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. Author manuscript; available in PMC: 2022 Sep 22.
Published in final edited form as: Curr Opin Hematol. 2020 Nov;27(6):378–385. doi: 10.1097/MOH.0000000000000608

Platelet transfusion for patients with platelet dysfunction: effectiveness, mechanisms, and unanswered questions

Robert H Lee 1,2, Raj S Kasthuri 1,3, Wolfgang Bergmeier 1,2
PMCID: PMC9495271  NIHMSID: NIHMS1651375  PMID: 32868672

Abstract

Purpose of review

In this review, we discuss current clinical guidelines and potential underlying mechanisms regarding platelet transfusion therapy in patients at risk of bleeding, comparing management of patients with thrombocytopenia versus those with qualitative platelet disorders.

Recent findings

Platelet transfusion therapy is highly effective in managing bleeding in patients with hypoproliferative thrombocytopenia. Clinical trials have demonstrated that platelet transfusion can be used at a lower trigger threshold and reduced platelet doses, and may be used therapeutically rather than prophylactically in some situations, although additional data is needed. In patients with inherited platelet disorders such as Glanzmann’s Thrombasthenia or those with RASGRP2 mutations, platelet transfusion may be ineffective due to competition between transfused and endogenous platelets at the site of vascular injury. Successful management of these patients may require transfusion of additional platelet units, or mechanism-driven combination therapy with other pro-hemostatic agents. In patients on anti-platelet therapy, timing of transfusion and inhibitor mechanism-of-action are key in determining therapeutic success.

Summary

Expanding our understanding of the mechanisms by which transfused platelets exert their pro-hemostatic function in various bleeding disorders will improve the appropriate use of platelet transfusion.

Keywords: Platelets, transfusion, bleeding, thrombocytopenia

1. Introduction

Platelets are the key cellular component of the hemostatic response. Platelets circulate in blood in a quiescent state but are readily activated and adhere to a site of vascular injury to prevent blood loss. Normal platelet function is dependent on expression of critical surface receptors and signaling proteins [1]. Additionally, a minimum number of platelets is required to maintain the vascular barrier. In relation to these requirements, platelet disorders can be grouped into two categories: quantitative (those causing changes in platelet numbers) and qualitative (those causing loss of expression or function of critical platelet proteins leading to platelet dysfunction) [2]. Additionally, platelet disorders can be either inherited (genetic; IPD), e.g. Glanzmann’s thrombasthenia, or acquired (APD), e.g. platelet dysfunction associated, for example, with trauma or anti-platelet drugs [3]. Bleeding associated with platelet dysfunction can be anywhere from mild to life-threatening. Minor bleeding may be controlled by external methods such as compression or topical thrombin. However, prolonged or massive bleeding requires parenteral, mechanism-based hemostatic agents. Currently, the main therapeutic options for bleeding due to platelet dysfunction are 1) desmopressin (DDAVP), 2) tranexamic acid (TXA) or other anti-fibrinolytics, 3) recombinant activated Factor VII (rFVIIa; NovoSeven), and 4) platelet transfusion [4]. These hemostatic therapies may be used individually or in combination. Importantly, while platelet transfusion is effective in preventing thrombocytopenia-associated bleeding [5], the impact of platelet transfusion in qualitative platelet disorders is not entirely clear. In this review, we focus on the use of platelet transfusion therapy in patients with qualitative IPDs or APDs and lay out current transfusion dogmas and guidelines used in clinical settings. We also discuss the mechanistic basis for competition between endogenous (dysfunctional) and transfused (healthy) platelets, and how this may affect the therapeutic effectiveness of platelet transfusion in various settings. Our goal is to highlight critical gaps in knowledge and to translate mechanistic findings into potential improvements in the clinical management of bleeding.

2. Platelets and hemostasis

Disruption of the vascular wall results in exposure of extracellular matrix (ECM) proteins such as collagen, and tissue factor (TF), which are normally kept isolated from blood. Von Willebrand factor (VWF) then immobilizes on the exposed vascular subendothelium [6]. The first critical event in hemostatic plug formation is platelet tethering to VWF via the glycoprotein (GP)Ib-IX-V receptor complex, which is necessary for platelet localization to the injury site [7]. Upon tethering, platelets are activated by collagen and by the small amount of thrombin generated by the TF/activated factor VII (FVIIa) complex on the surface of TF-expressing cells [8]. Subsequently, platelet-platelet cohesion is mediated by activated integrin αIIbβ3 bridging via fibrinogen and vWF [9], and other integrins such as α2β1 play important roles in platelet adhesion to the ECM [10]. Feedback mediators such as adenosine diphosphate (ADP) and thromboxane A2 (TxA2) are also released by adhered platelets to promote sustained platelet activation for hemostatic plug stability [11,12] (Figure 1A). Co-activation by collagen and thrombin can further induce a procoagulant platelet phenotype, further enhancing thrombin generation and leading to fibrin polymerization [13]. Importantly, although these events are described in sequence, they are occurring in vivo in a matter of seconds to minutes with significant overlap and crosstalk.

Figure 1:

Figure 1:

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Graphical depiction of platelet plug formation under normal conditions or in platelet disorders managed with platelet transfusion therapy. A) In a person with normal platelet function, platelets localize to the injury site by binding to von Willebrand Factor (VWF) via GPIb, and collagen. Platelet activation then occurs, driven by thrombin and collagen near the edges of the injury, and supported by feedback signaling from ADP and thromboxane A2 (TxA2) in the center of the plug. Thrombin can also be generated on the surface of highly activated platelets. Platelet-platelet cohesion is mediated by activated αIIbβ3 integrin and fibrinogen, allowing for the formation of a solid and stable hemostatic plug. B) In severely thrombocytopenic patients, the low numbers of endogenous platelets are unable to support hemostasis. Platelet transfusion therapy is typically effective in these patients by increasing the number of circulating platelets. C) In disorders of platelet integrin dysfunction, the patient’s endogenous platelets retain the ability to tether and adhere to the site of injury, but then either lack activation signaling (RASGRP2 variants, BDPLT18) or lack expression or function of αIIbβ3 integrin (GT). Therefore, the patient’s endogenous platelets are unable to effectively participate in platelet-platelet cohesion, and disrupt the ability of the hemostatic plug to properly form. D) In patients on anti-platelet therapy (aspirin + P2Y12 inhibitor), the endogenous platelets 1) produce ADP but are unable to respond to it and 2) respond to TxA2 but are unable to produce it. The patient’s platelets remain insensitive to ADP even in the presence of healthy transfused platelets, and can therefore disrupt stability of the center of the hemostatic plug. Additionally, transfused platelets can be inhibited by residual circulating inhibitors, thereby reducing their function and further impairing the hemostatic efficacy.

The conversion from a quiescent to an activated platelet depends on agonist receptors and intracellular signaling pathways. Platelet signaling is initiated by ligand (agonist) binding to receptors: collagen to GPVI, thrombin to protease activated receptor (PAR)1/4 (human) or PAR4/3 (mouse), ADP to P2Y1/P2Y12, and TxA2 to TP [1]. Downstream signaling leads to the formation of second messengers, which converge on the small GTPase Rap1, a central regulator of platelet integrin activation [14,15]. The activation status of Rap1 is balanced by a main activator, CalDAG-GEFI [16], and a main inhibitor, Rasa3 [17]. Ca2+-induced activation of CalDAG-GEFI mediates the immediate but transient activation of Rap1 [18], while P2Y12 signaling is necessary for sustained Rap1 activation by inhibiting Rasa3 [17,19]. There may also be a signaling role for GPIbα [20], although the specific pathways and functional consequences during hemostasis are still under debate. However, mechanoactivation and/or clustering of GPIb plays an important role in the rapid clearance of cold-stored platelets [21]. The importance of these receptors and signaling pathways is demonstrated by the clinically significant bleeding observed in patients with genetic disorders affecting protein expression or function.

3. IPDs and APDs

Qualitative IPDs are defined by platelet dysfunction with or without a change in platelet count. The two most well-described IPDs are Glanzmann’s Thrombasthenia (GT) and Bernard Soulier Syndrome (BSS), caused by loss of expression or function of integrin αIIbβ3 (encoded by the genes ITGA2B and ITGB3) or GPIb-IX-V complex (GP1BA, GP1BB, GP9, GPV), respectively. GT patients typically have normal platelet counts [22], while BSS patients have varying degrees of macrothrombocytopenia [23]. However, patients with novel variants of GT, such as acquired dysfunction due to anti-αIIbβ3 antibodies or gain-of-function mutations in αIIbβ3, often present with macrothrombocytopenia [24]. A more recently described IPD is caused by mutations in the gene encoding for CalDAG-GEFI, RASGRP2 (also called Bleeding disorder, platelet-type, 18; BDPLT18) [25]. These patients have a GT-like platelet disorder, with a variably impaired platelet aggregation response to collagen, ADP and thrombin, a normal response to ristocetin and PMA, and a normal platelet count [26]. Other qualitative IPDs include mutations in P2Y12, TP (TxA2 receptor), GPVI, and Kindlin3 [27]. Additionally, platelet storage pool deficiencies, including Gray and Quebec platelet disorders (α-granules) and Hermansky-Pudlak and Chediak-Higashi syndromes (δ-granules) are associated with bleeding, and variable thrombocytopenia [28]. Evolutions in gene sequencing technology have been instrumental in facilitating accurate diagnoses of genetic platelet disorders [29].

APDs are caused by platelet-extrinsic factors resulting in platelet dysfunction. Drug-induced platelet dysfunction can be caused by platelet-targeting drugs such as aspirin or P2Y12 inhibitors, or it can be an unwanted side effect such as with selective serotonin reuptake inhibitors (SSRIs) [30] or tyrosine kinase inhibitors (e.g., ibrutinib) [31]. In trauma patients, platelet dysfunction can result from reduced production of pro-hemostatic factors or from “platelet exhaustion” caused by systemic activation [32]. However, the underlying mechanisms are still incompletely defined.

4. Platelet transfusion therapy in thrombocytopenic patients

Platelet transfusion is standard therapy to prevent spontaneous bleeding in severely thrombocytopenic patients, with the goal of simply increasing the number of circulating platelets (Figure 1B). Platelets can be whole blood-derived from single donors and pooled (7 x 1010 per donor; 4-6 pooled donors = 3-4 x 1011 per unit- also called a platelet concentrate), or platelets can be collected from a single donor by apheresis (3-6 x 1011 or more) [33]. Transfusion of one platelet unit (pooled donors or single apheresis donor) is expected to increase the peripheral platelet count by ≥ 30 x 109/L. The circulating lifespan of transfused platelets may be similar to endogenous platelets in healthy subjects (6-8 days) [34], but this is reduced, for example, in leukemia patients [35]. A further reduction in transfused platelet half-life, potentially causing transfusion refractoriness, can occur under conditions of platelet sequestration/destruction such as splenomegaly or anti-platelet antibody production [36]. Platelet count thresholds for transfusion vary between countries and institutions, with some based on strong clinical evidence while others are based on weak or no evidence and are dependent on individual clinician judgement. To prevent spontaneous bleeding, prophylactic platelet transfusion is indicated in patients with platelets counts < 10 x 109/L (normal range 150-400 x 109/L) due to hypoproliferative thrombocytopenia [37]. Reduced from a previous threshold of 20 x 109/L [38], the lower threshold is associated with fewer adverse transfusion reactions and reduced platelet use [39], which could particularly benefit resource-poor countries [40]. Major bleeding is more likely to occur at higher platelet counts during surgical procedures, calling for a target platelet count of > 50 x 109/L [41,42]. Threshold guidelines also exist for some specific procedures, based on varying strength of evidence; for example, central venous catheter placement can be performed safely at platelet counts > 20 x 109/L, while the threshold for lumbar puncture is typically 50 x 109/L. However, the evidence to support these procedure-specific transfusion triggers remains relatively weak [41]. To conserve platelet units, studies have evaluated the safety and efficacy of using platelet transfusion therapeutically (only given to treat active bleeding) rather than prophylactically [43,44], as well as reduced platelet doses in select patient populations [45,46]. While more studies are needed, future guidelines may be adjusted for smaller and less frequent platelet transfusion doses. Lastly, platelet transfusion is typically contraindicated in disorders of platelet consumption, such as immune thrombocytopenia (ITP), thrombotic thrombocytopenia purpura (TTP) or heparin-induced thrombocytopenia (HIT) [47]. However, it may be utilized for severe active bleeding in these conditions at the clinician’s discretion [48].

5. Hemostatic therapy in qualitative IPDs

Bleeding associated with platelet function disorders is often moderate but can be severe or even fatal. Minor bleeding can typically be controlled using local measures such as compression or topical thrombin, or antifibrinolytics such as tranexamic acid (TXA) or ε amino caproic acid. Additionally, desmopressin (1-deamino-8-D-arginine vasopressin; DDAVP) can be administered, although it is used less frequently than TXA, mostly due to adverse side effects [49]. The canonical hemostatic mechanism of DDAVP is to increase VWF levels, thereby enhancing platelet adhesion [50]. More recently, DDAVP has also been shown to increase the function of pro-coagulant platelets in vivo [51]. The most potent coagulation-enhancing treatment for bleeding disorders is recombinant activated FVII (rFVIIa; NovoSeven) [52]. GT patients have impaired thrombin generation [53], and rFVIIa acts to enhance thrombin generation on the platelet surface, driving formation of fibrin to improve platelet plug stability [54,55]. Boosting thrombin activity and fibrin formation can induce αIIbβ3-independent platelet aggregation [56], potentially mediated by GPVI binding to fibrin [57]. rFVIIa has also been successfully used in BDPLT18 patients failing to respond to platelet transfusion [58]. Mechanistically, rFVIIa may have an even greater hemostatic benefit in these patients as RASGRP2 mutant platelets can typically aggregate normally in response to strong thrombin receptor stimulation in vitro [59].

6. Platelet transfusion therapy in qualitative IPDs

Despite the risk of alloimmunization, platelet transfusion remains a common first-line treatment for major bleeding or prophylaxis in patients with qualitative IPDs. In BSS, patients have platelet dysfunction but are also typically thrombocytopenic; thus, platelet transfusion augmented by anti-fibrinolytics effectively prevents bleeding [60–66]. Cases which reported pre- and post-transfusion platelet counts demonstrate the ability of platelet transfusion to increase platelet counts in thrombocytopenic BSS patients [60,62,63,65]. In contrast to BSS, GT and BDPLT18 patients predominantly have platelet counts within the reference range, but due to risk of major hemorrhage platelet transfusions are still often given to these patients, either prophylactically for surgical procedures or to treat ongoing intractable bleeding. However, a number of clinical reports and small studies have suggested a lack of efficacy of platelet transfusion in these two disorders [58,67–72]. Jennings and colleagues first reported a complete lack of response to a single transfused unit in a pediatric GT patient undergoing a dental procedure, who only responded after transfusion of 4 additional units [67]. They speculated that the patient’s endogenous patients were functionally interfering with the transfused platelets, and this was overcome by drastically increasing the number of transfused platelets to improve the transfused to endogenous platelet ratio. This concept was re-visited in a recent study by Al-Battat et al, who evaluated the response to platelet transfusion in GT patients using the PFA-100 assay and found that a high ratio of normal to GT platelets was required to normalize closure times [68].

We recently performed the first in-depth mechanistic study on platelet transfusion therapy in qualitative IPDs. Specifically, we sought to investigate the interaction and potential competition between endogenous (dysfunctional) and transfused (healthy) platelets during hemostatic plug formation. To visualize hemostatic plug formation, we used the murine saphenous vein laser ablation model coupled with time lapse intravital imaging [73]. Compared to platelet-depleted mice, we found that Rasgrp2−/− mice required a much larger number of transfused healthy platelets to normalize hemostasis [74]. We determined that, in our hemostasis model, a ratio of ≤ 2:1 dysfunctional:healthy platelets was required for hemostasis. This is likely due to Rasgrp2−/− platelets acting as “dominant negative” platelets by localizing to the site of injury without participating in platelet-platelet cohesion [75] (Figure 1C). This was clearly observed in plugs containing both WT and Rasgrp2−/− platelets or platelets deficient in integrin activation (similar to GT), which failed to maintain contraction and continuously shed platelets [74]. Consistent with the clinical literature, in a mouse model of BSS, only a small number of transfused platelets effectively normalized hemostasis. We observed that WT platelets rapidly formed a solid hemostatic plug in BSS mice without competition from endogenous platelets. Similarly, platelets lacking the VWF-binding domain of GPIbα are unable to integrate into growing arterial thrombi [76]. Our in vivo studies demonstrated important concepts underlying the efficacy of platelet transfusion for platelet function disorders; first, in qualitative IPDs characterized by impaired platelet activation but not adhesion, the endogenous platelets can interfere with the function of transfused platelets, and second, this competition can be overcome by reaching a key ratio of transfused to endogenous platelets. Our findings and those in patients suggest that the ratio of endogenous to transfused platelets may be key to determining whether platelet transfusion therapy will be successful.

Platelet transfusion to reverse anti-platelet therapy

Anti-platelet therapy (APT) is primarily utilized for secondary prevention of cardiovascular thrombotic events following myocardial infarction (MI) or ischemic stroke. Low-dose aspirin specifically and irreversibly inhibits the prostanoid-generating enzyme COX-1 in platelets. Aspirin is the most commonly used APT, as it is inexpensive, available over-the-counter, and may also be beneficial against some malignancies [77]. It is generally not associated with major bleeding but is also not potently anti-thrombotic, and is not recommended for primary prevention of atherothrombosis [78]. Clopidogrel is a first-generation P2Y12 inhibitor, which was followed by the development of the later generation agents prasugrel and ticagrelor. The thienopyridines clopidogrel and prasugrel are irreversible inhibitors of P2Y12; clopidogrel requires metabolism by the liver enzyme CYP450, causing reduced efficacy in some patients due to altered CYP450 activity [79], while prasugrel is CYP450-independent and thus has more consistent efficacy across patient populations but is also associated with a higher bleeding risk [80]. Ticagrelor is a potent reversible inhibitor of P2Y12 which does not require metabolism, and has the benefit of the development of a reversal agent [81,82]. Dual anti-platelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is typically prescribed for 1-12 months following a primary thrombotic event, most often to prevent secondary stent thrombosis [83].

Patients on single or dual APT are at increased risk for several characteristic types of bleeding-gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), and peri-procedural bleeding, for example during coronary artery bypass grafting (CABG) surgery. Temporary cessation of all APT may be required for the most severe bleeding episodes but may not be preferred in some patients due to the high risk of thromboembolic events. For patients on DAPT undergoing elective procedures, cessation of either the P2Y12 inhibitor or aspirin can reduce the risk of major bleeding while maintaining some level of anti-thrombotic protection [84]. Hemostatic management guidelines for ICH in patients on APT are still controversial. However, several recent studies including the PATCH trial have led to recommendations against the use of platelet transfusion to reverse APT in this setting [85,86]. However, while the PATCH trial observed increased morbidity and mortality in the platelet transfusion group, the mechanistic cause remains unknown. A recent post-hoc analysis suggested an imbalance of the treatment groups, but also speculated that transfusion-associated inflammation may have played a role in the worse outcomes [87]. Mixed results have also been reported for the effectiveness of platelet transfusion therapy for GI bleeding [88]. For elective procedures, temporary cessation of APT may allow for procedures to occur without clinically significant bleeding. However, platelet transfusion is often used prophylactically and/or therapeutically in emergency situations [89]. The hemostatic efficacy of transfused platelets depends on the timing and mechanism of the APT used. Aspirin-induced platelet dysfunction is readily reversed by the addition of healthy platelets, as COX-1 inhibited platelets can still respond to TxA2 released from uninhibited platelets. Of note, the majority of patients (≥ 70%) in the PATCH trial were on aspirin therapy alone [85]. However, clopidogrel or prasugrel exposed platelets are insensitive to ADP and remain dysfunctional in the presence of healthy platelets [90]. Residual circulating inhibitor will also bind and inhibit transfused platelets, so platelet transfusion will generally be ineffective if given too soon after the last dose of APT. Platelet transfusion is also generally contraindicated with ticagrelor which, as a reversible inhibitor, will rapidly bind and inhibit healthy transfused platelets. Indeed, ex vivo platelet mixing studies have demonstrated the inability of healthy platelets to reverse ticagrelor-induced platelet dysfunction [91,92]. Finally, our in vivo studies demonstrated that even in the presence of uninhibited platelets, the center of the hemostatic plug is unstable and prone to re-opening, suggesting an inability of normal platelets to rescue the function of P2Y12-inhibited platelets [74] (Figure 1D). The requirement for P2Y12 signaling to stabilize the middle of the hemostatic plug in vivo was also recently demonstrated in an elegant study showing that longer bleeding times correlated with larger injury sizes in cangrelor-treated mice [12]. In general, there is currently only weak evidence to support the use of platelet transfusion to reverse APT and it is no longer recommended in patients with ICH.

Conclusions

Platelet transfusion therapy has been instrumental in preventing fatal hemorrhage in patients with severe thrombocytopenia. However, the appropriate implementation of platelet transfusion in qualitative IPDs and APDs remains incompletely understood and potentially misguided. Competition between the endogenous dysfunctional and normal transfused platelets may reduce the therapeutic benefit of transfusion. Achieving a desired ratio would require the development of more accurate clinical methods to assess the post-transfusion platelet count. Moreover, it may be difficult to transfuse the required number of healthy platelets to achieve a hemostatic ratio in an adult patient (larger blood volume) with a high platelet count. To circumvent this issue, one potential approach would be to safely lower the patient’s platelet count before transfusion [93,94]. Another approach, mainly for GT and BDPLT18 patients, would be to render the patient’s platelets incapable of interfering in the hemostatic process by inhibiting or cleaving GPIbα. These approaches would require further evaluation in clinical trials. Finally, taking a mechanistic approach to the co-administration of platelets and pro-hemostatic agents could enhance treatment success rate; for example, rFVIIa may enhance the hemostatic function of dysfunctional platelets and thereby reduce the required platelet ratio to prevent bleeding. Mechanism-focused studies will continue to be crucial in guiding the development of new therapeutic strategies to manage bleeding in platelet disorders.

Key points.

  • Platelet transfusion has been used for more than a half-century to treat and prevent bleeding

  • Platelet transfusion has proven efficacy in patients with thrombocytopenia

  • Patients with inherited or acquired qualitative platelet disorders (normal number of dysfunctional platelets) often receive platelet transfusion for bleeding despite the lack of strong evidence demonstrating efficacy

  • Dysfunctional platelets which are able to localize to the site of injury but unable to participate in aggregation can interfere with the function of healthy transfused platelets

  • An improved understanding of mechanisms regulating efficacy of platelet transfusion at the cellular/molecular level will help clinicians better utilize this precious resource

Acknowledgements

Financial support and sponsorship

This work was supported by American Society of Hematology and National Blood Foundation (RHL), and National Institutes of Health (WB)

Abbrevations

IPD

inherited platelet disorder

APD

acquired platelet disorder

GT

Glanzmann’s thrombasthenia

BSS

Bernard Soulier syndrome

BDPLT18

Bleeding disorder platelet type 18

rFVIIa

recombinant activated factor VII

TXA

tranexamic acid

DDAVP

1-deamino-8-D-arginine vasopressin

TxA2

thromboxane A2

ADP

adenosine diphosphate

(D)APT

(dual) anti-platelet therapy

ICH

intracranial hemorrhage

Footnotes

Conflicts of interest

None

References

* of special interest

** of outstanding interest

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