Platelet Products Melissa M. Cushing, MD and Robert A. DeSimone, MD
Product Names: Platelet products include those derived from whole blood and those collected by apheresis. While the FDA has a nomenclature specific to each method of collection, many terms are in common use. This creates confusion in published papers and with ordering physicians. The FDA calls platelets derived from whole blood “platelets,” and these are sometimes also referred to as whole blood–derived platelets, random donor platelets, and platelet concentrates. Platelets collected by apheresis are called “platelets, pheresis” by the FDA, which are sometimes referred to as single donor platelets, apheresis platelets, and plateletpheresis. The method of collection does not reflect or define a platelet dose. Dose is patient-dependent and can vary given the clinical circumstance but usually approximates 3–4 × 1011 platelets for an adult and 10 mL/kg in pediatrics. As whole blood–derived platelet units typically contain 5.5 × 1010 platelets, 4–6 units must be “pooled” to make a dose. Many apheresis-derived platelet collections contain 2–3 times the required minimum of 3 × 1011 platelets and thus are “split” to make multiple platelet doses from a single collection.
Description: Platelets are an essential component of hemostasis, and deficiencies in platelet number or function can result in bleeding. Thrombocytopenia and/or platelet dysfunction may result from congenital diseases, medications, liver or kidney diseases, sepsis, disseminated intravascular coagulopathy (DIC), hematologic diseases, massive transfusion, and cardiac bypass or extracorporeal membrane oxygenation. Clinical signs of thrombocytopenia or platelet dysfunction include petechiae, easy bruising, or mucosal bleeding. The average in vivo life span of a platelet is ∼10 days, but that of a transfused platelet is ∼4–5 days. A platelet’s life span is shortened by bleeding, DIC, splenomegaly, platelet antibodies, medications, sepsis, endothelial cell or platelet activation, and thrombocytopenia.
Indications: Platelet transfusions are used for prophylaxis to prevent bleeding or for treatment of bleeding in patients who have thrombocytopenia, qualitative defects in their platelet function (inherited or acquired secondary to disease or antiplatelet medications), or in the setting of massive transfusion. AABB guidelines recommend a prophylactic platelet transfusion threshold of 10,000/μL; a higher threshold may be considered in patients with fever, bleeding, or sepsis. A threshold of 10,000/μL was recently validated in a large retrospective analysis of thrombocytopenic hematology/ oncology patients undergoing stem cell transplant or chemotherapy, in which a platelet count of <5000/μL was associated with increased bleeding. However, in the setting of autologous hematopoietic cell transplantation for adult patients, recent ASCO guidelines recommend platelet transfusions at the first sign of bleeding rather than prophylactic transfusions. The threshold is increased to >20,000/μL for central venous catheter Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00035-0 Copyright © 2019 Elsevier Inc. All rights reserved.
Melissa M. Cushing, MD and Robert A. DeSimone, MD
placement and >50,000/μL before lumbar puncture, biopsy, or nonneuraxial surgeries. For procedures involving neuraxial locations, such as the eye or brain, and for major surgery, a threshold of >100,000/μL is suggested. A threshold of >50,000/μL should be considered in actively bleeding patients. Thresholds for neonates are not clearly defined, and practices vary widely; for invasive procedures or bleeding, platelet counts are kept >50,000/μL and >100,000/μL in extremely ill, premature infants. Prophylactic platelet transfusions are generally administered for platelet counts <20,000/μL in neonates and <50,000/μL in extremely ill premature or critically ill neonates.
Relative Contraindications: Platelet transfusions are generally contraindicated in patients with thrombotic thrombocytopenic purpura (TTP) or heparin-induced thrombocytopenia (HIT) unless there is severe or life-threatening hemorrhage because they may increase the risk of thrombosis. In addition, a recent multicenter, randomized controlled trial associated platelet transfusions with greater mortality in patients with acute, spontaneous primary intracerebral hemorrhage on antiplatelet therapies. Thus, platelet transfusions may be contraindicated in this setting.
Whole Blood–Derived Platelets: In the United States using the platelet-rich plasma method (Chapter 9), per CFR and AABB Standards, whole blood–derived platelet units must contain ≥5.5 × 1010 platelets in 90% of the units tested. Before issuing whole blood–derived platelets, the platelet products must be pooled to make a sufficient adult dose. Transfusion services may pool platelet concentrates, which require bacterial screening and expire in 4 hours postpooling. The FDA has approved a system for prepooling, leukoreducing, and bacterial testing of platelet concentrates. These platelets are referred to as “prestorage pooled platelets.” Four to six units of platelets may be pooled using this system to achieve an FDA-approved dose of 2.2–5.8 × 1011.
Apheresis: Apheresis platelets are collected into an ACD-A (citric acid, sodium citrate, dextrose) solution as either platelet-enriched plasma or as a platelet pellet that requires resuspension in concurrently collected plasma. Apheresis-derived platelets are collected as leukoreduced.
Buffy Coat–Prepared Platelets: Some countries outside of the United States use buffy coat–prepared platelets derived from whole blood. These buffy coat platelet concentrates can be pooled (prestorage) and stored in a single donor’s plasma or platelet additive solution (PAS) (Chapter 9).
Storage: Platelets are stored at 20–24°C with continuous gentle agitation for up to 5 days or at 1–6°C without agitation for up to 3 days for transfusions in patients with active bleeding. Platelets may be stored in plasma or PAS. PAS contains only 35% of the plasma of a standard platelet unit. Platelets must be stored in oxygen-permeable containers because in anoxic conditions platelet metabolism shifts to the anaerobic glycolytic pathway leading to lactic acid production, acidosis, and platelet death. Adequate oxygenation allows aerobic mitochondrial oxidative phosphorylation and the maintenance of pH, as carbon dioxide diffuses as well as oxygen. With the introduction of rapid bacterial testing within 24 hours before issue, the dating of apheresis platelets may be extended up to 7 days (see Chapter 19).
Bacterial Testing: Room temperature storage and the plasma-rich, oxygenated environment of banked platelets may rarely lead to sufficient bacterial levels to cause fever, sepsis, shock, and death in recipients. Most cases have not been life-threatening. As many as 1 in 3000 plateletpheresis collections have evidence of bacterial contamination. Furthermore, late in the 5-day storage period, slow-growing bacteria such as gram-positive cocci may enter an exponential growth phase. To mitigate the risk associated with bacterial contamination, AABB created Standard 220.127.116.11 that requires methods to detect bacteria or use pathogen inactivation technology in all platelet products. Currently there are several methods to meet this Standard (see Chapters 19 and 48).
Pathogen-Reduced Versus Standard Platelets: A recent Cochrane review compared pathogen-reduced (both Mirasol and Intercept) platelets with standard platelets across 15 randomized controlled trials. There was no evidence of a difference in the incidence of clinically significant bleeding complications or serious adverse events. However, participants who received pathogen-reduced platelet transfusions had an increased risk of developing platelet refractoriness with lower 24-hour corrected count increments and required more platelet transfusions, with a mean difference of 1.2 transfusions.
Leukoreduction: Prestorage leukoreduction decreases febrile transfusion reactions by minimizing the level of cytokines released from white blood cells during storage and also reduces the risk of cytomegalovirus (CMV) transmission and human leukocyte antigen (HLA) alloimmunization. Most institutions use only prestorage leukoreduced platelet products (see Chapter 43).
Irradiation: Irradiation of platelet products prevents transfusion-associated graftversus-host disease (TA-GVHD) (see Chapter 42). Expiration time of platelets does not need to be altered after irradiation.
Washing or Volume Reduction: Volume reduction or washing will remove antibodies contained within the plasma for which the recipient carries the corresponding antigen. Examples include maternal platelets transfused to a neonate with neonatal alloimmune thrombocytopenia (NAIT) or ABO-incompatible platelet products. Patients with recurrent severe allergic reactions may benefit from removal of plasma proteins via washing or volume reduction. Washing or volume reduction results in loss of 5%–30% of the platelets and may also compromise platelet function (see Chapters 46 and 47).
Aliquots: Platelet products are often dispensed in small aliquots for neonatal transfusion. If dispensed in a syringe, these products are acceptable for approximately 4 hours. Syringes do not allow for gas exchange and are usually aliquoted in an open, nonsterile environment.
Quality Control: Per AABB Standards, at least 90% of whole blood–derived platelets
must contain ≥5.5 × 1010 platelets and have a pH of ≥6.2 at the end of storage. Ninety-five percent of leukoreduced whole blood–derived platelet units must have <8.3 × 105 residual leukocytes. Pooled platelet products must have <5.0 × 106 white blood cells. At least 90% of apheresis-derived platelets must contain ≥3.0 × 1011 platelets and have a pH of ≥6.2, and to be considered leukoreduced, 90% of the products tested must have <5.0 × 106
Melissa M. Cushing, MD and Robert A. DeSimone, MD
white blood cells. Per the CFR, apheresis collections can be split into up to three products: 95% of the products must have ≥3.0 × 1011 platelets, and 95% must have pH ≥ 6.2. For leukoreduction, 95% of single collections must have <5.0 × 106 white blood cells, 95% of double collections must have <8.0 × 106 white blood cells (and 95% of product must have <5.0 × 106 white blood cells), and 95% of triple collections must have <12 × 106 white blood cells (and 95% of products must have <5.0 × 106 white blood cells).
Dose: In the setting of hypoproliferative thrombocytopenia, AABB guidelines recommend transfusing 3.0 × 1011 platelets. The PLADO trial randomized patients with hypoproliferative thrombocytopenia to low-dose, medium-dose, or high-dose platelet transfusions (1.1 × 1011, 2.2 × 1011, or 4.4 × 1011 platelets per square meter of body surface area, respectively) and found no difference in significant bleeding between the groups, with significantly fewer median platelets transfused in the low-dose group (9.25 × 1011) relative to the medium-dose (11.25 × 1011) and high-dose (19.63 × 1011) groups. However, the low-dose group did require more median transfusions (5) relative to the medium and high-dose groups (3 each).
Product Selection ABO Compatibility: In general, ABO group–specific platelet transfusions should be administered. As platelet supply is often limited owing to the short shelf life, it may be necessary to select out of group platelets for transfusion. As ABO antigens are present on the surface of platelets, lower recovery of ABO-incompatible platelets (major incompatibility) will be observed compared with compatible platelets (i.e., group A product transfused to a group O recipient versus a group O product to a group O recipient). This difference is not typically of clinical significance. For minor incompatibility, ABO-incompatible plasma is present in the platelet product. As some group O platelet products have high-titer anti-A or anti-B, often of both IgG and IgM classes, a positive direct antiglobulin test and occasionally immediate hemolysis or rarely death can occur. It is thus recommended that the anti-A and anti-B titer of group O platelets be determined and only those with low titers be administered to group A or B patients. Studies demonstrate conflicting results about the potential impact of ABO major incompatibility on hematopoietic stem cell transplant (HSCT) outcome. For neonates and infants, ABO-incompatible products should be avoided if possible. If not available, institutions may use PAS platelets or volume-reduced platelets or limit the amount of incompatible plasma per day.
D Compatibility: While not present on platelets, the D antigen is present on residual RBCs within the product. When present in sufficient dose, the D-positive RBCs can result in alloimmunization (anti-D formation) and future risk of hemolytic disease of the fetus and newborn (HDFN). However, this rarely occurs with the minimal volume of RBCs present in today’s apheresis platelet products (approximately 0.00043 mL). In a recent study, only 7/485 (1.44%; 95% CI 0.58%–2.97%) recipients had a primary anti-D response after a median serological follow-up of 77 days (range: 28–2111 days). Given the low risk of anti-D formation, D-incompatible transfusions may be given. Hospital policies may include administering RhIg post D-positive platelet transfusion in some at risk patients.
Adverse Events: Platelet products, like other blood components, may result in adverse events that include infectious disease transmission and noninfectious hazards. Bacterial contamination is the most common infectious risk. The noninfectious hazards of transfusion include hemolytic transfusion reactions (usually from ABO-incompatible plasma within the product), allergic reactions, febrile nonhemolytic transfusion reactions (FNHTRs), transfusion-associated circulatory overload (TACO), and transfusionrelated acute lung injury (TRALI). Hemolytic transfusion reactions can be mitigated by use of PAS units or units with low-titer anti-A or anti-B. Allergic reactions may be mitigated by the use of PAS units. FNHTRs are mitigated by prestorage leukoreduction but are still common. TACO is mitigated by slowing the rate of transfusion or by splitting units in at risk patients. Lastly, TRALI is mitigated by the use of male-only donors or by excluding donors with HLA or human neutrophil antigens (HNA) antibodies.
Further Reading Baharoqlu, M. I., Cordonnier, C., Al-Shahi Salman, R., et al. (2016). Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): A randomized, open-label, phase 3 trial. Lancet, 387, 2605–2613. Cid, J., Lozano, M., Ziman, A., et al. (2015). Low frequency of anti-D alloimmunization following D+ platelet transfusion: The anti-D alloimmunization after D-incompatible platelet transfusions (ADAPT) study. Br J Haematol, 168, 598–603. Dunbar, N. M., Katus, M. C., Freeman, C. M., & Szczepiorkowski, Z. M. (2015). Easier said than done: ABO compatibility and D matching in apheresis platelet transfusions. Transfusion, 55, 1882–1888. Estcourt, L. J., Malouf, R., Hopewell, S., et al. (2017). Pathogen-reduced platelets for the prevention of bleeding. Cochrane Database Syst Rev. https://doi.org/10.1002/146 51858.CD009072.pub3. Goel, R., Ness, P. M., Takemoto, C. M., et al. (2015). Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood, 125, 1470–1476. Kaufman, R. M., Djulbegovic, B., Gernsheimer, T., et al. (2015). Platelet transfusion: A clinical practice guideline from the AABB. Ann Intern Med, 162, 205–213. McQuilten, Z. K., Crighton, G., Brunskill, S., et al. (2018). Optimal dose, timing, and ratio of blood products in massive transfusion: Results from a systematic review. Transfus Med Rev, 32, 6–15. Schiffer, C. A., Bohlke, K., Delaney, M., et al. (2018). Platelet transfusion for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol, 36, 283–299. Slichter, S. J., Kaufman, R. M., Assmann, S. F., et al. (2010). Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med, 362, 600–613. Solves, P., Carpio, N., Balaguer, A., et al. (2015). Transfusion of ABO non-identical platelets does not influence the clinical outcome of patients undergoing autologous haematopoietic stem cell transplantation. Blood Transfus, 13, 411–416. Uhl, L., Assmann, S. F., Haazma, T. H., et al. (2017). Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial. Blood, 130, 1247–1258.