Platelet Transfusion Medicine

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Platelet Transfusion Medicine Alexa J. Siddon*†‡, Christopher A. Tormey*‡ and Edward L. Snyder*

* Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States, †Department of Pathology, Yale University School of Medicine, New Haven, CT, United States, ‡Pathology & Laboratory Medicine, VA Connecticut Healthcare, West Haven, CT, United States

INTRODUCTION 1137 PLATELET PREPARATION 1137 Methods 1137 Quality Control 1139 PLATELET STORAGE AND STORAGE INJURY 1140 Platelet Concentrate Storage Conditions 1141 Platelet Storage Containers 1141 Metabolic Changes During Platelet Storage 1141 Anticoagulants 1141 Platelet Storage Solutions 1142 Platelet Activation During Storage 1142 Platelet-Derived Microparticle Formation in Platelet Concentrates 1143 Apoptotic Activity of Stored Platelets 1143 Cold Storage of Platelets 1143 POSTCOLLECTION PROCESSING 1143 Leukocyte Reduction of Platelet Components 1143 Gamma and Ultraviolet Irradiation of Platelets 1144 Pathogen Inactivation Technology 1144 Volume-Reduced Platelet Concentrates 1145 PLATELET TRANSFUSION THERAPY 1145 General Considerations in Platelet Transfusion Therapy 1145 Prophylactic Platelet Transfusion 1146 Efficacy of Platelet Transfusion 1147 Platelet Dosing 1147 Platelet Transfusions in Other Settings 1148 Autologous Platelet Donation and Cryopreserved Platelets 1149 ADVERSE REACTIONS TO PLATELET TRANSFUSION 1149 Febrile Reactions to Platelet Transfusion 1149 Bacterial Contamination of Platelet Concentrates 1150 Platelet Refractory State 1151 Hypotensive Reactions During Platelet Transfusions 1151 THROMBOPOIETIC GROWTH FACTORS IN PLATELET TRANSFUSION THERAPY 1152 CONTROVERSIES AND FUTURE DIRECTIONS IN PLATELET TRANSFUSION THERAPY 1152 CONCLUSIONS 1152 REFERENCES 1152

INTRODUCTION Platelets maintain normal hemostasis through their elaborate responses to vascular injury. Accordingly, patients with low numbers of circulating platelets or functionally hyporeactive Platelets. https://doi.org/10.1016/B978-0-12-813456-6.00064-3 Copyright © 2019 Elsevier Inc. All rights reserved.

platelets are at increased risk of spontaneous bleeding or hemorrhage following traumatic injuries or during surgical procedures. Thrombocytopenic bleeding was a major cause of death in patients with acute leukemia until platelet concentrates (PCs) became widely available in the early 1970s.1 Before then, the only source of viable platelets was freshly drawn whole blood. Routine platelet transfusion therapy was made possible in large part by the development of gas-permeable plastic containers that facilitate the collection, separation, and storage of platelets derived from whole blood.2 Today, PCs are used extensively to support patients who receive thrombocytopenia-inducing, intensive therapies for hematologic malignancies and solid tumors. Transfusion services strive to maintain an adequate supply of PCs that is both safe and efficacious to support patient needs. Unfortunately, the constrained 5-day (120 hour) shelf-life of modern-day room temperature PCs without any additional testing or modifications makes it impractical for blood banks to maintain large reserves of products. The safety of platelet transfusions, in terms of the risk of viral and bacterial transmission, has improved with advances in donor selection and testing. In addition, methods for inactivating contaminating bacteria and monitoring bacterial growth are being implemented in many countries, and this will further increase PC safety and availability.

PLATELET PREPARATION Platelets used in clinical transfusion practice are prepared by either centrifuging whole blood obtained from a volunteer donor following single blood donation, or by apheresis using automated cell separators. The processes used to separate platelets from the other parts of whole blood have evolved during the past several decades to maximize the yield of platelets while limiting the number of contaminating red and white blood cells. Isolating platelets from other blood cells also allows platelets to be stored under optimal conditions, which are different from the conditions used to store other blood components such as red blood cells and plasma.

Methods Platelet Concentrates Prepared From Whole Blood by Platelet-Rich Plasma and Buffy Coat Methods Blood is drawn through wide-bore, 16–17 gauge, siliconized needles to minimize the activation of platelets and clotting proteins. Extracted blood is immediately mixed with citrate anticoagulant. Before separation by centrifugation, whole blood must be left undisturbed at room temperature for a 45–60 minute period because platelets are activated during blood collection. Approximately 450 mL of whole blood is withdrawn during allogeneic donation, which is then separated to yield a unit each of red cells, platelets, and plasma. Platelets prepared in this manner are often referred to as whole blood “random donor” platelets (WB-RDP) because the human leukocyte antigen (HLA) and red cell antigen type of the donor is unknown

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PART VI Therapy to Increase Platelet Numbers and/or Function

+/– Leukoreduction Plasma PRP

Hard Spin

Soft Spin

Single-donor PC

Whole blood

(A) Plasma or platelet additive solution Plasma

Fig. 64.1 Preparation of platelet concentrates from anticoagulated whole blood by the (A) platelet-rich plasma and (B) buffy coat techniques. (Reprinted from Ref. 3, with permission.)

Pool buffy coats

Hard Spin

Whole blood

+/– Leukoreduction

Soft Spin

RBC

Pooled PC

(B)

(i.e., of random HLA or blood group type). Each WB-RDP contains on the order of 5.5
1010 platelets suspended in approximately 50–60 mL of the donor’s plasma. This volume of suspending plasma is required to maintain platelet viability during storage. The two major methods used to isolate platelets from whole blood are the platelet-rich plasma (PRP) and the buffy coat (BC) methods (Fig. 64.1).3 Most PCs in the United States are prepared by the PRP method, whereas the BC method is preferred in Europe. Anticoagulated blood is separated based on differential sedimentation, a process that is accelerated by centrifugation. The sedimentation rate is most heavily influenced by the physical properties of cells (specific gravity, size, and deformability) and the viscosity of the medium. Separation times and speeds are optimized to maximize platelet yields within short manufacturing time periods. PRP Method. In the PRP technique, whole blood first undergoes a low g force (“soft”) spin, which separates red cells from PRP (Fig. 64.1A). Low-speed centrifugation results in a supernatant (PRP) that contains the majority of suspended platelets, 30%–50% of the original white cells, and few red cells. The PRP is transferred to a satellite bag and centrifuged at a higher g force (“hard” spin). The platelet-poor plasma supernatant is removed, and the platelet pellet is gently resuspended in 50–60 mL of residual plasma. Leaving the product undisturbed for 1 hour at room temperature prior to resuspension is intended to minimize platelet aggregation and damage, although one study found no difference in platelet characteristics or in vivo platelet survival when comparing rest times of 0 minutes, 5 minutes, 1 hour, and 4 hours.4 The PRP method yields approximately 5.0–7.5
1010 platelets per bag, or 60%– 75% of the platelets found in the whole blood unit before separation. Multiple (e.g., four to six) PRP units are often combined to create a platelet “pool” that is more convenient to transfuse than are multiple, single PRP units. Platelets pooled in blood banks must be transfused within 4 hours of

preparation because of the risks of bacterial contamination during the pooling process. At present, it is rare for US-based blood banks and hospital transfusion services to pool individual concentrates on site; as further discussed below, technological advancements now allow for prestorage pooling of multiple concentrates at blood donor centers before issuance to hospital facilities for transfusion. Buffy Coat Method. When platelets are manufactured by the BC method, whole blood is first centrifuged at high force (3000g for 7–10 minutes) to create a buffy coat layer where platelets and leukocytes reside (Fig. 64.1B). Higher-speed centrifugation separates cells somewhat differently than slowspeed centrifugation. During high-speed centrifugation, white cells initially sediment with red cells, and platelets remain in the supernatant plasma. Next, red cells are packed closely together and rapidly fall to the bottom of the bag. This process forces plasma and white cells upward to the plasma interface. The platelets eventually accumulate on this interface. The settling of platelets on the red cell interface may explain the lesser degree of platelet activation when platelets are prepared by the BC compared to the PRP method.5 The resultant buffy coat, consisting of platelets and white cells, is removed along with small portions of the lower plasma layer and the upper red cell layer. The BC is then centrifuged at low g force to separate the platelets from leukocytes and red cells. “Top and bottom” bag systems facilitate separation by allowing the platelets in the buffy coat to remain relatively undisturbed in the primary separation bag (with the plasma and red cells removed from the top and bottom ports, respectively).6 In practice, four to six BCs are first pooled, diluted in plasma, and centrifuged at low speed. The resulting pooled platelet-rich supernatant is then transferred to a larger volume storage bag. Random-donor PCs can also be pooled at the collection facility to create “prestorage pooled whole blood derived platelets.” ABO identical PCs are pooled in a sterile closed system, leukocyte reduced, and tested for bacteria prior to storage.

Platelet Transfusion Medicine

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The dose of one of these pooled products is similar to that of an apheresis unit, 3
1011 platelets. A study comparing prestorage pooled PCs with nonpooled individual PCs found no differences in either platelet quality as assessed by common measures of platelet viability or inactivation of the coagulation or complement systems.7 Another study comparing these products found statistically significant differences in several in vitro tests of platelet degradation; however, these changes were not considered clinically relevant to transfusion therapy.8 Other studies have shown that prestorage pooled WB-RDP are not associated with any higher incidence of febrile transfusion reactions than are WB-RDP that are not pooled prestorage.9

are collected from donors lacking non-ABO antibodies; therefore “minor” cross-matching is not necessary. Transfusing apheresis-derived platelets that are ABO incompatible typically does not produce measurable hemolysis in adults.14 Some centers titer group O platelets to avoid the uncommon situation in which the platelet donor carries an exceptionally high-titer anti-A that could cause hemolysis if infused to a group A recipient.15 This situation is more dangerous when group O apheresis-derived platelets are given to group A infants and small children.16

Single-Donor Platelet Concentrates Prepared by Apheresis

Institutions that prepare PC used for transfusion therapy have quality control (QC) programs that detect problems in the collection, processing, or storage of these products.17 Guidelines for monitoring PC quality vary across different countries and are specific for the preparation technique.18 Most standards require measurements of platelet numbers, pH, and, when products are labeled leukoreduced, white blood cell count (Table 64.1). Platelet and white cell counts reflect the efficiency of the particular platelet collection and/or leukocyte reduction process utilized. The concentrations of platelets prepared from PRP (150,000–450,000/μL) are less than those collected by apheresis (>1,000,000/μL). In the era before widespread, prestorage bacterial contamination testing, pH was measured during storage, because a pH below 6.2 or above 7.6 correlates with decreased in vivo efficacy.20 The total volume of PCs is largely based on the amount of plasma needed to maintain product pH within an acceptable range during storage. Temperature control charts on platelet incubators verify that the platelets were stored between 20 and 24°C. Visual inspection of units is also critical, typically performed at the time of manufacture, at the time of receipt by a transfusion facility, and finally immediately before issuance from the blood bank. Such inspection can aid in the detection of significant bacterial contamination, which is often visible to the naked eye. For example, bacterial contamination can be visualized as noted in Fig. 64.2.

Platelets collected by cell separators are generally referred to as “platelets, apheresis” or “single-donor platelets (SDP) by apheresis.” Donor blood removed through a catheter in an arm vein is passed through an apheresis instrument in which platelets are separated from other cellular components by differential centrifugation. Instruments are automated in that separation parameters are determined by the instrument’s electronics based on input parameters, including the donor’s weight, platelet count, and hematocrit. PRP is separated from whole blood in the centrifuge; the residual red cells and plasma are returned to the donor. Most apheresis systems directly collect platelets as PRP, whereas other systems yield a concentrated platelet pellet that must be gently resuspended. Approximately 4 or 5 L of donor blood is processed during the 1.5- to 2-hour collection. Other systems have been developed that can collect not only platelets but also red cells and plasma during a single donation.10 Although platelet apheresis is well tolerated by most donors, adverse reactions related to citrate toxicity (hypocalcemia) and hemodynamic instability can occur.11 Interestingly, there is evidence of platelet activation in donors several days after platelets are collected by apheresis.12 Moreover, repeated platelet donations by apheresis can result in the transient appearance of mild platelet dysfunction in the donor.13 United States Food and Drug Administration (FDA) code of federal regulations require that an apheresis platelet product contain at least 3
1011 platelets suspended in approximately 200 mL of donor plasma. Thus, one apheresis SDP approximates six WB-RDP, but because of the variability in platelet collection, the range is four to eight WB-RDP. Because of increased machine efficiency, many blood centers can collect two, or up to three, SDP doses (6–9
1011 platelets) from a single apheresis procedure. Modern instruments collect concentrated platelets that contain few white cells—typically less than 1
106—and these SDP are considered leukocyte-reduced by most standards. Plateletpheresis products that undergo standard prestorage bacterial testing are stored at 20–24°C for up to 5 days, identical to platelets prepared by other methods. Apheresis-derived platelets, like BC- and PRP-prepared PCs,

Quality Control

Platelet Counting in Platelet Concentrates The original methods employed to enumerate platelets used small-volume chamber hemocytometers and phase contrast microscopy. These techniques required removal of red cells by lysis or sedimentation before counting and were timeconsuming, labor-intensive, and highly variable with coefficients of variation exceeding 10%. Thus, automated hematology analyzers are commonly used by blood banks to determine platelet counts in PCs in a more rapid and reproducible manner. Although the precision and accuracy of most instruments are generally considered acceptable, a multicenter study conducted by the Biomedical Excellence for Safer Transfusion (BEST) Collaborative group found significant interanalyzer

TABLE 64.1 Standards for Platelet Concentrate Quality Assurance United States18 Whole Blood Derived

Apheresis Derived

Platelets (
1010) Volume (mL)

5.5 Not specifieda

30 Not specifieda

White cells (
106) to label leukoreduced pH

<0.83b >6.2

Europe19 Whole Blood Derived

Apheresis Derived

<5.0b

PRP  0.02, BC  0.005 >40 mL per 60
109 platelets <1.0a

20 >40 mL per 60
109 platelets <1.0a

>6.2

6.4–7.4

6.4–7.4

Standard met if 90% of units tested fall within indicated values. Volume of plasma sufficient to keep platelet pH > 6.2. In 95% of units tested.

a

b

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PART VI Therapy to Increase Platelet Numbers and/or Function TABLE 64.2 Factors That Influence Development of the Platelet Storage Defect

Fig. 64.2 Visualization of bacterial contamination of a platelet product. Arrows indicate streaming, aggregated platelets, which have become activated with bacterial contamination.

variability among instruments used to count platelet numbers in PCs.21 There are several possible explanations for variability in PC platelet counting. First, hematology analyzers are designed for whole blood samples—not PRP—and thus are calibrated using whole blood controls. Second, analytic errors can be introduced when PC samples are diluted before analysis. Third, platelet aggregates can form during product sampling, which results in falsely low platelet counts.

Residual White Cell Counting in Platelet Concentrates Centers that produce leukoreduced PCs must ensure that a sufficient number of white cells have been removed from products.22 Automated hematology analyzers are inappropriate for determining white cell numbers in leukoreduced PCs because of their lack of sensitivity when trying to measure very low WBC counts such as are seen in leukoreduced PCs.23 Most residual white cell counts are therefore performed by manual chamber techniques using larger volume chambers such as the 50 μL Nageotte-type hemacytometer.24 While these “chamber” white cell counts are considered acceptable for monitoring PC quality, alternative approaches have been developed that are more precise and accurate at the low white cell counts found in leukoreduced PCs. These techniques, which are not routinely employed by blood centers to verify adequate leukoreduced PCs, include flow cytometry, microvolume fluorometry, and quantitative polymerase chain reaction (PCR).25

PLATELET STORAGE AND STORAGE INJURY PCs undergo alterations during collection, processing, and storage that adversely affect their structure and function. These changes, commonly referred to as the platelet storage defect (PSD) or platelet storage lesion (PSL), are important because they are associated with decreased post-transfusion in vivo platelet survival.26 Several factors related to the collection, processing, and storage of PCs that influence development of the PSD have been identified (Table 64.2).27 For example, centrifugation may damage platelets by exposing them to

Collection and Separation Techniques

Storage Conditions and Processing

Blood drawing flow rate Type of anticoagulant/preservative solution Ratio of anticoagulant to whole blood Time between whole blood collection and separation Centrifugation forces (time and g force) Processing temperature

Storage temperature Storage duration Form and intensity of platelet agitation Volume of suspending plasma in PCs Composition of storage container (permeability) Leukodepletion technique

conditions of high shear stress. Shear stress may cause the release of both cytosolic lactate dehydrogenase (LDH) and platelet granule contents.28 Residual leukocytes and platelets remain metabolically active during storage and continue to consume nutrients and produce potentially harmful metabolic products. Cellular debris and proteolytic enzymes are also found in the surrounding plasma. Interactions between stored platelets and suspending plasma may activate clotting factors and, thus, the coagulation system. Stored PCs have been studied using a wide variety of techniques including platelet morphology by microscopy, pH, LDH, platelet activation markers, osmotic recovery, platelet aggregation, and extent of shape change (Table 64.3).29,30 Simple evaluations include visually inspecting PCs before they are transfused. Normal discoid platelets, when exposed to a light source and the plastic storage bag is gently rotated or squeezed, refract light and produce a visual “swirling” phenomenon that can be identified by trained personnel.31 If the pH of the unit of PC falls below about pH 6.2, the platelet undergoes a disc-tosphere transformation and the refraction of light is lost and the platelet “swirl” disappears. The lack of swirling may thus correlate with a less-than-predicted post-transfusion platelet increment.32 In clinical practice, however, only platelet number, concentrate volume, supernatant pH, and white cell number are routinely measured in PCs; these tests likely reflect only a small subset of changes that occur during platelet storage. Many investigators believe that in vivo autologous recovery of radiolabeled platelets is the gold standard test of platelet viability TABLE 64.3 In Vitro Tests of Platelet Concentrate Quality PLATELET STRUCTURE Cellular content (platelet count) Visual inspection for swirling phenomena Platelet morphology by microscopy Platelet size distribution by automated counters FUNCTIONAL TESTS Platelet aggregation, spontaneous and to agonists Hypotonic shock response Extent of shape change Thrombin-stimulated ATP release METABOLIC STATUS Supernatant pH, pO2, pCO2, HCO3 Glucose consumption Lactate production PLATELET ACTIVATION P-selectin (CD62P) surface expression Soluble P-selectin release to supernatant Platelet factor 4 and β-thromboglobulin Annexin V binding Lactate dehydrogenase release to supernatant Platelet microparticle formation

Platelet Transfusion Medicine

and should be conducted when storage conditions and/or platelet substitutes are evaluated.33 The survival curves of transfused platelets, whether an allogeneic PC prepared by a standard or novel technique, should approximate those curves obtained when unaltered autologous platelets are infused. Standardized methods utilize radiolabeling of platelets with chromium or indium.34

Platelet Concentrate Storage Conditions Platelet Storage Temperature and Platelet Cold Injury PCs were originally stored refrigerated like red blood cell units until it was determined that platelet viability is severely compromised when stored at these colder temperatures.35 They are now most often stored at 20–24°C, which markedly improves post-transfusion viability as compared to cold storage.36 Alternatively, the viability of platelets stored at physiologic temperatures (closer to 37°C) is lower than those stored at 22°C. This observation may be related to the normal high metabolic rate of platelets with rapid adenosine triphosphate (ATP) turnover—a rate that can be decreased by maintaining platelets at lower than physiologic temperatures.37 Platelets stored at 4°C develop a sphere-like morphology, which is evidence of irreversible physical damage.38 When platelets are exposed to temperatures less than 20°C for 24 hours, as may occur during transport of platelets from a supplier to a hospital, there are observable differences in platelet morphology. These shape changes may involve actin assembly.39,40 Furthermore, refrigerated platelets are rapidly cleared from the circulation upon transfusion. Evidence suggests that this clearance is mediated by the integrin αMβ2 (Mac-1) on Kupffer cells in the liver that recognize clustered glycoprotein (GP) Ib receptors on chilled platelets, resulting in rapid platelet phagocytosis.41 The circulation of functional cooled platelets in mice can be prolonged through enzymatic galactosylation of chilled platelets, which effectively blocks a lectin that recognizes exposed β-N-acetylglucosamine (βGlcNAc) residues of N-linked glycans on GPIbα.42 However, post-transfusion survival of chilled platelets in humans was not improved by galactosylation.43 Despite these negative findings for cold stored platelets, the blood bank community has shown renewed interest in this type of storage because of some data indicating that cold exposure may actually make platelets “hyperhemostatic.” Given the rapid developments that have taken place regarding these products we will elaborate much more on their clinical use in the section on “Cold Storage of Platelets”, as well as later in this chapter in the section on “Controversies and Future Directions in Platelet Transfusion Therapy”.

Agitating Platelet Concentrates PCs are routinely stored with continuous gentle agitation in order to slow deterioration of in vitro measures of platelet function and structure.44 In addition, agitation appears to prolong platelet survival following transfusion.45 Horizontal agitation on a flat-bed agitator is generally preferred over circular rolling “Ferris wheel”-type agitation.46 Agitation is thought to enhance the transport of gases like O2 through the storage bag. There is evidence that PCs stored without agitation experience upregulated glycolysis, which may lead to increased lactic acid production and a fall in PC pH. The BEST Collaborative group reported that PCs could maintain a pH greater than 6.5 for up to 7 days storage after temporarily stopping agitation for the 20–24 hours that might be required to ship a PC from a blood supplier to a healthcare facility.47 These findings suggest that the PC glycolytic rate returns to lower levels after agitation is resumed.

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Platelet Storage Containers One of the most significant advances in platelet transfusion therapy was the development of plastic, gas-permeable storage containers that allow adequate O2 and CO2 exchange. The earliest storage bags composed of polyvinyl chloride (PVC) and a 2-diethylhexyl phthalate (DEHP) plasticizer did not allow platelet storage beyond 3 days. Aerobic metabolism was not maintained, which resulted in lactic acid production, a rapidly falling pH and, most importantly, poor in vivo platelet recovery and survival.48 The next generation of storage containers, composed of PVC and non-DEHP plasticizers such as butyryl-trihexyl citrate, was more gas permeable, allowing the storage of platelets for 5 days at 20–24°C, while maintaining acceptable degrees of in vitro function and survival after transfusion.49 Containers composed of polyolefin with even greater oxygen permeability have been shown to provide a stable in vitro environment for PCs stored for up to 7 days.50

Metabolic Changes During Platelet Storage The metabolic processes of human platelets continue after they are removed from the body and stored as PC.51 Moreover, the white cells found in PCs also maintain some metabolic activity. Thus, the pH of whole blood begins to decline soon after collection at a rate dependent on the buffering capacities of these cells and the suspending solution. Decrements in pH are relatively small within the first 14–24 hours after whole blood collection because of the buffering capacity of plasma and red cells. As in cold injury, platelets exposed to a pH < 6.3 exhibit morphologic changes and have diminished in vivo survival upon transfusion. Most of the pH-related effects of stored platelets appear permanent, although more modest damage may be partially reversible.52 Thus, the amount of plasma required in a PC is selected to ensure adequate buffering capacity to maintain the pH of the PC > 6.2 during the storage period. In general, 35 mL of plasma is sufficient for a single WB-RDP unit, but 50–60 mL is typically provided in practice. Platelets stored at room temperature have lower metabolic activity than platelets that circulate in vivo at body temperature and are therefore stored at 22°C.53 Based on the propensity of platelets stored at cooler temperatures to be cleared more quickly after transfusion, several studies have examined the effects of warming platelets to body temperature before transfusion. At least one recent study has found that heating autologous platelets stored at 4–6 to 37°C in a cyclic fashion resulted in some improvement in circulation kinetics, but this modification did not completely abrogate the effect of cold storage.54 Finally, the detrimental effects on platelet metabolism during storage appear at least partially reversible by “rescuing” the platelets with fresh plasma.55

Anticoagulants The anticoagulant-preservative solutions into which whole blood is drawn typically contain either of two formulations of citrate-phosphate-dextrose (CPD or CP2D) or CPD with adenine (CPDA-1). The cardiotoxic agent EDTA, used in the early days of platelet transfusion, is inappropriate because EDTAanticoagulated platelets are rapidly removed from the circulation. The concentration of citrate in CPD plasma is usually 20–22 mM. Apheresis platelets are generally collected into solutions containing citric acid, trisodium citrate, and dextrose (ACD-A). Dextrose provides a source of energy, and phosphate serves as a buffer. Adenine, which is added to blood collection bags to improve red cell survival during storage by increasing cellular ATP levels, does not appear to enhance platelet survival during storage. When pH levels and concentrations of calcium

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PART VI Therapy to Increase Platelet Numbers and/or Function

ions are maintained lower than in the physiologic state, platelets are less likely to become activated, release their intracellular contents, and undergo irreversible aggregation. The amount of citrate found in PCs does not usually produce hypocalcemia or systemic anticoagulation in recipients of PCs because the citrate is rapidly metabolized to bicarbonate in the liver. However, patients with end-stage liver disease are more prone to citrate toxicity, which can cause transient hemodynamic depression.56

Platelet Storage Solutions PCs are typically stored suspended in autologous plasma to better maintain pH and cell viability. However, a number of platelet storage solutions (PSS) have been developed that, like plasma, maintain platelet structure and function.57 A major reason for developing PSSs is that plasma not used to suspend platelets could be used for other purposes.58 This was particularly true in the 1970s and 1980s, when large amounts of plasma were needed to manufacture Factor VIII concentrates for patients with hemophilia. In addition, patients transfused with platelets stored in PSS may be less likely to experience allergic and febrile transfusion reactions and, possibly, antibody-mediated reactions like transfusion-related acute lung injury.57 Crystalloid solutions that do not contain glucose or bicarbonate do not maintain PC pH, and platelets stored in such solutions therefore exhibit reduced in vivo recovery after transfusion.59 Furthermore, at least some glucose is required in the Krebs cycle for oxidative processes and in glycolytic reactions that result in lactic acid production. Most PSS are buffered salt solutions that contain various additives (e.g., gluconate and acetate), designed to reduce oxygen consumption, glucose utilization, and lactate production, and also to limit in vitro platelet activation.60 Acetate also participates in platelet metabolism through the tricarboxylic acid (citrate) cycle and is oxidized through the respiratory chain.61 The use of acetate in PSS is thought to limit production of lactate and hence to replace glucose partially as a substrate for energy production.62 Removing plasma may decrease the incidence of certain transfusion reactions, but post-transfusion increments may be lower when platelets are resuspended in additive solutions alone.63 Other investigators, however, have been unable to demonstrate a difference in platelet recovery when PSS are used to suspend platelets.64 More recently, a study examining the use of a PSS found that apheresis platelets stored in a mixture of 65% of a PSS and 35% plasma maintained PC pH 6.9 for storage up to 5 days, while maintaining platelet survival upon transfusion.65 PSS have been used for some time in Europe when preparing buffy coat platelets,66 although they can also be used to produce platelets by the PRP technique. Various inhibitors of platelet and coagulation factor activation, such as theophylline, prostaglandin (PG) E1, and aprotinin, have been added experimentally to PSS in attempts to further preserve platelet function.67 PGE1 stimulates adenyl cyclase, whereas theophylline inhibits platelet phosphodiesterase; the net effect of both additives is increased cyclic adenosine monophosphate (cAMP) availability. cAMP at least partially inhibits calcium release from the dense tubular system membrane.68 Adding aprotinin, a broad-spectrum serine protease inhibitor, and a thrombin inhibitor (e.g., hirudin) to PGE1/theophylline PSS has also been studied in attempts to further improve in vitro platelet preservation.69 The newer PSS appear more capable of maintaining platelet integrity and metabolic properties than older formulations. Improvements include adding cations like K+ and Mg2+ to a PSS, which reduces in vitro indicators of platelet storage degradation (e.g., lower glucose uptake, decreased lactate production) after 7 days of storage; however, this was not

accompanied by improvements in platelet recovery following transfusion.70 In a similar study, platelet recovery was lower for PCs stored in a PSS containing cations than those stored in plasma, despite maintenance of in vitro indicators during storage.71 Most recently, little differences were seen in the metabolic and cellular functions of platelets stored with plasma alone compared to those stored in 20/80 plasma/PAS mixture PSS that contained higher levels of Mg2+, K+, and glucose.72 The Mg2+ appears to preserve better the ability of stored platelets to bind and aggregate to subendothelium.73 In another study, the effectiveness of PSS was questioned by investigators who found that autologous platelets stored in a 20/80 mix of plasma/PSS had poorer post-transfusion recovery than platelets stored in plasma.74 Thus, PSS may not be able to replace plasma entirely.

Platelet Activation During Storage Platelets become activated during the preparation process and during prolonged storage as assessed by flow cytometric analysis of the platelet surface expression of the α-granule membrane protein P-selectin (CD62P).75 Alternatively, soluble P-selectin can be quantified in supernatant plasma.76 P-selectin surface expression is one of the most commonly applied measures of platelet activation in PCs, and efforts have been made to standardize these measurements.77 Other proteins found within platelet granules, such as RANTES, β-thromboglobulin, platelet factor-4, and serotonin, have also been examined in stored PC.28 Annexin V binding, which is used as a marker of phosphatidylserine exposure on the platelet surface, has been examined as an alternative marker of platelet activation within the context of platelet preparation and storage. In general, annexin V binding increases during 5 days of platelet storage at room temperature.78 However, the degree of change in annexin V binding may be related in part to the method used to prepare platelets (e.g., PRP vs. apheresis-collected platelets).79 Materials and methods used to collect, prepare, and store PCs are generally designed to limit platelet activation.80 Increased platelet activation generally correlates with other adverse changes that occur during platelet storage. However, there is little evidence that the degree of platelet activation associated with platelet preparation and storage impairs the ability of transfused platelets to produce acceptable post-transfusion recovery or to arrest bleeding. Studies have been conducted to determine if activated, P-selectin-positive platelets are preferentially removed from the circulation in proportion to P-selectin surface expression. However, these studies are limited by the difficulty in controlling other factors (e.g., supernatant pH) that affect the survival of transfused platelets in the circulation.81 Michelson et al.82 demonstrated in a nonhuman primate model of platelet transfusion that transfused degranulated platelets rapidly lose surface P-selectin to the plasma pool but continue to circulate and function in vivo. This study demonstrated that platelet surface P-selectin molecules, rather than degranulated platelets, are rapidly cleared. These results were subsequently independently confirmed by Berger et al.,83 who found that the platelets of both wild-type and P-selectin knockout mice had identical life spans. When platelets were isolated, activated with thrombin, and reinjected into mice, the rate of platelet clearance was unchanged. The infused thrombin-activated platelets rapidly lost their surface P-selectin in circulation, and this loss was accompanied by the simultaneous appearance of a 100-kDa P-selectin fragment in the plasma. Storage of platelets at 4°C caused a significant reduction in their life span in vivo, but again no significant differences were observed between the two genotypes. Thus, the results of Berger et al. confirm that P-selectin does not mediate platelet clearance.83

Platelet Transfusion Medicine

Furthermore, in a thrombocytopenic rabbit kidney injury model, Krishnamurti et al.84 reported that thrombin-activated human platelets lose platelet surface P-selectin in the (reticuloendothelial system-inhibited) rabbit circulation, survive in the circulation just as long as fresh human platelets, and, most important, are just as effective as fresh human platelets at decreasing blood loss. Taken together, these studies82–84 strongly suggest that the measurement of platelet surface P-selectin in platelet concentrates stored in the blood bank should not be used as a predictor of platelet survival or function in vivo. However, platelet surface P-selectin could still be a useful measure of QC during processing, storage, and manipulation (filtration and washing). The reason is that, in contrast to the situation in vivo, the activation-dependent increase in platelet surface P-selectin is not reversible over time under standard blood banking conditions.85

Platelet-Derived Microparticle Formation in Platelet Concentrates Platelet-derived microparticles (PMPs), small particles derived from the membranes of intact platelets also known as plateletderived microvesicles, are present in PC. PMPs are strongly procoagulant, and there is evidence that they retain many of the biologic properties of intact platelets (see Chapter 22). Various mechanisms may contribute to PMP formation in PCs, including direct mechanical injury and exposure to stresses during component preparation. In addition, PMPs are formed as a result of the inevitable platelet activation that occurs during platelet processing and storage—activation that partially depends on interactions between platelets and the plastic storage container.86 PMP formation in PCs is most conveniently quantified by flow cytometric methods based on light-scattering properties and surface expression of GPIbIX or GPIIb-IIIa (integrin αIIbβ3).87 Differences in PMP formation observed when platelets are prepared using different component preparation techniques (e.g., apheresis vs. whole blood-derived PC) appear to be related to separation forces and anticoagulant concentrations.88 Platelets collected by apheresis contain more PMPs than the donor’s predonation plasma, and there is little increase in PMP number during storage, suggesting PMP formation resulted from the collection process.89 Thus, patients transfused with PCs prepared using modern techniques are exposed to significant numbers of PMPs. However, it remains unclear to what degree these procoagulant PMPs contribute to the hemostatic effectiveness of transfused platelets. In addition, fragments of white cells, endothelium, and platelets appear capable of provoking primary alloimmunization to HLA antigens in a transfusion recipient.90

Apoptotic Activity of Stored Platelets Apoptosis, or programmed cell death, plays an important role in many biological processes. During the past decade, it has been recognized that anucleate platelets undergo apoptotic-like changes in response to chemical and physical stimulation.91 Platelets contain enzymes that are central to apoptotic execution such as caspase-3, and key elements of the mitochondrial death pathway including cytochrome c, Apaf-1, and death regulators of the Bcl-2 family (see Chapter 4).92–95 Since platelets are anucleate, it is hypothesized that this apoptotic machinery originally resided in, and was programmed by, nucleated megakaryocytes from which platelets are derived. In vitro experiments demonstrate that platelet apoptosis can be induced by calcium ionophores, other platelet agonists, and following storage at room temperature under standard blood bank conditions. Platelet caspase activity is enhanced during storage at

1143

37°C; however, inhibition of caspase activity does not improve platelet viability at 37°C despite clear decreases in caspase activity.96 Evidence of platelet apoptosis also exists at the mitochondrial level in stored and experimentally stressed platelets.97,98 Understanding the role of apoptotic mechanisms in platelet survival (see Chapter 4) could contribute to a better understanding of the platelet storage lesion.

Cold Storage of Platelets The constant need for platelet products and their relatively short storage time at room temperature has prompted investigation of processes of cold storage that might prolong the shelflife of platelets for transfusion. In fact, and based on promising data regarding their hemostatic profile, cold stored apheresis platelets (held for up to 3 days without agitation) are approved by the FDA with the primary indication being hemorrhage associated with trauma.99 Investigative work continues in this domain to push the envelope of cold platelet storage, with the potential for longer storage durations and other indications outside of trauma. While current FDA approved platelets require no additional processing, there has been some work done looking at ways cold storage may be modified to reduce some of the damaging effects of lowered temperatures. For example, when Trehalosestabilized freeze-dried outdated platelets were used in a murine wound model, the preserved platelets induced wound healing to the same degree as standard PC.100 In vitro examination of Trehalose-treated platelets at 4°C showed that platelets did not undergo as rapid apoptosis as untreated platelets and were able to maintain aspects of function.101 Ultimately, platelets stored at 4°C are rapidly removed from the circulation after transfusion.102 The mechanism of this clearance is thought to be due to clustering of the platelet GPIbα receptors with a resulting increase in exposure of galactose residues; the latter are recognized by β2 integrin sialoglycoprotein receptors on hepatic macrophages which bind to and clear the platelets. This mechanism was confirmed in a murine model of thrombocytopenia.103 It was initially thought that galactosylation would block this interaction because galactosylated platelets maintained in vitro function after 14 days of cold storage and inhibited in vitro macrophage recognition.104 However, when UDP-galactose was added to platelets in a phase I trial of storage at 4°C, this treatment did not prevent clearance.43 It appears that capping the β-GlcNAc with galactosylation will prevent clearance with very short-term 4°C storage but is ineffective with the needed long-term storage; the latter continues to increase platelet-hepatic macrophage binding via both β2 integrin and Ashwell-Morell receptors.105

POSTCOLLECTION PROCESSING Leukocyte Reduction of Platelet Components In many countries, platelets, like red blood cells, are commonly leukoreduced. The United Kingdom implemented universal leukodepletion in 1999, largely based on the theoretical benefit of reducing the risk of variant Creutzfeldt-Jacob disease. The clearest benefits of leukoreduction include decreasing the risks of febrile nonhemolytic transfusion reactions, cytomegalovirus (CMV) transmission, and HLA alloimmunization.106 Platelets are most commonly leukoreduced soon after collection and before storage (prestorage leukoreduction). “Poststorage” leukoreduction refers to the less common practice of removing white cells immediately before transfusion. Prestorage leukoreduction can be performed when platelets are prepared by either the PRP method or the BC method. For the latter technique, BC concentrates are pooled and filtered through a single filter, either

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on the day of processing or after overnight storage. “Process” leukoreduction refers to the ability to collect platelets, by apheresis, with very little white cell contamination; platelets collected by apheresis are considered prestorage leukoreduced. Cotton wool was the first material used to remove white blood cells from donated whole blood.107 Currently, the three most commonly used leukoreduction filters are composed of negatively charged polyester, positively charged polyester, and noncharged polyurethane. Some polyester filters are constructed as a nonwoven mesh, whereas polyurethane filters form multilayer sponge networks. White blood cells are removed from blood by filters through several mechanisms, including simple sieving/mechanical retention based on cell size, direct adhesion of white cells to fibers, and indirect adhesion through platelets.108 Leukoreduction filters that were developed earlier removed not only leukocytes but also platelets, which adhered to the polyester fiber surface. Fibers were later modified, for example, by coating with polymers such as polyhydroxyethyl methacrylate/polystyrene, to minimize the loss of platelets during blood filtration.109 Two filters remain in widespread use: one to remove white cells from red cell concentrates and another to remove white cells from PC.

Gamma and Ultraviolet Irradiation of Platelets Residual white blood cells found in PCs can cause transfusionassociated graft-versus-host disease (TA-GVHD) in susceptible patients.110 This rare, albeit usually fatal, reaction is prevented by gamma- or X-ray irradiating PC before transfusion. Ionizing radiation inactivates residual T cells found in PCs by damaging nuclear DNA.110 Platelets that are stored for 1–5 days and then irradiated with 5000 cGy (1 rad ¼ 1 cGy) maintain normal in vitro measures of platelet structure and function.111 More important clinically, irradiated platelets (5000 cGy) produce the expected platelet increments and appear hemostatically effective when transfused to thrombocytopenic patients.112 When irradiation is performed, the FDA requires that a dose of 2500 cGy be delivered to the midplane of the irradiation canister and that a minimum dose of 1500 cGy be delivered to any other point in the canister.110 This irradiation dose effectively inactivates T cells and is well tolerated by both whole bloodand apheresis-derived products in terms of in vivo platelet recovery or platelet survival.113 Moreover, gamma irradiation does not harm in vitro measures of platelet function when apheresis-derived platelets are irradiated and stored for up to 7 days.114 However, gamma irradiation of platelets does not destroy bacteria and cannot be used to prevent bacterial or micro-organism proliferation in platelet components. Exposing platelet transfusion recipients to foreign major histocompatibility complex (MHC) antigens is a major cause of platelet alloimmunization. This in turn can lead to a platelet refractory state in which patients do not respond to platelet transfusions. The Trial to Prevent Alloimmunization to Platelets (TRAP) showed that ultraviolet B (UVB) irradiation at 1480 mJ/cm2 was equivalent to leukofiltration for decreasing the incidence of platelet refractoriness in patients with acute myeloid leukemia.106 Animal experimentation has shown that UVB-irradiated leukocytes induce a state of humoral immune tolerance in which recipients cannot respond to foreign MHC antigens.115 In vitro studies have verified that mediumwavelength (280–320 nm) UVB light inactivates leukocytes found in PCs, but the necessary dose is related to the type and size of the plastic container in which platelets are stored. When exposed to 3000 J/m2 UVB, PCs stored for up to 5 days exhibit no adverse effects on pH or aggregation responses.116 Higher doses of UVB irradiation (100,000 J/m2) cause changes in platelet structure and affects the expression of various platelet membrane proteins including GPIb.117

Pathogen Inactivation Technology Pathogen inactivation technologies (PITs), largely based on photochemical reactions or nonlight-dependent nucleic acid cross-linking, are being developed to inactivate viruses and bacteria that may contaminate blood products.118,119 An important feature of any photochemical treatment developed for platelet therapy is its ability to leave platelet function intact so that post-transfusion recovery and survival are not impaired.119 Importantly, a PIT platform based on the amotosalen-HCL (S-59) plus UVA irradiation method was approved by the FDA in 2014 for use in plasma and platelet components,120 while a platform involving riboflavin (vitamin B2) plus UVA irradiation remains under investigation.121,122 Obstacles to the implementation of the riboflavin-based platform are possibly related to the findings to be described later indicating concerns regarding loss of platelet numbers and function in stored PC treated by this technology.121–127 In one study, most platelet properties were preserved equally well after storage of PIT-treated concentrates versus PSS alone.73 However, there is contrasting evidence suggesting that treating PCs with this PIT can adversely affect platelet-dependent clot strength and aggregation after storage.128 Furthermore, platelet counts do not appear to be as well preserved after riboflavin PIT treatment, possibly related to enhancement of platelet activation and metabolic/cellular activity.129,130 A larger number of studies are available evaluating both the in vitro and in vivo experience with amotosalen and UVA (INTERCEPT, Cerus Corporation, Concord, CA). This process was shown to be fully functional in plasma and with platelets in additive solution, with complete inactivation of bacteria.131 Initial evaluations examining PIT in PC stored in plasma (rather than a storage solution) demonstrated little effect of the psoralen inactivation process on platelet morphology, hypotonic shock response, or shape change over 5 days of storage, although the pH in the PC did fall faster than in non-PRT-treated PC in plasma.132 Thus, subsequent studies have essentially examined INTERCEPT treatment in platelets stored with a PSS. In vitro studies of INTERCEPT-treated buffy coat PCs demonstrated superior in vitro platelet function and metabolic properties in PSS supplemented with Mg2+ and K+.133 When evaluating for a storage-induced increase in biologically active components, investigators found that INTERCEPT PRT did not affect the release of cytokines/chemokines over 7 days of PC storage.134 Ex vivo studies of this PRT versus conventional PCs stored for up to 7 days demonstrated a drop in platelet numbers, likely related to the inactivation process. However, under flow conditions, platelet adhesive function was maintained similarly to conventional PC. Early prospective transfusion studies demonstrated a low incidence (<1%) of transfusion reactions with this PRT process and a safety profile similar to conventional (without PRT) PC transfusion.135 Hemoviligance studies of larger patient numbers confirmed this low incidence of transfusion reactions.136 Since INTERCEPT PRT has been in use in several countries within the EU (with less practical experience among US facilities using this product given the recent FDA approval), clinical assessments of efficacy and safety from a large experience (200,000 PC transfusions) are possible. A recent review found no development of antibodies to neoantigens and no cytotoxic reactions to INTERCEPT-treated PCs.137 In fact, there appears to be a reduced incidence of febrile and allergic reactions since PRT was introduced; although there is some platelet loss during the process, there was no increase in the frequency of PC transfusion when compared to historical controls. A second retrospective review of PRT-treated patients and historical controls using data from the same database demonstrated a similar decrease in the incidence of transfusion reactions

Platelet Transfusion Medicine

and, additionally, no increase in platelet or red cell usage on a per patient basis following PRT introduction.138 In addition, a recent study on use of INTERCEPT treated products in the setting of massive transfusion indicated no adverse impacts on clinical outcomes, or increased mortality with use of these platelets.139 Thus, there appears to be no identifiable adverse impact of this PRT on component usage. These findings are supported by a report demonstrating that although the corrected count increment (CCI) in transfused patients was slightly better in standard PC versus PRT-PC (an expected finding given platelet loss during the PRT process), there were no differences in post-transfusion bleeding and overall red cell product usage, nor was there an increased interval to the next PC transfusion.140 INTERCEPT PRT side effects were also studied in a subset of atrisk subjects, namely patients receiving hematopoietic stem cell transplants (HSCT) who are thought to have a higher incidence of acute lung injury after PC transfusion.141 For HSCT patients with lung injury, there was no difference in mortality between those receiving PIT versus those receiving standard PC support. In addition, these investigators found no difference in the number of days of platelet support or the number of platelet transfusions between HSCT patients with and without acute lung injury. Finally, there is little reported experience on PIT platelet usage in pediatric populations.

Volume-Reduced Platelet Concentrates The total volume of PC prepared by the PRP technique is typically 40–60 mL. This volume is required to maintain PC pH > 6.2 during 5 days of storage, although smaller (35–40 mL) volumes of donor plasma may be adequate.142 In certain clinical situations, it may be necessary to reduce the volume of PC even further. For example, due to contained isoagglutinins (anti-A and/or -B) ABO-incompatible plasma can potentially harm neonates and small infants.143 Washing will remove platelet-specific antibodies (e.g., anti-HPA-1a) from platelets obtained from a mother who has delivered a child with neonatal alloimmune thrombocytopenia (NAT) may be indicated if the mother’s platelets are to be transfused to the newborn as a source of HPA-1a-negative platelets (see Chapter 45).

PLATELET TRANSFUSION THERAPY The earliest reports of the potential benefits of platelet transfusions utilized freshly drawn whole blood as a source of viable platelets.144 Bleeding times were reduced and hemorrhage stopped when thrombocytopenic patients were transfused with whole blood. Fresh whole blood, while now being used at some large trauma centers, is neither a convenient nor an optimal source of platelets (particularly for prophylactic transfusions), and thrombocytopenic bleeding remained a major cause of death in patients with acute leukemia.1 PC became widely available in the late 1960s and early 1970s when plastic collection/storage containers were developed that facilitated the separation of platelets from whole blood. These new sources of concentrated and viable platelets improved the outcomes of patients with hematologic malignancies and solid tumors who received intensive chemotherapy. Hematology/ oncology patients are the major recipients of PCs, although significant numbers of PCs are utilized by trauma, general surgery, cardiothoracic surgery, and solid-organ transplant services. Despite vast clinical experience with platelet transfusion therapy, transfusion practices vary widely and evidence-based guidelines are lacking.145 Platelet transfusions are primarily used to treat or prevent bleeding in patients with thrombocytopenia or platelet function defects. The majority of PCs are transfused to nonbleeding,

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thrombocytopenic patients as a prophylactic precaution.146 The effectiveness of platelet transfusions in bleeding thrombocytopenic patients has been well established through a vast accumulation of clinical experience, and not through controlled trials. It is generally agreed that increasing platelet counts to 40–50
109/L stops major bleeding. The benefit of prophylactic platelet transfusions in preventing hemorrhage in thrombocytopenic patients with bone marrow failure is more controversial. Importantly, the cause of thrombocytopenia should be established before initiating platelet transfusions because platelets are often ineffective in some thrombocytopenic conditions, such as immune thrombocytopenic purpura (ITP) (Chapter 39). In other conditions, such as thrombotic thrombocytopenic purpura (Chapter 42) and heparin-induced thrombocytopenia (Chapter 41), platelet transfusions could be harmful. Patients with congenital or acquired platelet function defects (Chapters 48 and 49) will usually have normal numbers of circulating platelets. However, since these platelets have decreased hemostatic capabilities, platelet transfusions can control or arrest bleeding in many circumstances.

General Considerations in Platelet Transfusion Therapy Each unit of WB-RDP platelets, prepared by either the PRP or BC technique, typically contains more than 5.5
1010 platelets in a volume of about 50 mL. When transfused, one WB-RDP unit is expected to increase a recipient’s platelet count by 5–10
109/L in the absence of conditions associated with decreased platelet survival such as fever, sepsis, splenomegaly, or alloimmunization to platelet antigens. Historically, WB-RDPs have been administered in “pools” of up to six units (300 mL of total volume). Many hospitals have decreased pool sizes to four or five WB-RDP units because processes used to separate platelets from whole blood have become more efficient with current technology; a WB-RDP often contains >8–10
1010 platelets per concentrate.147 Single-donor platelets collected by apheresis are highly concentrated and contain more than 3
1011 platelets, equivalent to four to eight average WB-RDP units. Testing requirements of platelet donors are the same as for any blood donor and include ABO and Rh(D) typing, as well as screens for human immunodeficiency virus (HIV)-1, HIV-2, HTLVI/II, hepatitis B, hepatitis C, syphilis, West Nile Virus, Chagas disease, and Zika virus. There is renewed emphasis on testing for emerging pathogens that threaten the blood supply and such testing (e.g., for Babesia microtii) may be available regionally in endemic areas. A subset of donors is tested for cytomegalovirus (CMV) IgG antibodies; products drawn from these CMV seronegative donors are labeled “CMV negative.” PCs that are leukoreduced under carefully controlled and monitored conditions are considered an acceptable alternative to CMV seronegative products to minimize the risk of CMV transmission in susceptible patient groups.148 Studies suggest that leukoreduced apheresis platelet products also do not pose a significant risk of transmitting CMV to patients given a platelet transfusion following stem cell transplantation.149 Many hospitals transfuse ABO-compatible or ABO-identical platelets whenever possible because data suggest that ABOincompatible platelet transfusions (e.g., group A platelets to group O recipient) are associated with decreased platelet survival.150 Transfusing platelets that are incompatible with the recipient’s blood type may also lead to increased levels of circulating immune complexes, the effects of which are unclear.151 Most PCs contain few red cells, and red cell crossmatching is unnecessary in most instances. Platelets do not possess Rh antigen. However, there may be enough red cells in a PC unit (up to a few mL) that some physicians, in an

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attempt to prevent active alloimmunization to the RhD antigen, would consider providing Rh Immune Globulin to RhD negative recipients who receive RhD positive platelets, especially children and women of child-bearing potential. Several recent studies suggest that the risk for RhD alloimmunization is exceedingly low, particularly with apheresis units and the practice of Rh Immune Globulin provision could be limited to those patients receiving whole-blood derived units only.152–154 An intravenous preparation is available to prevent RhD alloimmunization, which is a safe and effective alternative to intramuscular RhIG preparations for thrombocytopenic patients.153 The practical aspects of transfusing platelets are similar to those used to transfuse other cellular blood products. Both the platelet product and the intended recipient must be accurately identified before starting the transfusion. Vital signs should be taken before the transfusion and then soon thereafter or if there is any evidence of a transfusion reaction. Common signs of a reaction include temperature elevations and changes in blood pressure. Patients may develop symptoms such as chills, pruritus, rash, and shortness of breath. Platelets, like red cells and fresh-frozen plasma (FFP), as per FDA mandate, must be transfused at the bedside through an infusion set that contains a filter (usually a screen filter with a 170–265 μm pore size) to remove fibrin clots and larger debris that can form during storage. This is required even if the blood components are filtered prestorage with a leukoreduction filter. Routine platelet transfusions must be completed within 4 hours, although most require less than 2 hours.

Prophylactic Platelet Transfusion Decisions to transfuse any blood product, including platelets, should not be made based purely on transfusion “triggers.” The overall status of the patient (e.g., disease, medications, and coagulation status) must be considered when determining the need for platelet transfusions. Historically, many physicians have transfused platelets to maintain platelet counts higher than 20
109/L, believing that this level was required to prevent spontaneous bleeding.155 However, serious bleeding may not occur until platelet counts are <5
109/L in the absence of other conditions that impair hemostasis.156 The earliest efforts to determine thresholds for prophylactic platelet transfusion were complicated by the widespread use of aspirin as an antipyretic agent, before its detrimental effects on platelet function were established. There are three major issues to consider when attempting to define an optimal prophylactic platelet level: (1) serious hemorrhage is rare, even at very low platelet numbers; (2) minor clinical bleeding is difficult to quantify157; and (3) platelet counts are less accurately determined at the very low platelet numbers found in severely thrombocytopenic patients. Measurement of stool red cell loss by Cr red cell labeling to estimate spontaneous bleeding in patients with aplastic anemia revealed

that stool blood loss was not significantly elevated until platelet counts fell below 5
109/L.158 A small clinical trial reported at the same time suggested that major bleeding, mortality, and the use of red blood cell transfusions were not different in patients who received prophylactic platelet transfusions (<20
109/L) versus those who received platelet transfusions only when bleeding (other than from the skin or mucous membranes) developed.159 The most widely studied patients are those with acute leukemias, although similar studies of patients with solid tumors suggest that serious bleeding is uncommon until platelet counts are <10
109/L.160 One of the earlier larger trials designed to study the safety of lowering platelet transfusion thresholds prospectively followed 102 consecutive patients with acute leukemia.161 Patients with platelet counts <6
109/L received prophylactic transfusions, whereas those with counts >20
109/L were transfused only for major bleeding or before significant invasive procedures. Other thresholds were 6–11
109/L for patients with fever or minor bleeding and 11–20
109/L for patients with coagulation disorders and minor procedures. Thirty-one major bleeding episodes occurred on 1.9% of the study days when platelet counts were 10
109/L and on only 0.07% of study days when counts were between 10 and 20
109/L. The investigators concluded that a prophylactic level of 5
109/L was safe in the absence of fever or bleeding. However, several of the major bleeds occurred in the 6–10
109/L group of patients who were not receiving prophylactic platelet transfusions. Prospective randomized platelet transfusion trials have compared the bleeding risks and platelet transfusion needs of groups of thrombocytopenic patients who received platelets at either the 10
109/L or 20
109/L thresholds (Table 64.4).162–165 These studies suggest that there are no differences in hemorrhagic morbidity and mortality rates when the lower platelet transfusion trigger values are used. When lower prophylactic platelet transfusion thresholds are applied, recipients are exposed to less donor blood, which in turn will decrease the risk of transfusion-transmitted disease and other complications associated with blood transfusion. Two more recent multicenter randomized controlled trials have provided additional data regarding prophylactic platelet transfusions. The PLAtelet DOse study (PLADO) evaluated three prophylactic platelet doses based on the recipient’s body surface area (low: 1.1
1011 platelets/m2; medium: 2.2
1011 platelets/m2; and high: 4.4
1011 platelets/m2).166 The study compared the percentage of hospitalized oncology patients who experienced at least grade 2 WHO bleeding (i.e., mild but clinically significant blood loss). Stable nonbleeding patients were transfused when the morning platelet count was less than 10
109/L. No significant difference in the percent of patients experiencing at least grade 2 bleeding was found in the three arms of the trial (71% low dose, 69% medium dose, 70% high dose). The investigators concluded that the prophylactic transfusion of lower doses of platelets at a threshold of 10
109/L does not lead to increased bleeding

TABLE 64.4 Summary of Platelet Transfusion Trigger Trials Study Gil-Fernandez et al., 1996162 Heckman et al., 1997163 Rebulla et al., 1997164 Wandt et al., 1998165

No. of Patients 190 78 255 105

Type

Design

Platelet Count Trigger (×109/L)

Bone marrow transplant

Nonrandomized

10 vs. 20

Acute leukemia

Randomized

10 vs. 20

Newly diagnosed acute myeloid leukemia Acute myeloid leukemia

Randomized, multi-institution Prospective comparison

10 vs. 20 10 vs. 20

Findings No difference in bleeding; fewer platelet transfusions in 10k group No difference in bleeding No difference in major bleeding; no difference in red cell transfusions No difference in bleeding; fewer platelet transfusions in 10k group

Platelet Transfusion Medicine

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but may lead to more frequent albeit smaller-dosed platelet transfusions. The risk of significant bleeding did not appear to increase measurably until the platelet counts fell below 5
109/L. The Strategies for the Transfusion of Platelets study (SToP) evaluated two prophylactic doses (low: 1.5–2.9
1011 platelets; and high: 3.0–6.0
1011 platelets).167 Like the PLADO study, the SToP trial evaluated prophylactic platelet dose with at least grade 2 WHO bleeding as the endpoint. This study was halted prematurely due to a higher rate of serious grade 4 bleeds in the low-dose arm. However, there was no significant difference in the number of grade 2 bleeds between the two groups. The Trial Of Prophylactic Platelets Study (TOPPS)168 compared the efficacy of prophylactic and therapeutic platelet transfusions in hematologic malignancies. The prophylactic group received platelet transfusion at a 10
109/L threshold, whereas the therapeutic group received platelet transfusions only when actively bleeding. The results of this study indicated a utility of prophylactic transfusion as means to prevent bleeding specifically for hematologic malignancies.168 There is no clear consensus on clinical indications for prophylactic platelet transfusions, largely because available objective data are insufficient to develop evidence-based recommendations. Guidelines have been developed over the years by a number of professional groups, but there remains variability in the thresholds selected for prophylactic platelet transfusions. If other risk factors for bleeding exist, such as high fever, sepsis, hyperleukocytosis, or other hemostatic abnormalities, higher thresholds for prophylactic transfusion are indicated, although specific thresholds have not been defined for these patients.169 Finally, profound anemia can alter hemostasis and thus should be avoided in patients with thrombocytopenia or platelet function defects because red blood cells enhance the movement of platelets across parallel streamlines in flowing blood.170 The number of collisions between platelets and a vessel wall is directly related to the number of red cells (hematocrit), as demonstrated by a 50-fold increase in platelet deposition when blood is compared to PRP.171 Platelet counts are generally increased to at least 50
109/L before procedures such as lumbar puncture, indwelling catheter insertion, liver biopsy, thoracentesis, or transbronchial biopsy.172 Lower platelet counts are considered acceptable for adults with acute leukemia who undergo lumbar puncture.173 Children with acute lymphoblastic leukemia and platelet counts >10
109/L may tolerate lumbar puncture without serious complication174; however there are some concerns that circulating blasts may infiltrate CSF more commonly in such settings and higher prelumbar puncture counts (approaching 100
109/L) may be sought by pediatric providers. Higher platelet levels (>100
109/L) are generally recommended for other, significantly more invasive procedures involving the central nervous system in adults. However, the rationale for this threshold remains unclear. In general, platelet transfusions are not considered necessary prior to bone marrow aspiration or biopsy if adequate surface pressure is applied to the site after the procedure and if platelet counts are in excess of 20
109/L.172

function and biochemistry; (2) in vivo platelet survival in the circulation; and (3) clinical assessment of hemostatic efficacy, such as monitoring of epistaxis, hematuria, and petechiae. The latter measures are imprecise and difficult to reproduce. The bleeding time is not helpful in determining the effectiveness of platelet transfusions. The bleeding time becomes prolonged in a linear fashion as the platelet count falls below 100
109/L,176 and it is prolonged beyond measure (>30 minutes) when platelet counts fall below 10
109/L. In addition, the bleeding time is difficult to reproduce, has a wide normal range, is affected by a variety of drugs, and is prolonged in anemia (see Chapter 33). Although stool blood loss has been used to evaluate hemostasis in thrombocytopenic patients, this technique is not widely available.35 Response to prophylactic platelet transfusions can be estimated through the corrected-count increment (CCI). This is performed by measuring a platelet count 10–60 minutes post-transfusion and then calculating the CCI according to the following formula:

Efficacy of Platelet Transfusion

Doses of transfused platelets are typically in the range of 3
1011 platelets, which is approximately one single-donor apheresis product or six pooled random-donor PCs. This dose was not determined through clinical trials, but through experience. Optimal adult doses of platelets have not been clearly defined, and doses are typically based on a number of factors unrelated to efficacy, such as cost and availability.184 Unlike children, an adult patient’s body weight or body surface area is not usually considered when determining the dose of platelets to administer. Normal platelet survival is approximately

In clinical practice, it is difficult to evaluate the efficacy of platelet transfusions for several reasons. First, severe bleeding due to thrombocytopenia alone is rare. Second, hemorrhagic death in thrombocytopenia is even more uncommon in the absence of vascular damage or a coagulopathic state. Finally, the methods used to estimate the extent of bleeding remain challenging.175 Tests used to evaluate the effectiveness of platelet transfusions are classified into three general categories: (1) in vitro platelet

CCI ¼


Post ðμLÞ  Pre ðμLÞ
BSA m2 #platelets
1011

where Post is the post-transfusion platelet count/μL drawn 1 hour after completing the transfusion, Pre is the pretransfusion platelet count/μL, # platelets is the number of platelets transfused (1 WB-RDP  0.5
1011; 1 apheresis platelet 3.0
1011 platelets), and BSA is body surface area in square meters. In general, patients with a low CCI (<5000) have a less-than-expected response to platelet transfusion. Patients with a low 1-hour post-transfusion platelet increment may have become alloimmunized to platelet transfusions.177 These alloantibodies most commonly develop from previous transfusions or pregnancies. The results from the PLADO trial showed that 5% of patients became alloimmunized to platelets following transfusion, however not every alloimmunized patient had a low CCI.166 Autoantibodies encountered in ITP can also hasten platelet removal. Nonimmune conditions, such as fever, sepsis, and disseminated intravascular coagulation (DIC), may also dramatically reduce the expected increment. Overall, the CCI is considered a relatively crude, but often useful estimate of platelet survival.178 Other laboratory measures can be used to assess platelet status such as point of care platelet function tests and thromboelastography (TEG and ROTEM, discussed in Chapter 33).179–181 Whole blood thromboelastography is a viscoelastic hemostasis assay that can show the interaction of the coagulation cascade components with platelets, and is sometimes used to guide transfusion, particularly in the setting of major hemorrhage associated with trauma or surgery. Increasingly these modalities have led to reduced use of some blood products without increases in bleeding or adverse outcomes and thus may help reduce unnecessary or questionable transfusions in the bleeding patient,182,183 although the benefits of TEG in significantly reducing platelet transfusion remain to be determined.183.

Platelet Dosing

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9 days. However, patients undergoing induction chemotherapy for leukemia often require platelet transfusions at least every 3 days.185 Moreover, many patients require daily platelet transfusions during periods of severe bone marrow hypoplasia.185 Some practitioners advocate providing larger doses of platelets (e.g., 10–12 WB-RDP) every 2 or 3 days.186 Although this practice may not reduce the risk of spontaneous bleeding, larger platelet doses may result in a higher CCI and thus longer intervals between each transfusion.187,188 Others have suggested that smaller doses of platelets (e.g., 3 or 4 WB-RDP) can reduce the total number of platelets required during a patient’s thrombocytopenic period.189 Although decreasing pool size provides a more economical dose, this practice may result in an increased number of individual transfusions (as was demonstrated in the PLADO trial166), which can actually increase overall costs.190 In summary, the number of platelets provided per transfusion will remain largely based on local preferences until optimal platelet doses are better defined.

Platelet Transfusions in Other Settings Immune Thrombocytopenia Platelet transfusions are rarely indicated in patients with autoimmune thrombocytopenias such as ITP. Platelet transfusions are used only when these patients develop major bleeding, and not as a prophylactic measure (see Chapter 39). If a patient with ITP develops life-threatening bleeding, however, platelet transfusions have appeared effective in a small group of patients.191 Similarly, platelet transfusions are often ineffective in patients with post-transfusion purpura (Chapter 45), even when donor platelets are negative for the implicated platelet antigen (e.g., anti-HPA-1a). Selected donor platelets, however, play an important role in treating some newborns with neonatal alloimmune thrombocytopenia (NAIT; Chapter 45).192 The majority of these cases are attributed to fetomaternal incompatibility for the HPA-1a platelet-specific antigen. If infants are severely affected, they can be transfused with compatible HPA-1a-negative, washed platelets collected from the mother or a phenotyped donor. However, studies show that transfusing newborns with NAIT using platelets of unknown HPA type is an acceptable alternative when HPA-compatible platelets are not readily available.193

DIC and Massive Transfusion PCs are often transfused in acute DIC when patients are actively bleeding and severely thrombocytopenic (<50
109/L). Platelet transfusions do not, however, appear useful in preventing bleeding in chronic DIC. Massive blood transfusion, in which more than 1.0–1.5 times a patient’s blood volume is replaced with blood products and crystalloid, can cause significant thrombocytopenia. In this situation, platelets are being consumed, and there is a compounding dilution effect caused by transfusing products such as red cells and FFP that do not contain viable platelets. Fibrinogen and coagulation factors are similarly diluted during massive transfusions and, if not replaced with FFP, will diminish hemostatic capabilities further. Platelet transfusions were historically considered during massive transfusion when counts fell below 50
109/L. However, more recent trauma and battlefield experience suggests that hemostasis is more quickly achieved when a rapidly bleeding patient is transfused with red cells, PC, and FFP in a ratio of 1:1:1.194 Maintaining this ratio provides platelets and coagulation factors that more closely approximate normal whole blood. Platelet transfusions are frequently used during and following liver transplantation. These patients, like those with DIC, have complex hemostatic abnormalities, including

coagulation factor defects and hyperfibrinolysis that can further contribute to thrombocytopenic bleeding. The results of the PROPPR trial indicate that a 1:1:1 ratio may help improve hemostasis, but did not show a substantial mortality benefit versus a 1:1:2 approach.195 Further work in this area is clearly needed to establish the optimum approach to blood product resuscitation in the setting of trauma.

Bone Marrow Transplantation Patients who undergo autologous and, especially, allogeneic, bone marrow transplantation have prolonged periods of thrombocytopenia that can require substantial platelet transfusion support. In general, platelet recovery is fastest in the setting of autologous peripheral blood transplants and can be significantly slower in allogeneic peripheral blood stem cell transplants, transplants using bone marrow as a graft, and cord blood transplants.196 Because of this autologous transplant patients may require less platelet transfusion support than recipients of other types of grafts. There are several risk factors for prolonged thrombocytopenia (<20
109/L) in this patient population, but it is difficult to identify all patients at risk.196 For example, autologous transplant patients who receive numerous cycles of high-dose chemotherapy are predisposed to poorer CD34+ cell mobilization. This leads to lower CD34+ cell yields during harvesting and subsequently delayed platelet recovery following stem cell infusion.197 In contrast, patients who receive higher numbers of stem cells (e.g., 5
106 CD34+ cells/kg body weight) have shorter periods of severe thrombocytopenia.198 Platelet engraftment and recovery of platelet counts are preceded by an increase in reticulated platelets (see Chapters 32 and 35); however, reticulated platelets are rarely monitored following transplant.199 A retrospective study conducted in France found that patients undergoing reduced intensity conditioning for an allogeneic hematopoietic stem cell transplant required fewer platelet transfusions while engrafting and had shorter engraftment times than those patients receiving standard conditioning regimens.200 Alternatively, and as briefly mentioned earlier, umbilical cord blood transplants are often associated with a prolonged engraftment period, and thus, higher platelet transfusion needs.

Cardiac Surgery PCs are commonly provided during or soon after cardiac surgery in patients undergoing cardiopulmonary bypass (CPB) in an effort to limit postoperative bleeding. The hemostatic defects associated with CPB are complex but are generally related to anticoagulation, hypothermic temperature changes, length of time on bypass, and preoperative aspirin use (see Chapter 49). Effects of CPB on platelets include platelet activation due to exposure to foreign biomaterial surfaces, platelet fragmentation, and impaired aggregation responses to most agonists.201 There is usually some degree of platelet damage and thrombocytopenia during bypass surgery, and platelet function defects may persist for days after the procedure. However, the treatment of post-CPB bleeding is not usually based on laboratory monitoring and is largely empiric and institution dependent202; recent guidelines advise against prophylactic platelet transfusion without bleeding in the setting of CPB.172 Although clinical trials are limited, none have been able to demonstrate benefits of prophylactic platelet administration intra-operatively,172 as determined by decreased red cell transfusions, chest tube bleeding, or microvascular bleeding. Thus, many surgeons reserve platelet transfusions for patients who are actually bleeding despite adequate surgical hemostasis. There is some emerging data that use of techniques such

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as thromboelastography can be useful for a more rational approach to transfusion in this setting.179–181 Patients who have received aspirin or GPIIb-IIIa antagonists immediately before cardiac surgery are at additional risk for bleeding.203 In these cases, platelet transfusions are commonly provided before surgery; however, the dose of platelets required to minimize bleeding has not been clearly defined. Some cardiac programs utilized point-of-care testing technologies like thromboelastography to help guide platelet transfusion decisions (see Chapter 33). Like CPB, extracorporeal membrane oxygenation and the use of ventricular assist devices can result in severe hemostatic defects that require frequent platelet transfusions.204

Inherited and Acquired Platelet Function Defects Patients with inherited (Chapter 48) or acquired (Chapter 49) platelet function defects do not usually require prophylactic platelet transfusions. However, platelet transfusions are often used to treat bleeding episodes or are administered prior to surgery. Following platelet transfusion, patients with Glanzmann thrombasthenia may develop GPIIb-IIIa-specific antibodies that can compromise survival and, thus, the efficacy of further platelet transfusions.205 Similarly, patients with BernardSoulier syndrome can develop GPIb-IX-V-specific antibodies. Desmopressin acetate206 (Chapter 62) and recombinant activated factor VII (rFVIIa, Chapter 63),207 which shorten the bleeding time of many patients with congenital platelet function disorders, are potential alternatives or adjuncts to platelet transfusion therapy. In fact, use of rFVIIa is now considered an “on label” indication for bleeding in Glanzmann thrombasthenia, particularly for patients who are refractory to platelet therapy.208 Patients with acquired platelet defects caused by the myriad of drugs with antiplatelet activity should have these medications discontinued whenever possible prior to invasive procedures. Finally, platelet transfusions can increase platelet counts to safer levels without apparent adverse effects in patients with abciximab-induced thrombocytopenia (Chapter 40).209 Platelet transfusions are not recommended in the setting of heparin-induced thrombocytopenia (HIT, Chapter 41) because of the (poorly quantified) risk that the transfusion may precipitate acute thrombosis. However, many patients with antibodies directed against the complex of platelet factor 4 and heparin implicated in HIT have been transfused without developing thrombosis, and thus, platelet transfusion can be considered when these patients develop life-threatening bleeding.210

Autologous Platelet Donation and Cryopreserved Platelets Although autologous red cell donation is a standard practice, autologous platelet donations are used only rarely. Liquid stored platelets are not practical for these purposes because of their limited 5-day shelf-life. Thus, patients are unable to “bank” enough of their own platelets prior to prolonged periods of thrombocytopenia. However, platelets collected by apheresis can be placed in a dimethyl sulfoxide (DMSO) cryoprotectant and stored frozen at 80°C.211 They are then thawed, washed to remove DMSO, and resuspended in autologous plasma or other solution before transfusion. The techniques are not difficult to perform, but most blood banks have not developed procedures for preparing and storing such products. In addition, frozen and thawed platelets undergo a number of structural and metabolic changes that adversely affect their in vivo survival.212 The U.S. Department of Defense is interested in the further development and clinical testing of frozen and lyophilized platelets for battlefield supply.

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Preliminary results of a randomized trial suggest that the recovery and survival of autologous platelets collected by apheresis and cryopreserved are significantly less than autologous platelets stored in plasma under normal conditions.213 Although the cryopreserved platelets do not meet current FDA criteria for liquid-stored platelets, it remains unclear if the cryopreserved platelets prepared in this manner would have clinical utility in preventing or slowing thrombocytopenic bleeding. Autologous platelets have been studied to aid wound healing and tissue regeneration (Chapter 65).214 In one such approach, a platelet “gel” is produced by treating platelets with thrombin.215 Due to claims for this processing being able to promote healing of various joint or musculoskeletal problems, this procedure is also becoming popular in veterinary medicine and for treating some types of sports injuries.

ADVERSE REACTIONS TO PLATELET TRANSFUSION Platelet transfusion therapy is not without risk (Table 64.5). Common but nonlife-threatening complications of platelet transfusions include febrile and allergic transfusion reactions.216 Although PCs are capable of transmitting viral disease, improved donor testing has markedly decreased this risk. For example, the estimated risks of HIV-1 or hepatitis C transmission from a platelet transfusion are far less than 1 in 1 million transfusions.217 Transfused PCs are more likely to be contaminated by bacteria than by known viruses. Patients who receive such bacterially contaminated products can develop serious septic reactions. Because PCs contain viable lymphocytes, platelet transfusion can also cause transfusion-associated graft-versushost disease in susceptible patients, a rare but usually fatal reaction that is prevented by irradiating PCs before transfusion.218 Transfusion-related acute lung injury (TRALI), an often unrecognized cause of noncardiogenic pulmonary edema, can follow platelet, plasma, or red cell transfusion.219 The infusion of bioactive lipids found in stored platelets has been implicated in the pathogenesis of TRALI.

Febrile Reactions to Platelet Transfusion Febrile transfusion reactions (FTRs) are commonly encountered with platelet transfusions. They usually occur during the transfusion, but they may develop minutes to several hours after the transfusion is completed. In the current era of widespread leukoreduction, the frequency of FTR is estimated to be less than 1% of platelet transfusions.220 FTRs typically present as fever (>1°C increase) and shaking chills, and they may be accompanied by nausea, vomiting, dyspnea, and hypotension. The severity of symptoms appears related to the number of white cells found in the product and/or the rate of transfusion. Severe rigors promptly resolve when meperidine is administered,221 although this is an uncommon practice in

TABLE 64.5 Adverse Consequences of Platelet Transfusion Therapy Febrile transfusion reactions Allergic reactions (urticarial and anaphylactic) Septic reactions (bacterial) Viral transmission (hepatitis B and C, human immunodeficiency virus, cytomegalovirus) Parasitic infection (Babesia microti, Trypanosoma cruzi, Plasmodium sp.) Transfusion-associated graft-versus-host disease Transfusion-related acute lung injury Platelet refractory state due to HLA alloimmunization Transfusion-associated immune modulation (TRIM) Hypotensive reactions associated with angiotensin-converting enzyme (ACE) inhibition Post-transfusion purpura

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the modern era. Although patients are often medicated with an antipyretic such as acetaminophen before platelet transfusions to minimize FTRs, it is unclear if this practice actually minimizes these reactions.222 Premedication with intravenous corticosteroids in patients who have had repeated severe FTRs may be useful; however, to be maximally effective, these medications must be administered several hours before transfusion. Antihistamines do not appear useful in preventing or treating FTRs and should not be prescribed for this purpose. If a patient continues to have severe febrile reactions despite leukoreduction, washed platelets that have had most of the suspending plasma removed can be considered.223 The mechanism of FTR was originally attributed to interactions between cytotoxic antibodies in the platelet recipient and HLA and/or leukocyte-specific antigens on donor white cells found in the product.224 The formation of white cell antigenantibody complexes results in complement binding and subsequent release of endogenous pyrogens such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6. The direct activity of various biological response modifiers including cytokines plays a role in FTR.225 The incidence of FTR may be directly related to the duration of platelet storage.226 During PC storage, there is continued elaboration of biologically active cytokines by residual white cells, which include activated monocytes.227 The levels of these cytokines, particularly of IL-1β and IL-6, correlate with the frequency of FTR.228 Other mediators are primarily produced by platelets themselves. One such example is soluble CD40 ligand, which is produced by platelets and has been linked with febrile transfusion reactions due to its upregulation of IL-6 and IL-8.229 Preparation technique may also influence the risk of FTR. One prospective study designed to compare single-donor apheresis platelets and PC prepared by the BC and PRP techniques noted significantly more FTRs in patients who received PRP-prepared PCs.230 However, there was no difference in platelet survival between the different preparations based on CCI measured 1–6 and 18–24 hours post-transfusion. It is generally accepted that leukoreducing PCs can help minimize FTRs. The degree of leukoreduction is limited by the available techniques. Third-generation filters eliminate >99.9% of white cells in a unit of red cells obtained from a whole blood donation, leaving <5
106 residual leukocytes. Prestorage leukoreduction, in which white cells are removed soon after blood collection, may even further reduce the likelihood of FTR.231 Leukoreduction filters not only remove white cells but also have varying ability to remove biological response modifiers directly, such as the chemokines IL-8 and RANTES and the anaphylatoxins C3a and C5a.232, 233

Bacterial Contamination of Platelet Concentrates The shelf-life of PCs was decreased from 7 to 5 days in the mid1980s, largely based on observations that many cases of septic transfusion reactions occurred in patients who received PCs stored for more than 5 days.234 Moreover, in vitro studies performed by inoculating PCs with bacteria suggest that a significant number of PCs experience the most rapid rate of bacterial growth on days 6 and 7 of storage.235 The most commonly implicated organisms in platelet septic transfusion reactions are Gram-positive bacteria (Staphylococcus sp.), although Gram-negative organisms are also isolated (Table 64.6).236 Platelets, and other blood products, can be contaminated by bacteria if a donor is bacteremic during blood collection or if the arm is improperly cleansed before venipuncture. Blood donors must be in good health on the day of donation. However, asymptomatic donors who may have had gastroenteritis of short duration several days before donation are potentially infectious. These donors may have a prolonged period of

TABLE 64.6 Organisms That May Contaminate Platelet Concentrates Bacillus species B. cereus B. subtilis Candida albicans Clostridium perfringens Corynebacterium species Enterobacter cloacae Escherichia coli Klebsiella oxytoca Leishmaniasis Morganella morganii

Propionibacterium acnes Pseudomonas aeruginosa Salmonella species Staphylococcus species S. aureus S. epidermidis Serratia marcescens Streptococcus species S. pyogenes S. viridans

asymptomatic bacteremia that allows transmission of organisms like Escherichia coli.237 Transfusing bacterially contaminated PCs can cause septic reactions that may be fatal. Thus, standards have been adopted in most countries that require blood collection facilities and transfusion services to limit and detect bacterial contamination in all platelet components. No detection method has been universally adopted and, regardless of the method, no bacterial screening system is 100% sensitive to all bacterial pathogens. Different methods are used, depending on the type of platelet donation (e.g., whole blood-derived vs. apheresis). Most blood centers directly culture apheresis and prestorage pooled PCs for bacteria and release the unit after the culture has incubated between 12 and 36 hours.238 The most commonly cultured bacteria are gram-positive organisms such as Staphylococcus epidermidis, S. aureus, and Streptococcus pneumoniae; these are often skin commensals. Skin disinfection by povidone-iodine and isopropyl alcohol helps to minimize venipuncture-related contamination of platelet concentrates by skin flora.239 One method that can further reduce PC contamination by skin flora bacteria utilizes a bypass inlet tube in which the initial, and most likely contaminated, portion of blood removed from the donor is diverted from the remainder of the blood donation bag.240 Studies have been performed to determine if apheresis platelet shelf-life could be safely extended from 5 to 7 days using bacterial monitoring systems.241 PCs were cultured 24– 36 hours after collection and then released for transfusion if the screening culture was negative for 24 hours after sampling. The results indicated that screening cultures did prevent some infected units from being transfused; however, the strategy failed to identify all contaminated units successfully. Hence, platelet shelf-life remains 5 days until other methods can be developed to further reduce the risk of bacterial contamination. Given the limitations of current bacterial identification systems, considerable research has been devoted to improving these systems in order to limit PC contamination. One difficulty is that the majority of PC cultures that turn positive by automated bacterial culture screening systems do so well after 24 hours from time of sampling. In these cases, the product often has already been transfused.242 Delayed bacterial growth may be related to very low inoculum numbers and may also explain the relatively low sensitivity (40%) of bacterial culture screening techniques used to test PCs.243 Sensitivity of culture systems can be improved by increasing sample size. Doubling the sample size of apheresis platelet unit culture specimens from 4 to 8 mL can relatively increase the sensitivity of the culture by 54%.240 More sensitive bacterial screening systems are not expected to eliminate the release of potentially contaminated PCs. Thus, a number of techniques have been studied as alternatives to standard bacterial cultures. One simple technique utilizes PC glucose concentrations. A PC glucose level below 500 mg/dL, as measured by a glucometer on storage day 4 or 5, has been

Platelet Transfusion Medicine

proposed as a surrogate marker for positive cultures, yielding false-negative rates similar to that of culture.244 PCR using bacterial 16s rRNA as a target can detect bacteria in plasma and platelet-rich plasma in a rapid and sensible manner, but molecular techniques are not routinely used to monitor PCs.245 Bacteria can be detected in platelets using flow cytometry by staining bacterial DNA with a fluorescent dye such as thiazole orange. This technique can detect bacteria in PCs incubated for 24–48 hours; however, it may not be sensitive enough to detect slower-growing bacteria.246 Viable bacteria can be detected that are trapped on PC filters using a fluorescent esterase detector coupled to a bioimaging reader.247 Importantly, a number of “point of care” bacterial detection systems have been developed to identify potentially contaminated units immediately before the point of issue. We will discuss these platforms, as well as implications for their use, later in this chapter.

Platelet Refractory State Patients who receive long-term platelet support may develop a refractory state in which transfused platelets undergo accelerated destruction. Refractoriness to platelet transfusion is often related to clinical conditions that hasten platelet removal through either immune or nonimmune mechanisms (Table 64.7).248 In the former situations, foreign donor HLA evokes an immune response in the recipient that leads to the rapid removal of transfused platelets.249 Presumably, donor platelets become coated by HLA-specific, or in some cases platelet-specific, antibodies. The antibody-coated platelets are then removed from the circulation in a manner akin to other immune thrombocytopenias. Platelet alloimmunization rates are higher in patients with prior pregnancies or transfusion. Overall, nonimmune platelet destruction caused by conditions such as splenomegaly, infection, and antibiotic treatment with amphotericin B is more frequent than that related to immune mediated removal.250 The effects of amphotericin B on platelet survival can be lessened by transfusing platelets 2 hours after completing the amphotericin infusion.251 Platelets express ABH, Lewis, P, and I blood system antigens, as well as class I HLA-A, -B, and -C and platelet-specific antigens (HPA). The ABH, class I HLA, and HPA antigens are most relevant to allogeneic platelet survival.252 Platelet survival is impaired when recipients with higher titer anti-A or anti-B IgG antibodies are transfused with platelets carrying one of these antigens.253 Although this problem is avoided by using ABO-identical platelets (e.g., group O patients receive group O PC), this option is not always available during blood shortages.254 Alloimmunization against HLA-A and HLA-B class I antigens is the most common cause of an immune-mediated platelet refractory state; mismatches of HLA-C antigens are less important. Historically, patients at particular risk for HLA alloantibody formation included those who received multiple transfusions of nonleukocyte-reduced blood components.255 It was then discovered that primary HLA alloimmunization is reduced by removing antigen-presenting cells (leukocytes) TABLE 64.7 Conditions Associated With a Platelet Refractory State Nonimmune Mechanisms

Immune Mechanisms

Splenomegaly

Alloantibodies to class I HLA antigens Alloantibodies to platelet-specific antigens Autoantibodies to platelet-specific antigens Circulating immune complexes

Disseminated intravascular coagulation Drugs (antibiotics, amphotericin B) Sepsis, fever, viremia Graft-versus-host disease

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from PC before transfusion and UVB irradiating transfused platelets to inactivate antigen-presenting cells.106,256,257 Strategies used to reduce HLA alloimmunization are especially effective in patients with hematologic malignancies. Since the introduction of universal leukocyte reduction by some blood collection facilities, there has been a decrease in the rate of HLA alloimmunization in multiply transfused patients.258 The management of platelet refractory patients varies across institutions and is often related to the availability of specialized testing and products.259 In nonbleeding patients, prophylactic platelet transfusions are often withheld. However, patients with significant bleeding, other risk factors for bleeding, or those undergoing an invasive procedure may require transfusion. Platelet transfusion strategies in these cases include increasing the dose of platelets or providing either HLA-selected or crossmatch-compatible platelets. Ideally, anti-HLA antibodies should be identified in the patient before HLA-specific products are obtained.260 Products are collected by apheresis and are selected based on the HLA-A and HLA-B types of the donor and intended recipient. Because the HLA system is extremely polymorphic, a large number of HLA-typed donors is needed to support refractory patients.261 The use of HLA-selected or “matched” platelets in patients who are not alloimmunized with the goal of preventing such immunization is not warranted.262 Platelet cross-matching is performed by reacting recipient serum with potential donor platelets that are fixed to a solid support. The compatibility is determined based on the presence or absence of reactivity.263 An incompatible platelet cross-match predicts a poor response in more than 90% of transfusions, whereas a compatible cross-match is 50% predictive of a successful transfusion.264 Large collection facilities often combine the two approaches: PCs are selected for cross-matching based on the class I HLA types of the donor and recipient. Patients who have developed both HLA and platelet-specific antibodies are particularly difficult to manage. Other approaches that have been explored to support HLA-alloimmunized patients are based on reducing the expression of class I HLA antigens on platelets.265 Treatments that are effective for many autoimmune thrombocytopenias including corticosteroids, chemotherapy, and splenectomy are not useful in most patients who have become alloimmunized to platelet transfusions. Patients with ITP (see Chapter 39) usually respond very poorly to platelet transfusions because donor platelets are rapidly coated with platelet autoantibodies and are removed from the circulation. Interestingly, patients with ITP and extremely low platelet counts infrequently experience serious bleeding and hence do not usually require prophylactic platelet transfusions despite extremely low platelet counts. Intravenous immunoglobulin, which is often used as a treatment for ITP (see Chapter 39), may transiently improve the response to transfused platelets. Patients with ITP who are bleeding and responding poorly to standard platelet transfusions may benefit from continuous 24-hour infusions of both intravenous immunoglobulin and platelets.266 Continuous platelet infusions, or “platelet drips,” are typically performed by infusing three pooled WB-RDPs or a WB-RDP pooled product or one-half of an apheresis-derived PC every 4 hours. They can be infused through electromechanical pumps because these devices do not appear to harm platelets.267

Hypotensive Reactions During Platelet Transfusions Serious hypotensive episodes have been described in patients on angiotensin-converting enzyme (ACE) inhibitors who were transfused with PCs through negatively charged bedside leukocyte reduction filters.268 These reactions began soon after the

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infusion was initiated and subsided rapidly after the transfusion was terminated. The mechanisms responsible for the hypotension appear to involve bradykinin (BK)-related peptides with vasodilatory activity, which are generated when blood contacts a negatively charged artificial surface. BK and its active metabolites are rapidly degraded to inactive compounds through reactions that require ACE. Therefore, patients on ACE inhibitor medications are less able to degrade these vasodilatory substances and, presumably, are at risk for hypotension caused by decreased systemic vascular resistance. In vitro studies have shown that supernatant bradykinin levels markedly increase when PCs are passed through certain negatively charged filters.269 Furthermore, patients who receive PCs through a negatively charged filter experience significant increases in BK levels during the first 5 minutes of transfusion.270 A metabolic abnormality has been identified in several blood recipients who have developed such reactions.271 This defect affects the degradation of des-Arg9-bradykinin, a metabolically active metabolite of BK that is primarily inactivated by ACE and aminopeptidase P. Accordingly, the half-life of des-Arg9-bradykinin was significantly longer in patients on ACE inhibitors who experienced severe hypotensive reactions than in control patients. Based on these studies, it appears that both patient and product-related factors contribute to the pathogenesis of severe hypotensive reactions to platelet transfusion. The incidence of these reactions has decreased now that the vast majority of PCs are leukocyte reduced before storage; bedside filtration is rarely performed today.272

THROMBOPOIETIC GROWTH FACTORS IN PLATELET TRANSFUSION THERAPY The use of hematopoietic growth factors helps to limit patient exposure to allogeneic blood components. For example, recombinant erythropoietin (EPO) therapy has dramatically decreased the need for red cell transfusions in many patients, such as those with renal impairment.273 Thrombopoietin receptor agonists (Chapter 61) can be used in a comparable fashion to EPO to drive platelet production due to deficiencies or issues with endogenous thrombopoietin. These FDA-approved drugs (romiplostim, eltrombopag and avatrombopag) are applied in diverse settings including ITP (Chapter 39) and hepatitis C-induced cirrhosis (Chapter 61).273,274

CONTROVERSIES AND FUTURE DIRECTIONS IN PLATELET TRANSFUSION THERAPY • Cold storage of platelets: Now that FDA approval has been attained for apheresis products, further work is being proposed or carried out to extend the shelf lives of these products and expand their indications.275 Moreover, there remain questions on how they will best be implemented. The label indication for these products is actively bleeding trauma patients. Challenges blood banks face is whether or not they will stock these products; if stocked, then logistically how they will be stored in the appropriate cold-maintained, nonagitated environment and in what numbers (as trauma, itself, is a highly unpredictable indication); how they will be screened for usage to ensure they are being appropriately administered (i.e., for bleeding and not for prophylaxis); and finally whether (with additional data) the shelf-life of these products can be extended beyond 3 days. At least some authors have argued that the blood bank of the future will maintain at least two separate platelet inventories, one cold stored inventory for actively bleeding patients and one room

temperature inventory for routine or prophylactic platelet infusion.276 • Platelet bacterial testing at days 4–5 of storage and beyond: Despite regulations requiring US blood banks and transfusion services to stock platelet products that have undergone formal bacterial contamination testing at the time of collection, septic transfusion reactions persist. As such, a draft guidance has been issued by the FDA making recommendations for possible additional actions.19 Per the draft guidance, acceptable modes of risk reduction for bacterial contamination would include use of pathogen reduction technology (as discussed earlier in this chapter) or, for nonpathogen-reduced products, application of approved culture-based methods or secondary “rapid” testing platforms. Regarding the latter, there are currently two FDAapproved platforms for secondary bacterial testing (Pan Genera Detection; Verax Biomedical, Marlborough, MA & Immunetics, Oxford Immunotec, Boston, MA).277,278 The added promise of these methods is not only increased safety, but additionally the ability to extend platelet shelf-lives to 6 or 7 days with testing.279 If the draft guidance is ultimately implemented, blood banks will need to determine the best course for their hospitals, considering costs and logistics of either implementing pathogen reduced products or introducing novel (potentially laborious) additional bacterial testing assays. • Platelet transfusion for intracranial hemorrhage in patients on aspirin: While platelet transfusions are frequently used for reversal of antiplatelet medications in the clinical setting of intracranial hemorrhage, the results of the PATCH study suggest that not only is this practice of no benefit from a mortality standpoint, it may actually be of some harm.280 While a sweeping change of practice is not advised based on a single study, the blood bank community must pay close attention to future studies examining the benefits and possible risks of PCs for reversal of antiplatelet therapy.

CONCLUSIONS Platelet transfusion therapy has benefited large numbers of patients who are thrombocytopenic or have platelet function defects. In most cases, these transfusions occur without serious complications because of efforts to improve the safety of the blood supply. Platelet transfusions will become even safer with further advances in donor testing and the development of techniques that detect or eliminate bacteria and other pathogens that may contaminate PCs. The efficacy of platelet transfusion therapy has also improved during the past 40 years by optimizing the processes used to prepare and store PCs. Storage conditions have been selected to minimize the changes in platelet structure and function that occur during room temperature storage. A large number of in vitro laboratory tests have been used to compare different methods for PC preparation and storage. These tests correlate with tests of in vivo hemostatic function to varying degrees, but no single test provides a complete measure of platelet quality. Innovative yet practical in vitro methods are needed that more accurately predict and assess platelet function and viability in vivo. Although alternatives to liquid-stored PCs are under active development (e.g., making platelets ex vivo; see Chapter 66), it appears that whole bloodderived and apheresis PCs will remain in widespread clinical use for the foreseeable future. REFERENCES 1. Hersh EM, Bodey GP, Boyd AN, Freireich EJ. Causes of death in acute leukaemia: a ten year study of 414 patients from 1954– 1963. JAMA 1965;193:99–103.

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71. Zhang JG, Carter CJ, Culibrk B, Devine DV, Levin E, Scammell K. Buffy-coat platelet variables and metabolism during storage in additive solutions or plasma. Transfusion 2008;48(5):847–56. 72. Sandgren P, Mayaudon V, Payrat JM, Sjodin A, Gulliksson H. Storage of buffy-coat-derived platelets in additive solutions: in vitro effects on platelets stored in reformulated PAS supplied by a 20% plasma carry-over. Vox Sang 2010;98(3 Pt. 2):415–22. 73. Galan AM, Lozano M, Molina P, Navalon F, Marschner S, Goodrich R. Impact of pathogen reduction technology and storage in platelet additive solutions on platelet function. Transfusion 2011;51(4):808–15. 74. Slichter SJ, Bolgiano D, Corson J, Jones MK, Christoffel T. Extended storage of platelet-rich plasma-prepared platelet concentrates in plasma or Plasmalyte. Transfusion 2010;50 (10):2199–209. 75. Divers SG, Kannan K, Stewart RM, Betzing KW, Dempsey D, Fukuda M. Quantitation of CD62, soluble CD62, and lysosome-associated membrane proteins 1 and 2 for evaluation of the quality of stored platelet concentrates. Transfusion 1995;35(4):292–7. 76. Kostelijk EH, Fijnheer R, Nieuwenhuis HK, Gouwerok CW, de Korte D. Soluble P-selectin as parameter for platelet activation during storage. Thromb Haemost 1996;76(6):1086–9. 77. Dumont LJ, VandenBroeke T, Ault KA. Platelet surface P-selectin measurements in platelet preparations: an international collaborative study. Biomedical Excellence for Safer Transfusion (BEST) Working Party of the International Society of Blood Transfusion (ISBT). Transfus Med Rev 1999;13(1):31–42. 78. Shapira S, Friedman Z, Shapiro H, Presseizen K, Radnay J, Ellis MH. The effect of storage on the expression of platelet membrane phosphatidylserine and the subsequent impact on the coagulant function of stored platelets. Transfusion 2000;40(10): 1257–63. 79. Gutensohn K, Alisch A, Geidel K, Crespeigne N, Kuehnl P. Annexin V and platelet antigen expression is not altered during storage of platelet concentrates obtained with the AMICUS cell separator. Transfus Sci 1999;20(2):113–20. 80. Seghatchian J. Platelet storage lesion: an update on the impact of various leukoreduction processes on the biological response modifiers. Transfus Apher Sci 2006;34(1):125–30. 81. Rinder HM, Murphy M, Mitchell JG, Stocks J, Ault KA, Hillman RS. Progressive platelet activation with storage: evidence for shortened survival of activated platelets after transfusion. Transfusion 1991;31(5):409–14. 82. Michelson AD, Barnard MR, Hechtman HB, MacGregor H, Connolly RJ, Loscalzo J. In vivo tracking of platelets: circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function. Proc Natl Acad Sci U S A 1996;93 (21):11877–82. 83. Berger G, Hartwell DW, Wagner DD. P-selectin and platelet clearance. Blood 1998;92(11):4446–52. 84. Krishnamurti C, Maglasang P, Rothwell SW. Reduction of blood loss by infusion of human platelets in a rabbit kidney injury model. Transfusion 1999;39(9):967–74. 85. Holme S, Sweeney JD, Sawyer S, Elfath MD. The expression of pselectin during collection, processing, and storage of platelet concentrates: relationship to loss of in vivo viability. Transfusion 1997;37(1):12–7. 86. Bode AP, Orton SM, Frye MJ, Udis BJ. Vesiculation of platelets during in vitro aging. Blood 1991;77(4):887–95. 87. Bode AP, Hickerson DH. Characterization and quantitation by flow cytometry of membranous microparticles formed during activation of platelet suspensions with ionophore or thrombin. Platelets 2000;11(5):259–71. 88. Sloand EM, Yu M, Klein HG. Comparison of random-donor platelet concentrates prepared from whole blood units and platelets prepared from single-donor apheresis collections. Transfusion 1996;36(11–12):955–9. 89. Rank A, Nieuwland R, Liebhardt S, Iberer M, Grutzner S, Toth B. Apheresis platelet concentrates contain platelet-derived and endothelial cell-derived microparticles. Vox Sang 2011;100(2):179–86. 90. Blajchman MA, Bardossy L, Carmen RA, Goldman M, Heddle NM, Singal DP. An animal model of allogeneic donor platelet refractoriness: the effect of the time of leukodepletion. Blood 1992;79(5):1371–5.

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