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Optimizing platelet transfusions

Annen, Kylea,b,c; Olson, Jordan E.d

doi: 10.1097/MOH.0000000000000188

Purpose of review Platelet transfusion remains a challenging procedure. Concerns about bacterial contamination and other complications, and the interest in improving the evidence base for criteria for platelet transfusion thresholds and policies have provided impetus for studies that challenge the status quo. The current review highlights recent studies and reviews which address these questions in innovative and thoughtful ways.

Recent findings Randomized controlled trials have determined that prophylactic platelet transfusions for the prevention of bleeding in chemotherapy and hematopoietic stem cell transplant patients are superior to a therapeutic approach. For the treatment of immune refractoriness, an observational study identified that of the two main ways to treat, the provision of human leukocyte antigen-matched or cross-matched platelets, neither appears to be as effective as previously believed. When emergent reversal of antiplatelet medications is desired, platelet transfusion is common, however the evidence as to the benefit of this practice is indeterminate. ABO plasma-incompatible platelet transfusion remains a challenge as this product may pose an increased risk for hemolysis. Low-anti-A, anti-B titered products are encouraged, but are not routinely available.

Summary Platelet transfusion practices are being questioned more than ever before. As we develop better therapies and guidelines, the practice of platelet therapy can be expected to change in the near future.

aBlood Center of Wisconsin, Medical Sciences and Blood Research Institutes, Milwaukee, Wisconsin

bHeartland Blood Center, Aurora, Illinois

cDepartment of Pathology, McGaw Medical Center of Northwestern University, Chicago, Illinois

dDepartment of Laboratory Medicine, Geisinger Health System, Danville, Pennsylvania, USA

Correspondence to Kyle Annen, DO, Blood Center of Wisconsin, Medical Sciences Institute, 638 N. 18th Street, Milwaukee, WI 53233, USA. Tel: +1 224 388 0597; e-mail:

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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 [1]. 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.

Box 1

Box 1

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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 [3]. 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.[7], 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 [8] and a higher risk of bleeding [9]. 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 [11], 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.

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Platelet refractoriness can cause significant issues for a patient who is in need of adequate prophylaxis [13]. Refractoriness is caused by a variety of complications including sepsis and medications [14]. 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 [15]. 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.

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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.[24] 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 [23]. 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.[30] 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.

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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 [31]. 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 [32].

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 [33]. 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 [32]. 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’ [31].

One possible method for reducing the amount of incompatible plasma in ABO incompatible platelet transfusions is volume reduction [34]. However, volume reduction increases spontaneous activation of platelets, and impairs ADP-induced aggregability of platelets when compared with nonvolume reduced [35]. 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 [37]. 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.[32] 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.[38] 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.[40] 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.

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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.

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The authors thank Dale Laning, D.P.M., Mary Lou Rice, and Walter Kelley, D.O., for their assistance in preparing this manuscript.

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Financial support and sponsorship


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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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This is an exceptionally well done paper summarizing the evidence for platelet transfusion in a wide variety of scenarios.

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