A dose of platelets: getting it just right

Introduction

The role of platelets in reducing mortality from hemorrhage in cancer patients was first recognized in 1961 (1). The use of these products has expanded to the point that platelet transfusions are commonly administered therapeutically to manage hemorrhage, or prophylactically to prevent hemorrhage in patients with significant thrombocytopenia. Less commonly, platelets are given to patients with platelet dysfunction that may arise due to medication or a wide variety of medical conditions. The standard platelet dose for adult transfusions in the United States (US) is at least 3.0×10¹¹ platelets, considerably higher than in most European nations and Canada (which range from 2.0×10¹¹ to 2.5×10¹¹) (2). This standard is based largely on historical practices and aimed at ensuring effective prophylaxis for prevention of bleeding in thrombocytopenic patients (3). However, more recent research, including the pivotal Platelet Dose (PLADO) study among others, and technological advances have prompted a reevaluation of the dosing standard (4). This review examines platelet transfusion practices and the available evidence regarding the current definitions and possible optimizations of platelet doses for transfusion.

Indications and contraindications for platelet transfusion: prophylactic and therapeutic use

Prophylactic platelet transfusion thresholds to prevent bleeding in thrombocytopenic patients undergoing chemotherapy, other cancer treatments, or surgery are defined by current guidelines. Therapeutic platelet transfusions are used to control active bleeding in patients with low platelet counts or platelet dysfunction [most commonly due to antiplatelet (i.e., aspirin, clopidogrel) therapy, e.g., in cardiac surgery]. The Association for the Advancement of Blood and Biotherapies (AABB) published platelet transfusion guidelines in 2015 that recommended prophylactic transfusions of clinically stable [i.e., no active infection, bleeding, graft-versus-host disease (GVHD), or other significant clinical problems] thrombocytopenic patients with platelet count thresholds of 10×10⁹/L (10,000/µL) to reduce the risk of spontaneous hemorrhage, 20×10⁹/L (20,000/µL) for elective central venous catheter placement or patients with sepsis or acute GVHD, and 50×10⁹/L (50,000/µL) for elective diagnostic lumbar puncture or major elective non-neuraxial surgery (5). These recommendations were primarily based upon expert opinion and low-quality evidence. While the AABB guidelines do not specifically address platelet transfusions for neurosurgery, the generally accepted threshold is a platelet count of 100,000/µL, again based on expert opinion in the face of insufficient data (6-8). Most hospitals have developed internal guidelines regarding platelet thresholds in different situations which are agreed upon by their clinical departments through their established transfusion committees. These thresholds can be based on national standards but sometimes are adjusted to local practices. In regard to counteracting antiplatelet medications, typically in patients with normal platelet counts, though presumed to have platelet dysfunction, no platelet threshold has been defined.

Platelet transfusions are generally contraindicated unless there is an immediate life-threatening condition for patients with thrombocytopenia caused by heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), and patients with immune thrombocytopenic purpura (ITP). In these conditions, platelet transfusion can exacerbate the underlying condition or may not respond owing to immediate destruction of the transfused platelets (9,10).

Platelet products and doses

For prophylactic transfusions (i.e., given to prevent hemorrhage in patients with thrombocytopenia or platelet dysfunction), a single unit of apheresis platelets might be sufficient to achieve the minimal recommended protective platelet count. For therapeutic transfusions (i.e., given for active bleeding), multiple units may be required, depending on the patient’s baseline levels and the clinical context. The dose may be adjusted based on the severity of bleeding and procedural requirements. The dose of platelets required for a therapeutic transfusion can be calculated based on the platelet count in the unit and the clinical need of the patient. Of note, a typical unit of apheresis platelets or whole blood (WB)-derived platelet product pool (i.e., 4 to 6 units pooled together) should increase the platelet count in an average size recipient (i.e., a 70 kg patient) by 30,000 to 60,000/µL, assuming that the patient is not otherwise consuming platelets through bleeding, splenic sequestration, disseminated intravascular consumption (DIC), or immune-mediated destruction [ITP or refractoriness due to antibodies to human leukocyte antigens (HLA) or human platelet antigens (HPA)] (9). In the US, apheresis platelets (commonly referred to as single donor platelets for their method of collection and preparation involving only one donor compared with pooled WB-derived concentrates) have become the preferred platelet product because of higher platelet yields, reduced donor exposures, and reduced risk of bacterial contamination (although this has not been clearly demonstrated, especially since there are newer pre-storage pooled and bacterial-tested WB-derived platelet concentrates) compared with the latter product (3). Notably, the standard for platelet yield of apheresis platelet products, set by the US Food and Drug Administration (FDA) in 1972 at a minimum of 3.0×10¹¹, is higher than in most European nations and Canada, whereby platelet yield standards range from 2.0×10¹¹ to 2.5×10¹¹ (2). Nevertheless, transfusions using platelet products with lower platelet yields outside of the US has not resulted in an apparent increased risk for excessive bleeding (2). The US standard is not evidence based, having been adapted from the average number of platelets in the early 1970s era WB-derived platelet product pools of six units (2). In light of this, the optimal platelet doses for both prophylactic and therapeutic transfusions have long been questioned and Benjamin et al. have advocated for lowering the standard requirement for apheresis platelet yield in the US (2). Lowering the platelet dose, they argue, would allow for increasing the production of platelet units by up to 23% without changing collection procedures as a result of increased split units. In the US the platelet supply is often strained. Factors that contribute to chronic shortage of platelets include the short shelf life of platelet products [i.e., 5–7 days, because room temperature (RT) storage increases the risk of bacterial contamination] and to the high usage of platelets in the US, where approximately two million platelet transfusions are performed per year (primarily for prophylactic use). This represents the highest per capita use of platelets in the world (2,11). Lowering the standard dose would also be advantageous given that current bacterial risk control strategies, including large volume-delayed sampling (LVDS) and pathogen reduction (PR), require additional processing and can result in the loss of platelets and products with lower yields (12,13).

Yet, it is important to note that within the US, owing to increases in demands for platelet transfusions and challenges in recruiting dedicated volunteer donors for apheresis collections, there has been considerable weight given toward increasing production of WB-derived platelets. Notably, though, differences in the way WB-derived platelets are manufactured in the US versus Europe and Canada can affect platelet yield and impact dosing (14,15). In the US, WB-derived platelets are produced using the platelet-rich plasma (PRP) method, in which platelets are centrifuged against the container (15). In Europe and Canada, however, the buffy coat (BC) method of production is employed (14). PRP WB-derived platelets, produced by soft followed by hard centrifugation, results in higher red blood cell (RBC) recovery at the expense of lower plasma recovery (15). Nevertheless, the BC method, in which hard precedes soft centrifugation, results in less platelet activation due to the protective effect of cellular components [i.e., RBCs and white blood cells (WBCs) in WB] against platelet contact with the container during the hard spin (15). Activation in PRP-derived WB platelets contributes to platelet loss during storage and the accelerated development of the platelet storage lesion. Although conversion from the PRP to the BC method of production of WB-derived platelets is possible in the US, as it was in Canada in 2005, there are regulatory barriers to overcome (15).

Other modifications to platelet concentrates, such as leukodepletion, gamma irradiation, collection in platelet additive solutions (PAS) (i.e., PAS replacement of plasma), and PR may also impact platelet recovery after transfusion, though not found to have impact on hemostatic efficacy (14). In particular, though, concern of reduced post-transfusion platelet recovery and increased bleeding episodes has been raised surrounding the use of PR, a process in which platelet concentrates are treated with a photoactivating agent [i.e., amotosalen (which is approved for use in US) or riboflavin (which is not approved for use in the US)] followed by exposure to ultraviolet radiation [ultraviolet A (UVA) or ultraviolet B (UVB)] that results in pathogen inactivation (including bacterial, viral, and parasitic pathogens) as well as WBC inactivation to prevent transfusion-associated GVHD. Nevertheless, although there have been conflicting reports of reduced platelet recovery as measured by the corrected count increment (CCI), there is agreement that the hemostatic efficacy of PR platelets is maintained (14,16).

Other factors that can affect platelet recovery response to transfusions include storage conditions and ABO compatibility (14). Platelets are stored at RT (20–24 ℃) with gentle agitation to maintain proper pH (i.e., ≥6.2) and ensure adequate oxygen and carbon dioxide gas exchange through the storage bag. RT storage, however, limits the shelf life to a maximum of 5–7 days owing to greater risk of bacterial growth. RT storage also contributes to the practice of transfusing ABO-incompatible platelets since the rather short shelf life prohibits storage of large inventories which would increase product expiration and wastage. ABO-mismatched platelets, though, have lower posttransfusion recovery than ABO-matched platelets. Clinical conditions of patients may also impact platelet recovery, including splenomegaly, sepsis, medications, GVHD, microangiopathy, and immune refractoriness (i.e., patients with HLA or HPA antibodies), though transfusion in these cases may be effective in controlling microvascular bleeding even without significant increases in the posttransfusion count (14).

In considering platelet recovery, there are several methods that are used to measure clinical effectiveness. Traditionally, CCI and percent platelet recovery (PPR) have been used as indices because they correct for blood volume and number of platelets transfused (17). Yet Davis et al. implicated regression analysis as a more informative calculation that avoids the data distortion associated with ratio-based (i.e., CCI and PPR) calculations (17). Using data from the Trial to Reduce Alloimmunization to Platelets (TRAP) study, and comparing leukocyte filtered versus unfiltered pooled WB-derived platelets, these authors showed that regression analysis can evaluate the posttransfusion effectiveness of both the quality (i.e., leukocyte filtered versus unfiltered) and the quantity (i.e., the number of platelets transfused) of transfused platelets (17,18). Thus, Davis et al. indicated that while CCI and PPR are useful for patient care purposes, they are insufficient to define platelet refractoriness in research studies that compare platelet preparation techniques.

Prophylactic platelet dosing in hematology/oncology patients

Most experience with platelet transfusions comes from patients who receive them for prophylactic reasons. Examination of the relationship between bleeding risk and platelet count began from the time that platelet products came into use for leukemia patients in the early 1960s, with one report in 1962 correlating increased bleeding risk with lower platelet counts in patients with acute leukemia (Table 1 highlights selected articles on platelet dose published over the years) (19). The study authors observed high rates of bleeding with counts below 1,000/µL (i.e., bleeding occurred on 92% of days with counts below 1,000/µL) with lower risk for counts between 50,000–100,000/µL (i.e., only 8% of days). Although the report did not expressly find a “threshold level” for platelet count at which spontaneous bleeding can be expected, 20,000/µL was widely adopted thereafter based on the study finding of low risk of bleeding (less than 1% risk) associated with that platelet count level, though it has been speculated that many of the study patients were receiving aspirin, a platelet inhibitor, for fever (19,26,28). Not long after, additional studies began to investigate optimal prophylactic transfusion thresholds in leukemia patients, with one study finding that use of a 5,000/µL threshold did not increase bleeding risk and resulted in reduced platelet transfusions and a cost savings of £350,000 over the study period (20). Likewise, further studies in the 1990s supported lower thresholds for prophylactic platelet transfusions (21,22,23,26).

A 1987 US consensus conference commented that the common practice of transfusing WB-derived platelets at a dose of one unit/10 kg body weight or one apheresis unit was a reasonable starting point (39). A decade later, a 1997 United Kingdom (UK) conference recognized that there was still little available randomized clinical trial evidence on which to base either therapeutic or prophylactic platelet transfusions (40). Tinmouth and Freedman published an extensive review of the literature in 2003 in which they summarized evidence for different platelet transfusion doses (28). Notably, these authors highlighted the fact that prophylactic platelet transfusion dose recommendations were based upon limited evidence from consensus conferences and few clinical studies. Nevertheless, there were three prospective studies completed at the time of Tinmouth and Freedman’s review, comparing different doses for prophylactic apheresis platelet transfusions and concluding that higher platelet transfusion doses were beneficial (24,25,27,28). Norol et al. compared platelet dosing in patients (69 adults and 13 children) with hematologic malignancies, using fresh (less than 24 hours old), ABO-compatible apheresis platelets, at medium {[4–6]×10¹¹ platelets}, high {[6–8]×10¹¹ platelets}, and very high (>8×10¹¹ platelets) dose transfusions (24). Their findings showed a correlation between higher platelet increments and increased transfusion intervals associated with higher dose platelet transfusions, suggesting that high platelet doses can reduce the number of platelet products required by thrombocytopenic patients and significantly reduce donor exposure. Klumpp et al. investigated platelet dosing in 46 patients undergoing hematopoietic stem cell transplantation following high-dose therapy and who received 158 apheresis platelet transfusions (25). Their prospective, randomized, double-blind multiple-crossover study compared low-dose {mean, 3.1×10¹¹; range, [2.3–3.5]×10¹¹ platelets} to high-dose {mean, 5.0×10¹¹; range, [4.5–6.1]×10¹¹ platelets} platelet transfusions in matched pairs administered to the same patient in random order. The study excluded actively bleeding and platelet transfusion-refractory patients. Like Norol et al., these authors concluded that higher doses were beneficial in their study population for achieving higher post-transfusion increments (i.e., a higher likelihood of achieving counts greater than 20,000/µL) and longer transfusion-free intervals. Finally, Goodnough et al. studied prophylactic platelet transfusions using apheresis platelets collected from healthy platelet donors undergoing treatment with thrombopoietin (TPO) (i.e., pegylated recombinant human megakaryocyte growth and development factor, comparing two doses, 1 and 3 µg/kg) versus transfusions from placebo-treated healthy donors (27). Once again, the double-blinded study found a higher platelet posttransfusion count associated with TPO donor-treated platelets in a total of 160 platelet components transfused to 120 adult (age 18 years or older) patients with chemotherapy-induced thrombocytopenia. The effect was attributed to the higher median platelet counts found in the TPO donor-treated platelets (5.7×10¹¹ and 11.0×10¹¹ platelets for 1 and 3 µg/kg doses, respectively) versus placebo donor-treated platelets (3.4×10¹¹ platelets) and was more pronounced with the higher (3 µg/kg) TPO dose. TPO donor-treated platelets also produced longer median intervals to next platelet transfusion. Nevertheless, Tinmouth and Freedman were critical of these studies in that their designs allowed for only limited evaluation of bleeding outcomes and platelet utilization, that none of the studies could report on longer term effects on bleeding outcomes, and that it had been shown that, with repeated platelet transfusions, platelet count increments decrease with a general decrease in time between transfusions (28). Thus, they commented, that the true benefits of providing higher doses of apheresis platelets for prophylaxis remained unclear. Yet, Tinmouth and Freedman did concede that, in fact, there had not been any recent studies of platelet utilization over long-term support of thrombocytopenic patients to consider. What they did cite, however, were studies, including work done by Hanson and Slichter using ⁵¹Cr-labeled autologous WB-derived platelets given to normal and thrombocytopenic individuals, showing that the calculated mean life span of platelets in normal patients was estimated at 9.6±0.6 days decreasing to 7.0±1.5 days in persons with moderate thrombocytopenia (50–100,000/µL) and was even further reduced in severe thrombocytopenia (<50,000/µL, 6.0±1.7 days for autologous platelets and 3.4±1.1 days for allogeneic platelets) (28,41). In addition, the number of daily platelets lost to senescence and random processes (i.e., maintenance of vascular hemostasis) is constant at 7.1×10⁹ platelets/L/day with normal platelet counts, representing less than a 20% turnover rate, but greatly rising in severe thrombocytopenia (28). Based on these data, Tinmouth and Freedman asserted that the number of platelets required by a 70 kg person to maintain hemostasis is estimated at 3.6×10¹⁰ platelets/L/day, taking into account that one-third of platelets are sequestered in a normal-size spleen, such that one unit of WB-derived platelets (with minimum dose of 5.5×10¹⁰ platelets) would be sufficient to maintain hemostasis (28). Transfusing higher doses of platelets, they further argued, would lead to a higher percentage of platelets lost to senescence and thereby increase total platelet utilization (28). Meanwhile, Hersh et al. proposed a mathematical model (differential equation) to predict platelet survival in thrombocytopenia in uncomplicated (i.e., without sepsis, bleeding, or splenomegaly) patients who underwent marrow ablation for bone marrow transplant during the time that they were platelet transfusion dependent (42). Their model predicted a reduction in platelet transfusion requirements when the transfusion threshold was reduced from 20 to 10 ×10⁹/L, illustrating that larger platelet transfusions would result in greater time between transfusions, but that more units would be transfused when comparing a six-unit WB-platelet pool versus a three-unit pool. Thus, these authors concluded that consideration should be given to more frequent use of smaller-dose platelets in patients requiring chronic support with transfusions. Clearly, these studies were published at a time when WB-derived platelets were more commonly used than apheresis platelets.

Consideration of the matter of low-dose versus high-dose platelet transfusion support for patients with hematological malignancies continued unsettled with Tinmouth et al. in a 2004 published study and Sensebé et al. in a 2005 published study reporting opposite conclusions, the former supporting low-dose prophylactic transfusions (three versus five platelet units) and the latter supporting higher-dose platelet transfusions (0.5×10¹¹/10 kg versus 1×10¹¹/10 kg) in acute leukemia patients undergoing autologous hematopoietic stem cell transplants (29,30). Slichter et al. then challenged the US dosing standard in their landmark PLADO trial that compared low-dose [1.1×10¹¹ platelets/m² body surface area (BSA)/transfusion], medium-dose (2.2×10¹¹ platelets/m² BSA/transfusion), and high-dose (4.4×10¹¹ platelets/m² BSA/transfusion) platelet transfusion regimens in 1,272 hospitalized patients with hematological malignancies or solid tumors and hypoproliferative thrombocytopenia (3). This was a notable undertaking, considering that the year prior, Heddle at al. reported on an international, multicenter, noninferiority study [The Strategies for Transfusion of Platelets (SToP) study] comparing low-dose (1.5×10¹¹ platelets) to standard-dose (3.0×10¹¹ platelets) prophylactic platelet transfusions in patients with hypoproliferative thrombocytopenia, which was stopped by the Data Safety Monitoring Board because the difference in grade 4 bleeding reached the prespecified threshold of 5% (31). In PLADO, patients were assigned to receive platelet transfusions (either apheresis or pooled WB-derived platelets) at the assigned dose when the counts were 10,000/µL or lower (3). The calculated median total number of platelets transfused per patient for 1,000 patients was 9.25×10¹¹ (with a median number of five platelet transfusions administered per patient), 11.25×10¹¹ (median number of three platelet transfusions per patient), and 19.63×10¹¹ (median number of three platelet transfusions per patient) in the low-, medium-, and high-dose groups, respectively, showing that the platelet doses were significantly higher in the latter two groups despite the fact that they reported all known at-issue doses to be within the assigned ranges for only 51%, 63%, and 55% of the low-, medium-, and high-dose ranges, respectively. In addition, the authors reported that the transfusion trigger of 10,000/µL was adhered to on all study days in the three groups for only 53%, 63%, and 61% of patients, respectively. Although physicians ordered dose and trigger threshold changes for clinical reasons, only 3% of patients overall had a dose change and 7% had a change to the trigger threshold prior to the onset of grade 2 bleeding or higher. The study reported that lower dose prophylactic platelet transfusions did not affect bleeding in hospitalized patients undergoing hematopoietic stem cell transplantation or chemotherapy. The authors also reported that bleeding occurred on 25% of days with platelet counts lower than 5,000/µL versus 17% with counts 6,000–80,000/µL. Unlike SToP, which was stopped after only 58 low-dose and 61 standard-dose patients were enrolled owing to three patients in the low-dose group developing grade 4 bleeding, the much larger PLADO study did not find a significant difference in severe bleeding related to platelet dose. The PLADO investigators attributed this to the fact that they adjusted the platelet dose for BSA whereas the same dose range was received for all patients in each of the two groups in SToP (3,31).

More recently, Stanworth et al. challenged the 10,000/µL platelet count threshold in a randomized, open-label, noninferiority trial conducted in the UK and Australia (33). The study included 600 patients (age 16 or older) receiving chemotherapy or undergoing stem-cell transplantation (both autologous and allogeneic transplantation) who had or were expected to have thrombocytopenia. Patients were randomized to either receive (prophylaxis) or not receive (no-prophylaxis) platelet transfusions once the platelet count dropped below 10,000/µL. The authors found that patients in the no-prophylaxis group had more days with bleeding [World Health Organization (WHO) grade 2 or higher] and a shorter time to first bleeding episode than patients assigned to the prophylaxis group, supporting continued use of prophylactic transfusions in severe thrombocytopenia in patients with hematologic malignancies.

Studies continue to find rates of excessive prophylactic platelet transfusions in hematology/oncology patient as well as in other patient groups, with about a third of prophylactic platelet transfusions administered above accepted platelet count thresholds. Liker et al. found a 33% rate (78 of 235) of inappropriate prophylactic transfusions in a Croatian retrospective study of hematology patients [i.e., patients diagnosed with acute and chronic leukemia, myelodysplastic syndrome (MDS), multiple myeloma, and lymphoma] with hypoproliferative thrombocytopenia (37). Stanworth et al. found that 34% of prophylactic platelet transfusions occurred in patients with nadir platelet counts greater than 50,000/µL on days when no bleeding was recorded in their prospective, multicenter, observational study. The study included all patients sequentially admitted to 29 intensive care units (ICUs) across the UK over an 8-week period (1,923 admissions), including medical, surgical, and trauma patients with conditions related to hematology/oncology, chronic liver disease, chronic kidney disease, and sepsis (34).

Platelet transfusion dosing in pediatric patients

The PLADO trial data showed higher rates of bleeding in a subset analysis of children, suggesting that data from adult studies may not be generalizable to younger populations (32,43). In regard to neonatal patients, Curley et al. published the Platelets for Neonatal Transfusion-2 (PlaNet-2) study, a multicenter, randomized trial of platelet transfusion thresholds in preterm neonates (36). The study found that among preterm infants with severe thrombocytopenia, those randomly assigned to receive platelet transfusions at a threshold count of 50,000/µL had a higher rate of death or major bleeding within 28 days after randomization than those receiving transfusions at a threshold of 25,000/µL. The authors hypothesized that the difference in adverse outcomes may have been related to immunologic and inflammatory effects of platelets on neonates. Rates of bronchopulmonary dysplasia (BPD) also appeared to be correlated to higher transfusion rates, possibly linked to platelet-derived reactive oxygen species aggravating aberrant angiogenesis characterizing BPD in addition to vessel occlusion by platelet microthrombi. Most recently, Heeger et al. reported on a Dutch retrospective, observational cohort study, which included all preterm neonates (less than 32 weeks gestation) admitted to a neonatal ICU between 2004 and 2022 (38). The investigators compared platelet transfusions and mortality and bleeding rates over three time periods (Epoch I, II, and III) in which the platelet transfusion thresholds changed from 30,000/µL (January 2004–December 2009) to 20,000/µL (January 2010–June 2019) to 25,000/µL (July 2019–July 2022) for stable neonates in the three time periods, respectively, and 50,000/µL for unstable neonates in Epoch I and II, and neonates with major bleeding in Epoch III. Implementation of restrictive platelet transfusion guidelines led to a reduction of the rate and number of platelet transfusions. The study found that lower doses of platelet transfusions were sufficient to prevent severe bleeding in preterm neonates, supporting the use of reduced dosing regimens.

Platelet dosing in massive transfusion

Reports that massive transfusion using high plasma to RBC ratios was independently associated with improved survival in combat trauma led to adoption of massive transfusion packs of 1:1:1 ratios of RBCs to plasma to platelets in civilian trauma centers (44). The inclusion of platelets in massive transfusion packs was further supported by the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial (35). Although not standardized, a typical ratio used by trauma centers includes five units each of RBCs and plasma and an equivalent dose of five units of platelets (i.e., one apheresis or five pooled WB-derived platelets). More recent adoption of group O WB units by some trauma centers has reinvigorated interest in cold-stored platelet efficacy. WB for trauma resuscitation has been associated with a better hemostatic profile by viscoelastic testing (i.e., rotational thromboelastometry) which may partly be due to the effect of cold activation on platelets (45). As such, cold activation induces platelets to be more hemostatically active, desirable in the setting of acute bleeding, though at the expense of more rapid clearing.

Conclusions

Returning to the argument for lowering the dose of platelets posed by Benjamin et al., is the US in a position to accept platelet products with lower yields (10)? Evidence to support the use of a lower platelet dose includes a preponderance of study data, clinical experience of using lower yield platelets in European nations and in Canada, as well as use of platelets with unintended reduced yields produced as a result of LVDS or PR processing in the US. However, in spite of this favorable evidence, it is not apparent that the FDA has this under consideration at this time (2). Thus, in managing platelet supplies, transfusion services are encouraged to implement appropriate patient blood management (PBM) tools, including monitoring transfusion practices for adherence to practice guidelines and evidence-based transfusions, educating clinicians who order blood products, and using computer-physician order entry with clinical decision support (CPOE/CDS) and best practice alerts (46). Expanding the platelet inventory, too, is a major objective to mitigate the impact of severe shortages caused by weather events and other disasters or prolonged crisis, such as the coronavirus disease 2019 (COVID-19) pandemic. Stubbs et al. proposed four approaches to strengthen donor recruitment and improve utilization: use of a paid donor model, continued efforts toward production of WB-derived platelets, improved logistics to distribute platelets for optimal use, and use of cold-stored platelets (47). Of these approaches, the blood collection community does not seem accepting of paid donations, citing concerns in regard to negative effects on donor altruism, blood product safety, and the vulnerability of disadvantaged people who might be incentivized to donate (48,49). Meanwhile, cold stored platelets, although having an extended shelf-life up to 14 days, may not be the ideal product for patients with hematological disorders, given their short circulatory half-life owing to cold activation (50). Alternatives to platelet products also deserve consideration, including off-label use of TPO mimetics and other hemostatic agents that mimic platelet function, such as synthetic platelets, though there is only limited evidence of effectiveness of the former in patients with hypoproliferative bone marrow conditions, such as MDS and acute myeloid leukemia, and the latter are not yet approved by the FDA for clinical use (6,51).

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-21/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-21/coif). M.T.F. serves as an unpaid editorial board member of Annals of Blood from November 2024 to October 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Association for the Advancement of Blood and Biotherapies (AABB). Highlights of transfusion medicine history. [accessed 20 June 2024]. Available online: https://www.aabb.org/news-resources/resources/transfusion-medicine/highlights-of-transfusion-medicine-history
2. Benjamin RJ, Katz L, Gammon RR, et al. The argument(s) for lowering the US minimum required content of apheresis platelet components. Transfusion 2019;59:779-88. [PubMed]
3. Friedman MT. Lowering the standard dose of platelets: is the timing right for the U.S.? Association of Blood and Biotherapies (AABB). PBM Column. October 2023. [accessed 18 June 2024]. Available online: https://www.aabb.org/docs/default-source/default-document-library/resources/lowering-the-standard-dose-of-platelets.pdf?sfvrsn=59b51da1_4
4. Slichter SJ, Kaufman RM, Assmann SF, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 2010;362:600-13. [PubMed]
5. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2015;162:205-13. [PubMed]
6. Li D, Glor T, Jones GA. Thrombocytopenia and Neurosurgery: A Literature Review. World Neurosurg 2017;106:277-80. [PubMed]
7. Capraru A, Jalowiec KA, Medri C, et al. Platelet Transfusion-Insights from Current Practice to Future Development. J Clin Med 2021;10:1990. [PubMed]
8. Garraud O, Hamzeh-Cognasse H, Chalayer E, et al. Platelet transfusion in adults: An update. Transfus Clin Biol 2023;30:147-65. [PubMed]
9. Nalezinsky S. How do I select evidence-based transfusion thresholds for platelets, plasma, and cryoprecipitate? Association for the Advancement of Blood and Biotherapies (AABB). PBM Column. July 2022. [accessed 18 June 2024]. Available online: https://www.aabb.org/docs/default-source/default-document-library/resources/how-do-i-select-evidence-based-transfusion-thresholds-for-platelets-plasma-and-cryoprecipitate.pdf?sfvrsn=217ea1a9_0
10. Yuan S, Otrock ZK. Platelet Transfusion: An Update on Indications and Guidelines. Clin Lab Med 2021;41:621-34. [PubMed]
11. World Health Organization (WHO). Global status report on blood safety and availability. 2016. [accessed 19 June 2024]. Available online: https://apps.who.int/iris/bitstream/handle/10665/254987/9789241565431-eng.pdf
12. Solves Alcaina P. Platelet Transfusion: And Update on Challenges and Outcomes. J Blood Med 2020;11:19-26. [PubMed]
13. United States Food and Drug Administration. Guidance for the industry: Bacterial risk control strategies for blood collection establishments and transfusion services to enhance the safety and availability of platelets for transfusion. December 2020. [accessed 19 June 2024]. Available online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bacterial-risk-control-strategies-blood-collection-establishments-and-transfusion-services-enhance
14. Holbro A, Infanti L, Sigle J, et al. Platelet transfusion: basic aspects. Swiss Med Wkly 2013;143:w13885. [PubMed]
15. Gammon RR, Devine D, Katz LM, et al. Buffy coat platelets coming to America: Are we ready? Transfusion 2021;61:627-33. [PubMed]
16. Kaiser-Guignard J, Canellini G, Lion N, et al. The clinical and biological impact of new pathogen inactivation technologies on platelet concentrates. Blood Rev 2014;28:235-41. [PubMed]
17. Davis KB, Slichter SJ, Corash L. Corrected count increment and percent platelet recovery as measures of posttransfusion platelet response: problems and a solution. Transfusion 1999;39:586-92. [PubMed]
18. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med 1997;337:1861-9. [PubMed]
19. Gaydos LA, Freireich EJ, Mantel MA. The quantitative relationship between platelet count and hemorrhage in patients with acute leukemia. N Engl J Med 1962;266:905-9. [PubMed]
20. Gmür J, Burger J, Schanz U, et al. Safety of stringent prophylactic platelet transfusion policy for patients with acute leukaemia. Lancet 1991;338:1223-6. [PubMed]
21. Wandt H, Frank M, Ehninger G, et al. Safety and cost effectiveness of a 10 × 10⁹/L trigger for prophylactic platelet transfusions compared with the traditional 20 × 10⁹/L trigger: a prospective comparative trial in 105 patients with acute myeloid leukemia. Blood 1998;91:3601-6. [PubMed]
22. Heckman KD, Weiner GJ, Davis CS, et al. Randomized study of prophylactic platelet transfusion threshold during induction therapy for adult acute leukemia: 10,000/microL versus 20,000/microL. J Clin Oncol 1997;15:1143-9. [PubMed]
23. 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;337:1870-5. [PubMed]
24. Norol F, Bierling P, Roudot-Thoraval F, et al. Platelet transfusion: a dose-response study. Blood 1998;92:1448-53. [PubMed]
25. Klumpp TR, Herman JH, Gaughan JP, et al. Clinical consequences of alterations in platelet transfusion dose: a prospective, randomized, double-blind trial. Transfusion 1999;39:674-81. [PubMed]
26. Lawrence JB, Yomtovian RA, Hammons T, et al. Lowering the prophylactic platelet transfusion threshold: a prospective analysis. Leuk Lymphoma 2001;41:67-76. [PubMed]
27. Goodnough LT, Kuter DJ, McCullough J, et al. Prophylactic platelet transfusions from healthy apheresis platelet donors undergoing treatment with thrombopoietin. Blood 2001;98:1346-51. [PubMed]
28. Tinmouth AT, Freedman J. Prophylactic platelet transfusions: which dose is the best dose? A review of the literature. Transfus Med Rev 2003;17:181-93. [PubMed]
29. Tinmouth A, Tannock IF, Crump M, et al. Low-dose prophylactic platelet transfusions in recipients of an autologous peripheral blood progenitor cell transplant and patients with acute leukemia: a randomized controlled trial with a sequential Bayesian design. Transfusion 2004;44:1711-9. [PubMed]
30. Sensebé L, Giraudeau B, Bardiaux L, et al. The efficiency of transfusing high doses of platelets in hematologic patients with thrombocytopenia: results of a prospective, randomized, open, blinded end point (PROBE) study. Blood 2005;105:862-4. [PubMed]
31. Heddle NM, Cook RJ, Tinmouth A, et al. A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. Blood 2009;113:1564-73. [PubMed]
32. Josephson CD, Granger S, Assmann SF, et al. Bleeding risks are higher in children versus adults given prophylactic platelet transfusions for treatment-induced hypoproliferative thrombocytopenia. Blood 2012;120:748-60. [PubMed]
33. Stanworth SJ, Estcourt LJ, Powter G, et al. A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med 2013;368:1771-80. [PubMed]
34. Stanworth SJ, Walsh TS, Prescott RJ, et al. Thrombocytopenia and platelet transfusion in UK critical care: a multicenter observational study. Transfusion 2013;53:1050-8. [PubMed]
35. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015;313:471-82. [PubMed]
36. Curley A, Stanworth SJ, Willoughby K, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. N Engl J Med 2019;380:242-51. [PubMed]
37. Liker M, Bašić Kinda S, Duraković N, et al. The appropriateness of platelet transfusions in hematological patients and the potential for improvement. Transfus Clin Biol 2023;30:212-8. [PubMed]
38. Heeger LE, Houben NAM, Caram-Deelder C, et al. Impact of restrictive platelet transfusion strategies on transfusion rates: A cohort study in very preterm infants. Transfusion 2024;64:1421-7. [PubMed]
39. Consensus conference. Platelet transfusion therapy. JAMA 1987;257:1777-80. [PubMed]
40. Norfolk DR, Ancliffe PJ, Contreras M, et al. Consensus Conference on Platelet Transfusion, Royal College of Physicians of Edinburgh, 27-28 November 1997. Synopsis of background papers. Br J Haematol 1998;101:609-17. [PubMed]
41. Hanson SR, Slichter SJ. Platelet kinetics in patients with bone marrow hypoplasia: evidence for a fixed platelet requirement. Blood 1985;66:1105-9. [PubMed]
42. Hersh JK, Hom EG, Brecher ME. Mathematical modeling of platelet survival with implications for optimal transfusion practice in the chronically platelet transfusion-dependent patient. Transfusion 1998;38:637-44. [PubMed]
43. Slichter SJ. Eliminate prophylactic platelet transfusions? N Engl J Med 2013;368:1837-8. [PubMed]
44. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007;63:805-13. [PubMed]
45. Hanna M, Knittel J, Gillihan J. The Use of Whole Blood Transfusion in Trauma. Curr Anesthesiol Rep 2022;12:234-9. [PubMed]
46. Friedman MT. How do I use clinical decision support for patient blood management? Association for the Advancement of Blood and Biotherapies (AABB). PBM Column. October 2022. [accessed 16 July 2024]. Available online: https://www.aabb.org/docs/default-source/default-document-library/resources/how-do-i-use-clinical-decision-support.pdf?sfvrsn=a9315ba1_0
47. Stubbs JR, Shaz BH, Vassallo RR, et al. Expanding the platelet inventory to mitigate the impact of severe shortages. Hematology Am Soc Hematol Educ Program 2022;2022:424-9. [PubMed]
48. Dodd RY, Stramer SL, Smith R, et al. Paid platelet donors: Points to consider. Transfusion 2021;61:1000-3. [PubMed]
49. Ochoa A, Shaefer HL, Grogan-Kaylor A. The interlinkage between blood plasma donation and poverty in the United States. J Sociol Soc Welfare. 2021;48:56-71.
50. Gammon RR, Hebert J, Min K, et al. Cold stored platelets - Increasing understanding and acceptance. Transfus Apher Sci 2023;62:103639. [PubMed]
51. Chen X, Wang Y, Zang Y, et al. Recombinant human thrombopoietin promotes platelet recovery in DCAG-treated patients with intermediate-high-risk MDS/hypoproliferative AML. Medicine (Baltimore) 2023;102:e33373. [PubMed]