNNI trial,38 all FP studies were rated as Level B evidence. Interestingly, a small survey in 2001 on clinical practices in NICUs in Ireland revealed that nearly half of the surveyed practitioners used FP in LBW infants to treat hypotension, despite the high level of evidence to the contrary.42 At this point, the studies addressing potential indications for FP only support its use to reconstitute blood for ECMO cir-

B.S. Poterjoy and C.D. Josephson

70 cuit priming,82 and to treat coagulopathy associated with the disease processes listed in Table 3.

Cryoprecipitate Cryoprecipitate is an insoluble precipitate that forms from the thawing of FFP and is refrozen in plasma within 1 hour. Among all the plasma-based products, cryoprecipitate contains the highest concentrations of Factor VIII, von Willebrand Factor (vWF), fibrinogen, factor XIII, and fibronectin. Cryoprecipitate is stored at temperatures ⱕ⫺18°C for up to 1 year. As with all FP products, sufficient time for component preparation must be allowed to thaw and relabel the product.7

Indications Cryoprecipitate is indicated as a second-line therapy for von Willebrand’s disease (vWD) and factor VIII deficiency, when specific coagulation factors or recombinant factors are unavailable. Other indications include factor XIII deficiency and control of bleeding in patients with congenital fibrinogen deficiency or dysfunction.5,8 Twelve manuscripts consisting of case series or case reports were found describing the use of cryoprecipitate in newborn infants. Cryoprecipitate has been used in cardiac disease complicated by sepsis,43 congenital protein C deficiency,44,45 Kasabach-Merritt Syndrome,46,47 Type 3 vWD,48 and in infants with hemophilia A/B.49 Two publications reported no benefit in a preterm infant with a ruptured umbilical artery,50 and in an 11-day-old with aortic occlusion unresponsive to fibrinolytic therapy, presumably Table 3 Uses of FFP/F24 Plasma6 Indicated Multiple acquired coagulation factor deficiency Liver disease Massive transfusion Disseminated intravascular coagulation Rapid reversal of warfarin effect Plasma infusion or exchange for thrombotic thrombocytic purpura, hemolytic uremic syndrome Congenital coagulation defects* C1-esterase inhibitor deficiency*—acute episodes and prophylaxis of angioedema Reconstitution of packed red blood cells Investigational Meningococcal sepsis Acute renal failure in the context of multiorgan failure Not Indicated Immunodeficiency Infection Prevention of intraventricular hemorrhage in preterm neonate Improvement of preterm neonatal neurodevelopmental outcomes Burns Wound healing Volume expansion (hypotension) Source of nutrients *Fresh-frozen plasma is used in the absence of specific factor concentrate.

due to low plasminogen concentrations.51 One clinical trial noted correction of hematologic abnormalities in high-risk neonates with laboratory evidence of coagulopathy with the use of FP, cryoprecipitate, and/or platelets, yet had no impact on overall mortality in either preterm or term infants.52

Dosing Cryoprecipitate (a single unit has 15-20 mL) is prepared in the blood bank by thawing and pooling several individual units together and then issuing the product. It is generally known that, to increase the fibrinogen level by 60 to 100 mg/dL in children and adults, fibrinogen replacement is dosed at 1 U/10 kg. Yet in neonates, 1 unit may increase the fibrinogen level by more than 100 mg/dL. Several publications have recommended dosing regimens in neonates that range from 2 mL/kg to 1 U/7 kg.53,54 The half-life of fibrinogen (3-5 days), along with the underlying cause for the deficiency (hemorrhage/DIC versus congenital hypofibrinogenemia), will determine the dosing frequency. Thus, the administration of cryoprecipitate may vary from every 8 to 12 hours for up to every several days.

Rate the Evidence Most of the evidence in the literature regarding the use of cryoprecipitate in neonates is Level B (Table 2). As standard practice, cryoprecipitate has been used to treat congenital hypofibrinogenemia and factor XIII deficiency. In addition, the use of cryoprecipitate has been extrapolated from the adult literature to treat neonates with acquired hypofibrinogenemia during DIC or liver failure. This is now considered standard therapy, despite the lack of evidence specifically in the neonatal population. Similarly, patients with vWD or FVIII deficiency who are bleeding warrant a transfusion of cryoprecipitate when a vWF-containing concentrate or a recombinant FVIII product is unavailable. These recommendations are Level C evidence, because they are based on expert opinion rather than scientific evidence.

Transfusion-Related Morbidity and Mortality Several studies have consistently reported an association between platelet transfusions and increased mortality in neonates. Del Vecchio and coworkers28 evaluated 114 neonates who received platelet transfusions in a NICU, and found that those who received a single transfusion during their hospital stay had a relative risk of death 10.4 times greater than those who received no platelets. Furthermore, the risk of death of infants who received more than 4 platelet transfusions was 29.9 times greater than that of nontransfused neonates. A subsequent study by Garcia and coworkers29 also found a significantly higher mortality among neonates who received platelet transfusions compared with those who did not (24.5% versus 3.7%). More recently, Baer and coworkers55 reported a near-linear correlation between the number of platelet transfusions and the mortality among 1600 thrombocytopenic NICU patients. Specifically, the mortality rate

Platelets, frozen plasma, and cryoprecipitate

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Table 4 Risks of Plasma Product Transfusion Transfusion Complication

Description

Transfusion Related Acute Lung Injury (TRALI)

Two formal definitions: (1) “A new acute lung injury (ALI) that develops with a clear temporal relationship to transfusion, in patients without or with alternate risk factors for ALI” (NHLBI). (2) “A new episode of ALI that occurs during or within 6 hours of a completed transfusion which is not temporally related to a competing etiology for ALI” (Canadian Consensus Conference on TRALI, 2004). Signs and Symptoms: Shortness of breath (from noncardiogenic pulmonary edema), fever, and hypotension. Diagnosis: Clinical and radiographic, not a laboratory test. Pathogenesis: Injury mediated by HLA/complement or donor granulocytes.

Transfusion Associated Circulatory Overload (TACO)

Signs and Symptoms: Noncardiogenic pulmonary edema; absence of fever, hypotension. Pathogenesis: Not immunologically based, rather related to transfusion of excessive fluid to the recipient over a short period of time.

Acute Hemolytic Transfusion Reactions (AHTR) (ABO incompatibility)

Signs and Symptoms: fever, chills, rigors, facial flushing, nausea and vomiting, hypotension, hemoglobinuria, oliguria/anuria. Pathogenesis: Preexisting antibody in a patient’s plasma that binds to an incompatible cognate antigen on the transfused red blood cell (RBC) surface resulting in destruction; alternatively, antibodies exist in the donor plasma and bind to the patient’s RBCs and cause hemolysis.

Febrile Non-hemolytic Transfusion Reactions

Symptoms: Temperature increase of greater than 1°C (1.8°F) associated with a transfusion that cannot be attributed to another cause. Pathogenesis: Leukocyte contamination from the donor.

Metabolic Complications

Hyperkalemia, hyper- and hypoglycemia, hypocalcemia, and hypothermia.

Septic/Bacterial Contamination

Symptoms: Range from no obvious signs or symptoms of reactions, to fever with evidence of sepsis, or the most extreme, septic shock and death. Platelet transfusions are more commonly associated with septic reactions, compared with RBCs or plasma products.

Viral Contamination

Viruses: Human immunodeficiency virus (HIV), Hepatitis B (HBV), Hepatitis C (HCV), and Cytomegalovirus (CMV). Blood banking efforts have reduced overall risk of HIV, HBV, HCV. The risk of transfusion-transmitted CMV infection is higher in multi-transfused LBWI born to seronegative mothers.86,87 For this reason, it is recommended that LBW infants born to CMV-seronegative mothers receive CMV-reduced-risk-blood for transfusion. Blood from CMV-seronegative donors, or leukocyte-reduced components can effectively be used to reduce the risk of transfusion-transmitted CMV.88,89

was 2% among infants who received no platelet transfusions, 11% among those with 1 to 2 transfusions, 35% among those with ⬎10 transfusions, and 50% among those who received ⱖ20 transfusions. In a retrospective review focused exclusively on preterm neonates ⬍28 weeks gestation, Bonifacio and coworkers reported a 51% mortality rate among thrombocytopenic infants who received platelet transfusions, compared with 14% among nontransfused age-matched infants.56 Thrombocytopenia is also a well-known hematological abnormality in infants with necrotizing enterocolitis (NEC),57 and in this setting also receiving a greater number of platelet transfusions was associated with a higher incidence of short bowel syndrome and cholestasis.58 Thus, an association between platelet transfusions and higher neonatal mortality and morbidity has been established by a number of studies in different clinical settings. However, it is still unclear whether the platelet transfusions per se contribute to the higher mortality and morbidity, or whether the need for platelet transfusions is simply a marker of severity of illness among neonates, with the sickest

neonates receiving more transfusions and also logically having worse outcomes. Prospective studies designed to answer this question are imperative. The literature addressing the association between FP transfusions and mortality in neonates is sparse. Although specific mortality data in adults is also meager, the association between specific morbidities and FP transfusions has been well documented in that population (see Table 4). Moreover, recent adult studies have challenged the efficacy of FP in correcting mild coagulopathy. For instance, Dara and coworkers59 retrospectively reviewed coagulopathic adults (INR ⱖ 1.5) with no bleeding, and found that FP failed to correct the INR in 67% of those patients. Furthermore, the mortality rate was similar among those who received FP transfusions compared with those who did not.

Transfusion-Associated Complications Transfusion-related acute lung injury, or TRALI, is clinically defined as dyspnea, hypoxia, and pulmonary infiltrates man-

B.S. Poterjoy and C.D. Josephson

72 ifesting on chest radiograph within 6 hours of receiving a blood transfusion. The underlying mechanism of TRALI is not completely understood, and despite its seemingly common occurrence, it is likely underreported.60,61 Whereas the blood component thought to confer the greater risk for developing TRALI remains vague, some have implicated wholeblood platelets,62 and others have linked anti-HLA antibodies present in plasma to this reaction.63 In support of the latter hypothesis, the plasma of female, multiparous donors, which is most likely to have multiple anti-HLA antibodies, has been causally associated with TRALI.63,64 This observation led to the deferral of these donors in the UK10 as well as in the U.S. Recently, the occurrence of TRALI in pediatric patients was reviewed and was thought to be more common than previously appreciated in the setting of hematologic malignancy.65 To date, no studies have explored the incidence of TRALI in neonates, hence its prevalence remains unknown in this population. A second transfusion complication, transfusion-associated circulatory overload (TACO), appears in its clinical features similar to TRALI, yet the underlying pathophysiology is more related to fluid volume rather than to an immunologic response.11 Other differentiating features of TACO include a relationship with the rate of infusion66 and its association with platelets rather than plasma.11 Despite the clinical similarities of acute hypoxemia and lung infiltrates, the hallmark of TACO is a fluid-overloaded state, manifested by typical signs such as jugular vein distension and hypertension, both of which respond to diuretic therapy. To aid in the clinical distinction of TRALI and TACO, some practitioners have utilized the pathophysiologic differences to establish diagnostic algorithms.67,68 As with TRALI, studies describing TACO in neonates are nonexistent. It may be fair to say that TRALI/TACO may go unrecognized and are thus likely underreported in neonates, particularly among ELBW infants who undergo prolonged hospitalizations and among neonates with surgical complications, such as NEC. Accordingly, it remains of clinical importance to maintain TRALI/TACO in the differential diagnosis of any infant whose respiratory status and chest radiograph unexplainably deteriorate during or shortly after the infusion of a plasma-containing blood product. A third concern in transfusing plasma-containing products is the risk for bacterial contamination. This is a particularly serious concern with platelets, as these are stored at room temperature for up to 5 days, thus allowing for bacterial proliferation. Multiple studies, case reports, and case series have implicated the transfusion of blood products in the pathogenesis of bacterial bloodstream infections, which certainly contribute to increased lengths of stay and mortality rates.69-72 One UK report on the possible transmission of Creutzfeld-Jacob disease through contaminated plasma resulted in a policy change on the administration of U.S.-imported FFP to children from that country.73 As the demographics in the U.S. continue to change secondary to immigration, the risk of transfusion transmitted infections has become an increasingly important topic of surveillance and investigation (Table 4).74-76

Conclusion The intent of this paper was to review and evaluate the existing literature on the transfusion of platelets, plasma, and cryoprecipitate in neonates. To a large extent, the basis for transfusion of these blood components was found in lower quality clinical studies (Level B). Current recommendations for platelet transfusions in neonates are mainly derived from expert opinions, rather than evidence-based science. Two publications stand alone that attempted to identify transfusion triggers for prophylactic platelet transfusions in nonbleeding neonates.25,27 Current guidelines for frozen plasma and cryoprecipitate transfusions in neonates are based not on evidence, but rather opinion. The risks associated with transfusions are several, and transfusion complications may be more common than currently recognized or reported. Thus, the greatest challenge for the neonatologist is to behold the risks of transfusing (or not) a nonbleeding patient, while weighing the possibility of developing a complication related to the transfusion. To quantify the potential risks associated with transfusion, practitioners must design, implement, and publish the results of prospective trials in the NICU.

References 1. Andrew M, Paes B, Milner R, et al: Development of the human coagulation system in the full-term infant. Blood 70:165-172, 1987 2. Andrew M, Paes B, Milner R, et al: Development of the human coagulation system in the healthy premature infant. Blood 72:1651-1657, 1988 3. Hellstern P, Muntean W, Schramm W, et al: Practical guidelines for the clinical use of plasma. Thromb Res 107:S53-S57, 2002 (suppl 1) 4. Stanworth SJ, Brunskill SJ, Hyde CJ, et al: Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol 126:139-152, 2004 5. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al: Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 126:11-28, 2004 6. Josephson C, Hillyer CD: Transfusion of plasma derivatives: fresh frozen plasma, cryoprecipitate, albumin and immunoglobulins, in Benz E, Cohen HJ, Furie B, et al (eds). Hematology, Basic Principles and Practice. (ed 4). New York, NY, Churchill-Livingston, 2009 (in press) 7. Josephson C: When and how to use blood products, in Rudolph AM, Rudolph C, First L, Lister G, et al (eds). Rudolph’s Pediatrics (ed 22). Media, PA, McGraw Hill, 2009 (in press) 8. Josephson C: Neonatal and pediatric transfusion practice, in Roback J (ed). Technical Manual (ed 16). Bethesda, MD, AABB Press, 2008 9. Stanworth SJ, Brunskill SJ, Hyde CJ, et al: Appraisal of the evidence for the clinical use of FFP and plasma fractions. Best Pract Res Clin Haematol 19:67-82, 2006 10. MacLennan S, Williamson LM: Risks of fresh frozen plasma and platelets. J Trauma 60:S46-S50, 2006 (suppl) 11. Gajic O, Dzik WH, Toy P: Fresh frozen plasma and platelet transfusion for nonbleeding patients in the intensive care unit: benefit or harm? Crit Care Med 34:S170-S173, 2006 (suppl) 12. Muntean W: Fresh frozen plasma in the pediatric age group and in congenital coagulation factor deficiency. Thromb Res 107:S29-S32, 2002 (suppl 1) 13. Goldenberg NA, Manco-Johnson MJ: Pediatric hemostasis and use of plasma components. Best Pract Res Clin Haematol 19:143-155, 2006 14. Siwek J, Gourlay ML, Slawson DC, et al: How to write an evidencebased clinical review article. Am Fam Physician 65:251-258, 2002 15. Castle V, Andrew M, Kelton J, et al: Frequency and mechanism of neonatal thrombocytopenia. J Pediatr 108:749-755, 1986

Platelets, frozen plasma, and cryoprecipitate 16. Mehta P, Vasa R, Neumann L, et al: Thrombocytopenia in the high-risk infant. J Pediatr 97:791-794, 1980 17. Hill A: Neurological and neuromuscular disorders, in Taeusch HW, Ballard RA, Gleason CA (eds). Avery’s Neonatology. Pathophysiology and Management of the Newborn (ed 6). Philadelphia, PA, Lippincott Williams and Wilkins, 2005, pp 1384-1409 18. Horbar JD, Badger GJ, Carpenter JH, et al: Trends in mortality and morbidity for very low birth weight infants, 1991-1999. Pediatrics 110:143-151, 2002 19. Lemons JA, Bauer CR, Oh W, et al: Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 107:E1, 2001 20. Setzer ES, Webb IB, Wassenaar JW, et al: Platelet dysfunction and coagulopathy in intraventricular hemorrhage in the premature infant. J Pediatr 100:599-605, 1982 21. McDonald MM, Johnson ML, Rumack CM, et al: Role of coagulopathy in newborn intracranial hemorrhage. Pediatrics 74:26-31, 1984 22. Beverley DW, Chance GW, Inwood MJ, et al: Intraventricular haemorrhage and haemostasis defects. Arch Dis Child 59:444-448, 1984 23. Van de Bor M, Briet E, Van Bel F, et al: Hemostasis and periventricularintraventricular hemorrhage of the newborn. Am J Dis Child 140:11311134, 1986 24. Amato M, Fauchere JC, Hermann U Jr: Coagulation abnormalities in low birth weight infants with peri-intraventricular hemorrhage. Neuropediatrics 19:154-157, 1988 25. Andrew M, Vegh P, Caco C, et al: A randomized, controlled trial of platelet transfusions in thrombocytopenic premature infants. J Pediatr 123:285-291, 1993 26. Blanchette VS, Kuhne T, Hume H, et al: Platelet transfusion therapy in newborn infants. Transfus Med Rev 9:215-230, 1995 27. Murray NA, Howarth LJ, McCloy MP, et al: Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients. Transfus Med 12:35-41, 2002 28. Del Vecchio A, Sola MC, Theriaque DW, et al: Platelet transfusions in the neonatal intensive care unit:factors predicting which patients will require multiple transfusions. Transfusion 41:803-808, 2001 29. Garcia MG, Duenas E, Sola MC, et al: Epidemiologic and outcome studies of patients who received platelet transfusions in the neonatal intensive care unit. J Perinatol 21:415-420, 2001 30. Kahn DJ, Richardson DK, Billett HH: Inter-NICU variation in rates and management of thrombocytopenia among very low birth-weight infants. J Perinatol 23:312-316, 2003 31. Josephson CD, Su L, Christensen RD, et al: Platelet transfusion practices among neonatologists in the U.S. and Canada: results of a survey. Pediatrics 2009 (in press) 32. Calhoun DA, Christensen RD, Edstrom CS, et al: Consistent approaches to procedures and practices in neonatal hematology. Clin Perinatol 27:733-753, 2000 33. Gibson BE, Todd A, Roberts I, et al: Transfusion guidelines for neonates and older children. Br J Haematol 124:433-453, 2004 34. Roberts IA, Murray NA: Management of thrombocytopenia in neonates. Br J Haematol 105:864-870, 1999 35. Roseff SD, Luban NL, Manno CS: Guidelines for assessing appropriateness of pediatric transfusion. Transfusion 42:1398-1413, 2002 36. Strauss RG: Transfusion therapy in neonates. Am J Dis Child 145:904911, 1991 37. Eder AF, Sebok MA: Plasma components: FFP, FP24, and thawed plasma. Immunohematology 23:150-157, 2007 38. The Northern Neonatal Nursing Initiative [NNNI] Trial Group: A randomized trial comparing the effect of prophylactic intravenous fresh frozen plasma, gelatin or glucose on early mortality and morbidity in preterm babies. Eur J Pediatr 155:580-588, 1996 39. Northern Neonatal Nursing Initiative Trial Group: Randomised trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: outcome at 2 years. Lancet 348:229-232, 1996 40. Beverley DW, Pitts-Tucker TJ, Congdon PJ, et al: Prevention of intraventricular haemorrhage by fresh frozen plasma. Arch Dis Child 60: 710-713, 1985

73 41. Osborn DA, Evans N: Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev 2:CD002055, 2004 42. Hussein T, Clarke T, Girim HA, et al: Questionnaire on practices and priorities in neonatal care in Ireland. Ir Med J 94:74-76, 78, 2001 43. Stammers AH, Rauch ED, Willett LD, et al: Pre-operative coagulopathy management of a neonate with complex congenital heart disease: a case study. Perfusion 15:161-168, 2000 44. Yuen P, Cheung A, Lin HJ, et al: Purpura fulminans in a Chinese boy with congenital protein C deficiency. Pediatrics 77:670-676, 1986 45. Branson HE, Katz J, Marble R, et al: Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 2:1165-1168, 1983 46. Bell AJ, Chisholm M, Hickton M: Reversal of coagulopathy in Kasabach-Merritt syndrome with tranexamic acid. Scand J Haematol 37: 248-252, 1986 47. Larsen EC, Zinkham WH, Eggleston JC, et al: Kasabach-Merritt syndrome: therapeutic considerations. Pediatrics 79:971-980, 1987 48. Pomper GJ, Rick ME, Epstein JS, et al: Management of severe VWD with cryoprecipitate collected by repeated apheresis of a single dedicated donor. Transfusion 43:1514-1521, 2003 49. Mba EC, Kulkarni AG, Fleming AF, et al: Haemophilia in northern Nigeria. Cent Afr J Med 41:59-62, 1995 50. Chuansumrit A, Nuntnarumit P, Okascharoen C, et al: The use of recombinant activated factor VII to control bleeding in a preterm infant undergoing exploratory laparotomy. Pediatrics 110:169-171, 2002 51. Corrigan JJ Jr, Jeter M, Allen HD, et al: Aortic thrombosis in a neonate: failure of urokinase thrombolytic therapy. Am J Pediatr Hematol Oncol 4:243-247, 1982 52. Turner T, Prowse CV, Prescott RJ, et al: A clinical trial on the early detection and correction of haemostatic defects in selected high-risk neonates. Br J Haematol 47:65-75, 1981 53. Erber WN, Perry DJ: Plasma and plasma products in the treatment of massive haemorrhage. Best Pract Res Clin Haematol 19:97-112, 2006 54. Fritsma MG: Use of blood products and factor concentrates for coagulation therapy. Clin Lab Sci 16:115-119, 2003 55. Baer VL, Lambert DK, Henry E, et al: Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare system. J Perinatol 27:790-796, 2007 56. Bonifacio L, Petrova A, Nanjundaswamy S, et al: Thrombocytopenia related neonatal outcome in preterms. Indian J Pediatr 74:269-274, 2007 57. Taeusch HW, Ballard RA, Gleason CA: Avery’s Diseases of the Newborn (ed 8). Philadelphia, PA, Elsevier Saunders, 2005 58. Kenton AB, Hegemier S, Smith EO, et al: Platelet transfusions in infants with necrotizing enterocolitis do not lower mortality but may increase morbidity. J Perinatol 25:173-177, 2005 59. Dara SI, Rana R, Afessa B, et al: Fresh frozen plasma transfusion in critically ill medical patients with coagulopathy. Crit Care Med 33: 2667-2671, 2005 60. Wallis JP: Transfusion-related acute lung injury (TRALI)– under-diagnosed and under-reported. Br J Anaesth 90:573-576, 2003 61. Wallis JP, Lubenko A, Wells AW, et al: Single hospital experience of TRALI. Transfusion 43:1053-1059, 2003 62. Silliman CC, Boshkov LK, Mehdizadehkashi Z, et al: Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood 101:454-462, 2003 63. Holness L, Knippen MA, Simmons L, et al: Fatalities caused by TRALI. Transfus Med Rev 18:184-188, 2004 64. Rana R, Fernandez-Perez ER, Khan SA, et al: Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study. Transfusion 46:1478-1483, 2006 65. Sanchez R, Toy P: Transfusion related acute lung injury: a pediatric perspective. Pediatr Blood Cancer 45:248-255, 2005 66. Popovsky MA: Pulmonary consequences of transfusion: TRALI and TACO. Transfus Apher Sci 34:243-244, 2006

74 67. Gajic O, Gropper MA, Hubmayr RD: Pulmonary edema after transfusion: how to differentiate transfusion-associated circulatory overload from transfusion-related acute lung injury. Crit Care Med 34: S109-S113, 2006 (suppl) 68. Skeate RC, Eastlund T: Distinguishing between transfusion related acute lung injury and transfusion associated circulatory overload. Curr Opin Hematol 14:682-687, 2007 69. Shorr AF, Jackson WL, Kelly KM, et al: Transfusion practice and blood stream infections in critically ill patients. Chest 127:17221728, 2005 70. Elward AM, Fraser VJ: Risk factors for nosocomial primary bloodstream infection in pediatric intensive care unit patients: a 2-year prospective cohort study. Infect Control Hosp Epidemiol 27:553-560, 2006 71. Richards C, Alonso-Echanove J, Caicedo Y, et al: Klebsiella pneumoniae bloodstream infections among neonates in a high-risk nursery in Cali, Colombia. Infect Control Hosp Epidemiol 25:221-225, 2004 72. Pessoa-Silva CL, Miyasaki CH, de Almeida MF, et al: Neonatal lateonset bloodstream infection: attributable mortality, excess of length of stay and risk factors. Eur J Epidemiol 17:715-720, 2001 73. Norfolk DR, Glaser A, Kinsey S: American fresh frozen plasma for neonates and children. Arch Dis Child 90:89-91, 2005 74. Centers for Disease Control and Prevention (CDC): Blood donor screening for chagas disease–United States, 2006-2007. MMWR Morb Mortal Wkly Rep 56:141-143, 2007 75. Diaz JH: Chagas disease in the United States: a cause for concern in Louisiana? J La State Med Soc 159:21-23, 25-29, 2007 76. Leiby DA, Herron RM Jr, Read EJ, et al: Trypanosoma cruzi in Los Angeles and Miami blood donors: impact of evolving donor demographics on seroprevalence and implications for transfusion transmission. Transfusion 42:549-555, 2002 77. Blanchette VS, Hume HA, Levy GJ, et al: Guidelines for auditing pediatric blood transfusion practices. Am J Dis Child 145:787-796, 1991 78. Strauss R: Blood Banking and Transfusion Issues in Perinatal Medicine. Philadelphia, PA, W.B. Saunders, 2000

B.S. Poterjoy and C.D. Josephson 79. Strauss RG: How I transfuse red blood cells and platelets to infants with the anemia and thrombocytopenia of prematurity. Transfusion 48:209217, 2008 80. Roberts I, Murray NA: Neonatal thrombocytopenia. Semin Fetal Neonatal Med 13:256-264, 2008 81. Malan AF, de V Heese H. The management of polycythaemia in the newborn infant. Early Hum Dev 4:393-403, 1980 82. Gross SJ, Filston HC, Anderson JC: Controlled study of treatment for disseminated intravascular coagulation in the neonate. J Pediatr 100: 445-448, 1982 83. Emery EF, Greenough A, Gamsu HR: Randomised controlled trial of colloid infusions in hypotensive preterm infants. Arch Dis Child 7:1185-1188, 1992 84. Supapannachart S, Siripoonya P, Boonwattanasoontorn W, et al: Neonatal polycythemia: effects of partial exchange transfusion using fresh frozen plasma, Haemaccel and normal saline. J Med Assoc Thai 82:S82S86, 1999 (suppl 1) 85. Mou SS, Giroir BP, Molitor-Kirsch EA, et al: Fresh whole blood versus reconstituted blood for pump priming in heart surgery in infants. N Engl J Med 351:1635-1644, 2004 86. Adler SP, Chandrika T, Lawrence L, et al: Cytomegalovirus infections in neonates acquired by blood transfusions. Pediatr Infect Dis 2:114-118, 1983 87. Gilbert GL, Hayes K, Hudson IL, et al: Prevention of transfusion-acquired cytomegalovirus infection in infants by blood filtration to remove leucocytes. Neonatal Cytomegalovirus Infection Study Group. Lancet 1:1228-1231, 1989 88. Brady MT, Milam JD, Anderson DC, et al: Use of deglycerolized red blood cells to prevent posttransfusion infection with cytomegalovirus in neonates. J Infect Dis 150:334-339, 1984 89. Bowden RA, Slichter SJ, Sayers M, 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 86:3598-3603, 1995