Platelets are one of the most challenging blood products to manage. Because of the high cost, short shelf life and higher risk for transfusion complications such as bacterial contamination, transfusion-related acute lung injury (TRALI), allergic transfusion reactions, and febrile nonhemolytic transfusion reactions, interest in reducing platelet transfusions has evolved in recent years . Issues that are at the forefront of platelet transfusion are prophylactic platelet transfusion in oncology, management of platelet refractoriness, platelets as therapy for patients on antiplatelet medications with intracranial hemorrhage (ICH), and ABO incompatible platelets. For each of these areas, the question of what level to transfuse or whether to transfuse at all has become of primary interest.
The significance of these topics were recently addressed by an AABB Task Force [2▪▪], which systematically reviewed randomized clinical trials and observational studies from 1900 to 2014. The group established six recommendations for the use of platelet transfusion. They recommended platelets for the prevention of spontaneous bleeding in hospitalized patients with therapy induced hypoproliferative thrombocytopenia at a threshold of 10.0 × 109/l. They recommended prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count of less than 20.0 × 109/l, elective diagnostic lumbar puncture with a platelet count less than 30.0 × 109/l, and patients undergoing major elective nonneuraxial surgery with a platelet count of less than 50.0 × 109/l. The task force recommended against the use of prophylactic platelet transfusion for patients who are nonthrombocytopenic for cardiac surgery with cardiopulmonary bypass. The task force could not determine a recommendation for or against the use of platelets for the reversal of antiplatelet therapy in patients with ICH. This last issue is one we address in more detail, as it has been a challenge to find good quality evidence to support or deny the common practice of giving 1–2 units of platelets for any patient with ICH who is on or is suspected to be on antiplatelet therapy.
PROPHYLACTIC PLATELET TRANSFUSION
For decades, the threshold for platelet transfusion in oncology patients was 20.0 × 109/l. This was established not by a study but by a case report in 1962 . Multiple randomized controlled trials have since established that a threshold of 10.0 × 109/l is effective for the prevention of spontaneous bleeding in otherwise stable oncology patients, and one study suggested that a threshold of 5.0 × 109/l was adequate [4,5][4,5].
The question of whether prophylaxis was required at all was recently addressed in the No Prophylaxis Platelet Transfusion Strategy for Hematologic Cancers Trial [6▪], which looked at 600 patients randomized to either traditional prophylaxis or only therapeutic platelet transfusion for active bleeding. The end-point was to determine if the no-prophylaxis arm was noninferior to the traditional practice of platelet transfusion at 10.0 × 109/l. The results were that 50% in the no-prophylaxis group had bleeding, compared with 43% of the prophylaxis group. The no-prophylaxis group also had less time to the first bleed and more days with bleeding. Overall, the study authors concluded that prophylaxis is the superior method for prevention of bleeding in hematological oncology patients. A study by Wandt et al., also looking at prophylactic versus therapeutic platelet transfusion, came to a similar conclusion; however, they suggested that the safety threshold was acceptable for patients with autologous HCST, as this group has no increase in major hemorrhage. On the basis of these results, supportive platelet transfusions in patients with severe thrombocytopenia (<10.0 × 109/l) due to hematopoietic stem cell transplant (HSCT), hematological cancers, and solid-organ cancers undergoing chemotherapy should continue. If careful monitoring is available, consideration can be given to switching to a therapeutic policy for patients with autologous HSCT.
Additional consideration is warranted for patients in the critical care setting. Patients who are thrombocytopenic (<150.0 × 109/l) and are in the ICU have been found to have higher mortality rates  and a higher risk of bleeding . The risks of thrombocytopenia may deter or delay physicians from performing interventional procedures that are frequently necessary in this population, as summarized by Lieberman et al.[10▪]. They looked at published work in thrombocytopenia and platelet transfusion in critical care patients in both adult and pediatric populations. In reviewing the available studies on critically ill adults with thrombocytopenia, they concluded that they could not make a recommendation for or against platelet transfusion. This was because of the generally low quality of the available studies. Despite the frequent use of platelet transfusion in the critical care setting, there was little evidence to support or refute the practice. They concluded randomized controlled trials are needed in critically ill patients to determine the true value of platelet transfusion in a number of related scenarios, such as sepsis and therapeutic interventions. Critically ill patients may have many comorbidities and other confounding factors, which complicate the appearance of benefit for platelet transfusion. Thus, until more satisfactory evidence is available, the current practice will likely continue, such as the recommendation for the threshold of 20.0 × 109/l in patients with septicemia , which the authors felt was a weak recommendation.
Prophylactic platelet transfusion is routinely performed for interventional procedures for which a low platelet count is perceived as an increased risk of bleeding; however, the validity of this practice is unknown. Kander and Tanaka [12▪] sought to determine the effect of platelet transfusion on coagulation enhancement posttransfusion in patients with thrombocytopenia (<50.0 × 109/l) because of bone marrow failure secondary to chemotherapy and/or malignancy, who were about to undergo central venous catheter (CVC) insertion. For this study, they used thromboelastometry, multiple electrode aggregometry, and flow cytometry to evaluate the effect of platelet transfusion on stimulation of the coagulation cascade and effective hemostasis. Thirty-nine patients were identified. Of these patients, all received a platelet transfusion prior to CVC insertion. PT/INR, aPTT, and fibrinogen levels were measured in addition to more advanced assays. All of the study patients had statistically significant rise in their 1-h posttransfusion platelet count, and that count was adequately maintained at 4 h. The authors suggest that this reflects that this 1–4 h window may be the optimal time for CVC. Of interest, the flow cytometry analysis showed that after activation CD62P was unchanged after the use of several different platelet activators. The authors suggest that because approximately half of the tested platelets were transfused, this indicated that the transfused platelets were performing as equally as the patient's own. The authors felt that overall, their study indicated that improvement in coagulation could be attributed to increased numbers of platelets rather than improved function.
Platelet refractoriness can cause significant issues for a patient who is in need of adequate prophylaxis . Refractoriness is caused by a variety of complications including sepsis and medications . It is often multifactorial, thus careful evaluation for the cause or causes is warranted. Unfortunately, it is the patients who are chronically transfused (chemotherapy, hematology, oncology patients) who frequently develop immune refractoriness, which is most often caused by multiple antibodies to human leukocyte antigens (HLA) or human platelet antigens . Immune refractoriness has typically been treated with HLA-matched platelets, in which donors with known HLA-types compatible with the recipients type (or at least lacking the antigen for the known antibody) are recruited. An alternative method is to provide cross-matched platelets, in which available platelets are tested for compatibility with the intended recipient. Both methods are believed to be effective and have distinct advantages; however, they may not be as effective as previously believed. A recent study compared the effectiveness of these two methods [16▪]. Rioux-Massé et al. assessed 32 patients who received either cross-matched or HLA-matched platelets for immune refractoriness. Patients received random-donor (routine), cross-matched or HLA-matched (A, B1U or B1X only) platelet transfusions and corrected count intervals (CCI) were determined 1–4 h posttransfusion. A CCI of more than 5.0 × 109/l was considered a successful transfusion. Of 354 platelet transfusions, 161 were random-donor, 152 were cross-matched and 41 were HLA-matched. When the resulting CCIs were analyzed, 12% of random donor platelets were successful, but only 25% of cross-matched and 29% of HLA-matched achieved the desired threshold, a surprising result. These studies suggest that HLA-matched and cross-matched platelets may not be as clinically effective as previously believed. The authors note that patients may be more complex now than when the original studies comparing these methods were performed. Thus, they believe that a trial of two HLA-matched or cross-matched platelets may be warranted, but if the patient does not show an adequate response, that they return to ABO-compatible platelet transfusions.
INTRACRANIAL HEMORRHAGE AND PLATELET TRANSFUSION
ICH may be secondary to traumatic brain injury, or stroke. ICH is associated with a poor outcome when compared with all other subtypes of stroke, and carries a significant mortality rate. The use of anticoagulant agents is a risk factor for ICH. However, the proper use of platelets in a patient with an ICH is unclear.
The AABB's landmark set of guidelines [2▪▪] that were published in 2014 briefly discuss platelet transfusions for ICH. It cites seven observational studies [17–23][17–23][17–23][17–23][17–23][17–23][17–23] that examined clinical outcomes among patients with traumatic brain injury and the role of platelet transfusion. These studies provide conflicting or neutral evidence regarding a benefit from platelet transfusion. As the evidence was low quality and did not show a clear benefit or detriment to patients, the guideline authors do not provide a recommendation concerning the use of platelet transfusion in patients receiving antiplatelet therapy who have ICH.
Campell et al. published a platelet transfusion review, citing many of the same articles as the AABB guidelines. The current review concluded that because of the small number of studies and lack of randomized control trials, the relationship between antiplatelet agents in the setting of ICH is conflicting, and more study is needed to determine if platelet transfusion is worthwhile in this setting.
In 2015, Kumar et al.[25▪▪] published an expansive look at platelet transfusions in the journal Transfusion. One question was ‘Should patients with traumatic brain injury or nontraumatic intracerebral hemorrhage receive prophylactic platelet transfusions?’. While they looked at several of the same studies, the AABB guidelines considered [17–21,23,26][17–21,23,26][17–21,23,26][17–21,23,26][17–21,23,26][17–21,23,26][17–21,23,26] several of the studies that were reviewed were not cited by the guideline authors [27–29][27–29][27–29]. Most studies compared platelet transfusion versus no platelet transfusion, looking at mortality for outcome. Some studies included patients taking antiplatelet drugs preinjury, and one included patients with preinjury thrombocytopenia without antiplatelet medications . The current review concludes that the overall results from all 11 studies they evaluated indicate no significant differences in mortality for any comparison.
In a related topic to ICH, the proper management of neuraxial anesthesia (e.g. epidural anesthesia) in thrombocytopenic individuals engenders much debate. There is a lack of prospective, randomized trials to answer these questions, although Van Veen et al. published a comprehensive list of the retrospective studies. They conclude that a platelet count of 80.0 × 109/l is a safe count for placing epidural anesthetic and 40.0 × 109/l is a safe platelet count for lumbar puncture in patients without anticoagulants, antiplatelet agents or platelet function defects.
ABO INCOMPATIBLE PLATELET TRANSFUSIONS
ABO compatibility of blood products is a fundamental of blood banking. The need to provide compatible blood products for red blood cell and large volume plasma transfusions to avoid hemolytic transfusion reactions is undisputed. However, the importance of ABO compatible platelet transfusions is less well established, and ABO plasma incompatible platelet transfusions are routinely given . Given the short shelf-life of the platelet product and inventory management concerns, this practice may be necessary. However, transfusions of ABO nonidentical platelets may cause patient harm .
The transfusion of major ABO incompatible platelets (donor ABO antigen expression is incompatible with the recipient plasma) is associated with a decreased response to platelet transfusion, and higher alloimmunization . Conversely, the transfusion of minor ABO incompatible platelets (donor plasma is incompatible with the recipient red blood cell ABO antigen expression) has been associated with hemolytic transfusion reactions . Because of these potential patient issues, the AABB requires accredited laboratories to ‘have a policy concerning transfusion of components containing significant amounts of incompatible ABO antibodies’, and the CAP requires laboratories to have a policy to ‘prevent the administration of ABO incompatible donor plasma in platelets given to infants’ .
One possible method for reducing the amount of incompatible plasma in ABO incompatible platelet transfusions is volume reduction . However, volume reduction increases spontaneous activation of platelets, and impairs ADP-induced aggregability of platelets when compared with nonvolume reduced . This degradation in platelet function is even more pronounced in washed platelets [35,36][35,36]. However, the degradation in platelet function caused by washing can be somewhat decreased by utilizing a pH-neutral and calcium-free solution, such as plasmalyte . Thus, providing platelets is a balancing act between providing an adequate product to improve hemostasis versus the risk of providing a product that could cause a hemolytic reaction.
Another method to avoid hemolytic transfusion reactions from incompatible plasma is to provide products that do not contain ‘high-titer’ anti-A or anti-B. Berseus et al. provide an excellent review of the literature reporting hemolytic transfusion reactions caused by incompatible plasma. They demonstrate that nearly all reactions were caused by high-titer anti-A or anti-B (>1000 antiglobulin titer) or high-titer and high volume (>400 antiglobulin with >200 ml of plasma). The suggestion is that a low-titer of anti-A/B will minimize the risk of hemolytic reaction. The data presented by Karafin et al. in their 2012 study suggest that even when plasma-incompatible blood products were given to recipients, the overall rate of hemolysis (as indicated by a positive DAT) was still low.
The driving force behind the transfusion of ABO incompatible product is inventory management. The short shelf life of platelets means it is extremely challenging for a transfusion service to provide both ABO-identical and D-antigen matched platelets. Dunbar et al.[39▪] reported that their ability to provide ABO identical platelets for patients was only 54% because of platelet supply issues. Cid et al. published similar results of providing ABO-identical platelet product in 65% of cases in 2011. A study by Cohn et al.[41▪] may present a possible solution to this problem. They evaluated platelets stored in platelet additive solution (PAS), which reduces plasma in the platelet product by 65%, compared to standard issue platelets. The results were that PAS platelets were superior to standard issue platelets in the reduction of adverse reactions.
A consistent finding in reviewing the most recent literature is that the available evidence as to the appropriateness and threshold for platelet transfusion is still unclear in many areas. Although the need for prophylactic platelet transfusion in stable oncology patients is well established, many other decisions cannot be supported with quality data. With few exceptions, practitioners have no choice but to use standards that have been established not by careful research, but by consensus and trial-and-error. More quality, randomized controlled trials are needed to firmly determine appropriate thresholds and timeframes for the most effective use of platelets for patient benefit.
The authors thank Dale Laning, D.P.M., Mary Lou Rice, and Walter Kelley, D.O., for their assistance in preparing this manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Spiess BD. Platelet transfusions: the science behind safety, risks and appropriate applications. Best Pract Res Clin Anaesthesiol 2010; 24:65–83.
2▪▪. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2015; 162:205–213.
Landmark guidelines based on available evidence on platelet thresholds and therapy.
3. Gaydos LA, Freireich EJ, Mantel N. The quantitative relation between platelet count and hemorrhage in patients with acute leukemia. N Engl J Med 1962; 266:905–909.
4. Rebulla P, Finazzi G, Marangoni F, et al. The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto. N Engl J Med 1997; 337:1870–1875.
5. Gmür J, Burger J, Schanz U, et al. Safety of stringent prophylactic platelet transfusion policy for patients with acute leukaemia. Lancet 1991; 338:1223–1226.
6▪. Stanworth SJ, Estcourt LJ, Powter G, et al. A No-Prophylaxis
Platelet-Transfusion Strategy for Hematologic Cancers. N Engl J Med 2013; 368:1771–1780.
This study determined that prophylactic platelet transfusion is superior to therapeutic transfusion for patients with thrombocytopenic cancer.
7. Wandt H, Schaefer-Eckart K, Wendelin K, et al. Therapeutic platelet transfusion versus Routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet 2012; 380:1309–1316.
8. Hui P, Cook DJ, Lim W, et al. The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest 2011; 139:271–278.
9. Lauzier F, Arnold DM, Rabbat C, et al. Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis. Intensive Care Med 2013; 39:2135–2143.
10▪. Lieberman L, Bercovitz RS, Sholapur NS, et al. Platelet transfusions for critically ill patients with thrombocytopenia. Blood 2014; 123:1146–1151.quiz 1280.
Review of current literature for guidelines on platelet therapy in critical care in both adult and pediatric populations.
11. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intens Care Med 2013; 39:165–228.
12▪. Kander T, Tanaka KA, Norström E, et al. The effect and duration of prophylactic platelet transfusions before insertion of a central venous catheter in patients with bone marrow failure evaluated with point-of-care methods and flow cytometry. Anesth Analg 2014; 119:882–890.
Study concludes that central venous catheterization procedures are best performed within 1–4 h post platlelet transfusion.
13. Triulzi DJ, Assmann SF, Strauss RG, et al. The impact of platelet transfusion characteristics on posttransfusion platelet increments and clinical bleeding in patients with hypoproliferative thrombocytopenia. Blood 2012; 119:5553–5562.
14. Böck M, Muggenthaler KH, Schmidt U, Heim MU. Influence of antibiotics on posttransfusion platelet increment. Transfusion 1996; 36:952–954.
15. Dzik S, Dzik WH. How I do it: platelet support for refractory patients. Transfusion 2007; 47:374–378.
16▪. Rioux-Massé B, Cohn C, Lindgren B, et al. Utilization of cross-matched or HLA-matched platelets
for patients refractory to platelet transfusion. Transfusion 2014; 54:3080–3087.
Study provides evidence that HLA-matched and cross-matched platelets may no longer be as valuable as previously established.
17. Creutzfeldt CJ, Weinstein JR, Longstreth WT, et al. Prior antiplatelet therapy
, platelet infusion therapy
, and outcome after intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2009; 18:221–228.
18. Ohm C, Mina A, Howells G, et al. Effects of antiplatelet agents on outcomes for elderly patients with traumatic intracranial hemorrhage. J Trauma 2005; 58:518–522.
19. Wong DK, Lurie F, Wong LL. The effects of clopidogrel on elderly traumatic brain injured patients. J Trauma 2008; 65:1303–1308.
20. Downey DM, Monson B, Butler KL, et al. Does platelet administration affect mortality in elderly head-injured patients taking antiplatelet medications? Am Surg 2009; 75:1100–1103.
21. Ivascu FA, Howells GA, Junn FS, et al. Predictors of mortality in trauma patients with intracranial hemorrhage on preinjury aspirin or clopidogrel. J Trauma Inj Infect Crit Care 2008; 65:785–788.
22. Washington CW, Schuerer DJE, Grubb RL. Platelet transfusion: an unnecessary risk for mild traumatic brain injury patients on antiplatelet therapy
. J Trauma 2011; 71:358–363.
23. Anglin CO, Spence JS, Warner Ma, et al. Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses. J Neurosurg 2013; 118:676–686.
24. Campbell PG, Sen A, Yadla S, et al. Emergency reversal of antiplatelet agents in patients presenting with an intracranial hemorrhage: a clinical review. World Neurosurg 2010; 74:279–285.
25▪▪. Kumar A, Mhaskar R, Grossman BJ, et al. Platelet transfusion: a systematic review of the clinical evidence. Transfusion 2015; 55:1116–1127.
This is an exceptionally well done paper summarizing the evidence for platelet transfusion in a wide variety of scenarios.
26. Washington CW, Schuerer DJE, Grubb RL. Platelet transfusion: an unnecessary risk for mild traumatic brain injury patients on antiplatelet therapy
. J Trauma Inj Infect Crit Care 2011; 71:358–363.
27. Ducruet AF, Hickman ZL, Zacharia BE, et al. Impact of platelet transfusion on hematoma expansion in patients receiving antiplatelet agents before intracerebral hemorrhage. Neurol Res 2010; 32:706–710.
28. Naidech AM, Jovanovic B, Liebling S, et al. Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage. Stroke 2009; 40:2398–2401.
29. Naidech AM, Liebling SM, Rosenberg NF, et al. Early platelet transfusion improves platelet activity and may improve outcomes after intracerebral hemorrhage. Neurocrit Care 2012; 16:82–87.
30. Van Veen JJ, Nokes TJ, Makris M. The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. Br J Haematol 2010; 148:15–25.
31. Fung MK, Downes KA, Shulman IA. Transfusion of platelets
containing ABO-incompatible plasma: a survey of 3156 North American Laboratories. Arch Pathol Lab Med 2007; 131:909–916.
32. Berséus O, Boman K, Nessen SC, Westerberg LA. Risks of hemolysis due to anti-A and anti-B caused by the transfusion of blood or blood components containing ABO-incompatible plasma. Transfusion 2013; 53:114S–123S.
33. Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program 2007; 172–178.
34. Fontaine MJ, Mills AM, Weiss S, et al. How we treat: risk mitigation for ABO-incompatible plasma in plateletpheresis products. Transfusion 2012; 52:2081–2085.
35. Schoenfeld H, Muhm M, Doepfmer UR, et al. The functional integrity of platelets
in volume-reduced platelet concentrates. Anesth Analg 2005; 100:78–81.
36. Veeraputhiran M, Ware J, Dent J, et al. A comparison of washed and volume-reduced platelets
with respect to platelet activation, aggregation, and plasma protein removal. Transfusion 2011; 51:1030–1036.
37. Kelley WE, Edelman BB, Drachenberg CB, Hess JR. Washing platelets
in neutral, calcium-free, ringer's acetate. Transfusion 2009; 49:1917–1923.
38. Karafin MS, Blagg L, Tobian AAR, et al. ABO antibody titers are not predictive of hemolytic reactions due to plasma-incompatible platelet transfusions. Transfusion 2012; 52:2087–2093.
39▪. Dunbar NM, Katus MC, Freeman CM, Szczepiorkowski ZM. Easier said than done: ABO compatibility and D matching in apheresis platelet transfusions. Transfusion 2015; 55:1882–1888.
Demonstrated the logistical realities of providing ABO matched platelets.
40. Cid J, Carbassé G, Pereira A, et al. Platelet transfusions from D+ donors to D− patients: A 10-year follow-up study of 1014 patients. Transfusion 2011; 51:1163–1169.
41▪. Cohn CS, Stubbs J, Schwartz J, et al. A comparison of adverse reaction rates for PASC versus plasma platelet units. Transfusion 2014; 54:1927–1934.