Role of Platelet Transfusion in the Reversal of Anti-Platelet Therapy

Transfusion Medicine Reviews 33 (2019) 92–97

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Transfusion Medicine Reviews journal homepage: https://www.journals.elsevier.com/transfusion-medicine-reviews/

Role of Platelet Transfusion in the Reversal of Anti-Platelet Therapy Srikanth Nagalla a, Ravi Sarode a,b,⁎ a b

Division of Hematology/Oncology, UT Southwestern Medical Center, Dallas, TX Division of Transfusion Medicine and Hemostasis, UT Southwestern Medical Center, Dallas, TX

a r t i c l e

i n f o

Available online 25 January 2019 Keywords: Antiplatelet therapy Aspirin P2Y12 inhibitors Platelet transfusion

a b s t r a c t Antiplatelet therapy is extensively used in the primary and secondary prophylaxis of arterial thrombotic disorders. Aspirin, the most commonly used antiplatelet agent, is a cyclooxygenase−1 inhibitor and considered a mild to moderate inhibitor of platelet function. Therefore, often a second antiplatelet agent is necessary in certain clinical conditions requiring greater inhibition of platelet function. An adenosine diphosphate (ADP) receptor, P2Y12, is an important target for this purpose; several agents inhibit this receptor providing potent antiplatelet effect. One of the side effects of these agents is bleeding, which in some patients may require reversal of antiplatelet effect. Similarly, patients undergoing emergent surgeries may benefit from reversal of antiplatelet effect to avoid excessive surgical bleeding. This article reviews current literature on this topic. © 2019 Elsevier Inc. All rights reserved.

Contents Platelet physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology of APAs (Tables 1 and 2) . . . . . . . . . . . . . . . . . . . . . . . . Cyclooxygenase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADP receptor inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GP IIb/IIIa receptor blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . Phosphodiesterase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . In vitro assessment of platelet function . . . . . . . . . . . . . . . . . . . . . . Light transmission platelet aggregometry (LTA) and impedance platelet aggregometry . Platelet function analyzer (PFA)-100. . . . . . . . . . . . . . . . . . . . . . . . VerifyNow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Platelet-mapping assay. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Platelet transfusions to reverse the effect of antiplatelet therapy . . . . . . . . . . . . . Studies with clinical endpoints with a focus on aspirin (Table 3) . . . . . . . . . . . Studies with non-clinical endpoints with a focus on P2Y12 inhibitors and DAPT . . . . Studies involving coronary artery disease patients . . . . . . . . . . . . . . . . . Studies involving healthy subjects . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Platelets play an important role in the pathogenesis of thrombosis in the coronary, cerebral and peripheral arterial circulation. Antiplatelet agents (APAs) are the mainstay of therapy in the primary and secondary ⁎ Corresponding author at: Ravi Sarode, MD, Professor of Pathology, Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390. E-mail address: [email protected] (R. Sarode). https://doi.org/10.1016/j.tmrv.2019.01.002 0887-7963/© 2019 Elsevier Inc. All rights reserved.

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prevention of arterial thrombotic disorders [1]. Bleeding on antiplatelet therapy, though less common than on anticoagulants, is still a significant side effect in some patients. Numerous other prescription medications, as well as over the counter medicines, dietary supplements and herbal medications, also impair platelet function. The bleeding incidence on antiplatelet therapy is dependent upon factors that are both intrinsic as well as extrinsic to the patient. Concomitant problems

S. Nagalla, R. Sarode / Transfusion Medicine Reviews 33 (2019) 92–97

with primary or secondary hemostasis, other comorbidities such as liver and kidney dysfunction, or connective-tissue disorders are examples of intrinsic patient factors that could affect the bleeding phenotype on antiplatelet therapy. Physical Injuries, surgical procedures, class of APA and combination with another APA, anticoagulants, or other drugs and dietary supplements are some of the extrinsic factors that affect the bleeding phenotype. A clinician takes into account the following factors in the management of a patient bleeding on antithrombotic therapy: (1) severity and location of the bleed, including hemodynamic instability, (2) timing of the last dose and the half-life of the agent, (3) availability of appropriate reversal agent and (4) need for blood transfusions. Unlike anticoagulants, there are no specific reversal agents for APAs and often platelet transfusions are considered in bleeding patients to achieve hemostasis. Apart from bleeding, the effect of antiplatelet therapy might need to be reversed in patients undergoing urgent invasive procedures or surgeries that may necessitate platelet transfusions. This review will address these issues.

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platelets and other tissues, COX-2 is expressed at low levels in newly formed platelets [5]. Aspirin is the only commonly used APA in this class. Though aspirin irreversibly acetylates COX-1 and COX-2, it is 170 times more potent against COX-1 as compared to COX-2 [6]. Aspirin inhibits TxA2 mediated platelet activation and aggregation. Since platelets are anucleated and hence cannot regenerate COX-1, the antiplatelet effect of aspirin lasts for the life of the platelet. Though the antiplatelet effect of aspirin can be observed at a daily dose of 30 mg, a very high dose of aspirin in the magnitude of 1 gram or more per day could inhibit endothelial prostacyclin production via COX-1 pathway, counteracting the benefits derived from COX-1 inhibition of platelets [7]. The antiplatelet effect of aspirin can be seen within 15 to 30 minutes after ingestion with maximal platelet function inhibition occurring at 60 minutes. The effect of the drug ceases once metabolized by the liver. Based on a platelet life span of 10 days, a patient with a platelet count of 200 × 109/L should be able to produce 60 × 109/L normally functioning platelets in 3 days, which is adequate to achieve good hemostasis in most situations.

Platelet physiology ADP receptor inhibitors An average adult makes about 1011 platelets per day with a platelet life span of 8–10 days. Platelets play a crucial role in primary hemostasis, which starts with shape change and platelet adhesion. Endothelial injury exposes sub-endothelial extracellular matrix components such as collagen, von Willebrand factor (VWF) and fibronectin. Under increased shear stress of the arterial circulation, VWF undergoes conformational change from a globular form to a linear form exposing the A1 domain that binds to platelet glycoprotein (GP) Ib/IX/V receptor. The conformational change of VWF is initiated by the binding of VWF to the sub-endothelial collagen. The platelets undergo irreversible shape change and secrete their granular contents [2]. ADP is released from the dense granules whereas thromboxane A2 (TxA2) and other prostaglandins are synthesized by the enzyme cyclooxygenase-1 (COX1) from arachidonic acid. ADP activates resting platelets by binding to the P2Y1 (shape change) and P2Y12 (aggregation) receptors [3]. Similarly, TxA2 activates neighboring platelets by binding to the thromboxane receptor. Platelet activation exposes the negatively charged phospholipids due to a flip-flop phenomenon on the platelet surface, which aid in secondary hemostasis. Inside out signaling results in the conversion of low affinity fibrinogen receptor GP IIb/IIIa into a high affinity state with an ability to bind to fibrinogen and VWF [4]. Thrombin generated from the secondary hemostasis pathway activates protease activated receptor (PAR) on platelets, further enhancing platelet aggregation. The currently used APA target COX1, ADP receptor P2Y12, GP IIb/IIIa receptor and PAR-1. Pharmacology of APAs (Tables 1 and 2) Cyclooxygenase inhibitors COX converts arachidonic acid to prostaglandin H2, which in turn is converted to TxA2 by thromboxane synthase. There are 2 isoforms of COX: COX-1 and COX-2. While COX-1 is constitutively expressed in

P2Y1, P2Y12 and P2X1 are the platelet P2 purinergic receptors. ADP is the agonist for 2 G protein coupled receptors: Gq-coupled P2Y1 receptor and Gi-coupled P2Y12 receptor with ATP acting as the agonist for the P2X1 ligand-gated channel [8]. The antiplatelet effect of P2Y12 receptor inhibitors is due to the blockage of ADP-induced amplification of platelet activation. The thienopyridines (clopidogrel, prasugrel, and ticlopidine) and the nucleoside–nucleotide derivatives (ticagrelor and cangrelor) are the 2 classes of P2Y12 inhibitors currently used in clinical practice. Clopidogrel and other thienopyridines are prodrugs metabolized by the hepatic cytochrome P450-dependent pathway, resulting in an active metabolite that irreversibly modifies the P2Y12 receptor by forming a disulfide bridge between one or more cysteine residues of the receptor [9]. Altered clopidogrel metabolism due to interaction with other drugs metabolized by the cytochrome P450 enzymes, and functional polymorphisms in the CYP2C9 and CYP2C19 enzymes, could result in inter-individual variability in the antiplatelet effect of clopidogrel. Though the loading dose of clopidogrel (300-600 mg) exerts an antiplatelet effect in 2 to 4 hours, the antiplatelet effect with 75 mg dose of clopidogrel might take up to 24 hours with steady state of inhibition attained in 3 to 7 days. The half-life of clopidogrel active metabolite is 0.5 hours with the normalization of platelet function occurring at 5–7 days after clopidogrel withdrawal [10]. Ticlopidine is rarely used due to its association with acquired thrombotic thrombocytopenic purpura. Prasugrel (a third generation thienopyridine) is metabolized by different CYP enzymes compared to clopidogrel and has less inter-individual variability with a more predictable antiplatelet inhibition and greater bioavailability [11]. The half-life of prasugrel active metabolite is 3.7 hours with a 7day time to normalization of platelet inhibition [10]. Ticagrelor and cangrelor, unlike thienopyridines, do not require activation in the liver and directly inhibit the P2Y12 receptor. Ticagrelor is an oral reversible P2Y12 inhibitor that is metabolized by the CYP

Table 1 Antiplatelet agents Drug Class

Drugs

Loading dose

Time to antiplatelet effect

Cyclooxygenase inhibitors ADP P2Y12 receptor inhibitors Thienopyridines

Aspirin

81–325 mg oral

b60 mins

Clopidogrel Prasugrel Ticagrelor Abciximab Eptifibatide Dipyridamole Cilostazole

300–600 mg oral 60 mg oral 180 mg oral 0.25 mg/kg IV 180 mcg/kg IV 75–100 mg oral 100 mg oral

b2 hours b30 mins b30 mins b10 mins b5 mins b60 mins b6 hours

Nucleoside–nucleotide derivatives Glycoprotein IIb/IIIa receptor blockers Phosphodiesterase inhibitors

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Table 2 Half-lives and time to normalization of IPA for oral APA Clopidogrel AM

Prasugrel AM

Ticagrelor

Ticagrelor AM

ASA

Abciximab/ Eptifibatide

Dipyridamole/ Cilostazol

T1/2 (hours)

0.5

3.7

6.7–9.1

8.5–12.4

0.5–3

0.5/2.5

Time to normalize IPA (Days)

7

7

5

5

3

2/0.4

10–12/ 11–13 3

T1/2-half-life; IPA-inhibition of platelet aggregation; AM-active metabolite.

enzymes with both the drug and the active metabolite exerting antiplatelet effect. The maximum half-life of the drug and the active metabolite is 9.1 and 12.4 hours respectively [10]. Since ticagrelor causes reversible inhibition of P2Y12, the time to normalization of platelet inhibition is shorter than the thienopyridines at 5 days. Cangrelor is an intravenous reversible P2Y12 inhibitor with a rapid onset of action and a short half-life of 3 to 6 min [12]. GP IIb/IIIa receptor blockers GP IIb/IIIa antagonists block the binding of fibrinogen or VWF to the GP IIb/IIIa receptor. Abciximab, a chimeric monoclonal antibody, was the first drug developed in this class for clinical use. Subsequently, small synthetic molecules blocking GP IIb/IIIa receptors, such as eptifibatide and tirofiban, were developed. Eptifibatide is a cyclic heptapeptide antagonist, whereas tirofiban is a non-peptide tyrosine derivative [13]. Abciximab, eptifibatide and tirofiban are intravenous drugs. Parenteral GP IIb/IIIa antagonists are used in patients undergoing various endovascular procedures where immediate, short-term and intense inhibition of platelet function is a requisite. The platelet function returns to normal in 24 to 48 hours after the discontinuation of abciximab and about 4 hours after the last dose of eptifibatide or tirofiban. Severe thrombocytopenia and paradoxical platelet activation could be side effects of this class of drugs [14]. Phosphodiesterase inhibitors Dipyridamole and cilostazol inhibit the enzyme phosphodiesterase, which in turn elevates the platelet cyclic adenosine monophosphate content, thereby inhibiting ADP-induced platelet aggregation. Dipyridamole is approved for use in stroke prevention and cilostazol for peripheral arterial disease [15,16]. In vitro assessment of platelet function Platelet function testing (PFT) performed in real time could be useful when patients on antiplatelet therapy need to undergo urgent procedures, or in a patient with major bleeding, to assess the degree of platelet inhibition [17]. Though the gold standard for platelet function assessment is either light transmission aggregometry performed on platelet rich plasma or whole blood impedance aggregometry, the time taken to perform these tests is a deterrent for use in a bleeding patient. In the setting of antiplatelet therapy, the currently available platelet function testing is used to tailor the treatment to decrease the rate of recurrent thrombotic events despite the lack of strong data to support this approach. We will discuss some of the PFTs that use whole blood to assess residual platelet inhibition from antiplatelet therapy in a bleeding patient or a patient needing urgent surgery. Light transmission platelet aggregometry (LTA) and impedance platelet aggregometry As mentioned above, these tests are not useful in situations requiring urgent decisions. LTA is performed on platelet rich plasma (PRP) and a photometer measures the change in light transmission when platelets aggregate in response to various agonists [17]. The commonly used agonists are arachidonic acid, epinephrine, ADP, collagen, thrombin

receptor activating peptide (TRAP), ristocetin and thromboxane A2 mimetic U46619. The lag phase, slope of the curve and maximal aggregation percentage are measured [17]. Unlike LTA, impedance whole blood aggregometry (WBA) is performed using anticoagulated whole blood which simplifies the testing process since there is no requirement to prepare PRP. The increase in electrical impedance, as platelets aggregate on to the surface of electrodes in response to various agonists, is measured instead of light transmission in LTA. Whole blood platelet aggregation takes into account other components of blood making it more physiological than LTA [17]. The quantity of whole blood required in WBA is less compared to the PRP volume required to perform LTA. Platelet function analyzer (PFA)-100 The PFA-100 uses cartridge membranes with an aperture that are coated with collagen/epinephrine or collagen/ADP [18]. The test is performed at high shear rate using whole blood and the time taken for the formation of a VWF-platelet plug is read as a closure time. A prolonged collagen/epinephrine cartridge closure time is observed with aspirin use. However, the collagen/ADP cartridge closure time is not prolonged with P2Y12 ADP receptor inhibitors because of a presence of a high concentration of ADP in the cartridge [19]. In patients on aspirin presenting with major bleeding or undergoing urgent procedures, a normal PFA100 collagen/epinephrine closure time would rule out any significant anti-platelet effect from aspirin. PFA-100 test is limited in its ability to detect platelet secretion defects and the results are affected by low platelet count and hematocrit [17]. VerifyNow The VerifyNow system (Instrumentation Laboratory, Bedford, MA) uses fibrinogen-coated beads along with a platelet agonists AA, ADP and TRAP to evaluate aggregation of platelets in whole blood with change in light transmittance as the read-out [18]. The system was developed to evaluate high on-treatment platelet reactivity on aspirin or P2Y12 inhibitors. AA is used in the aspirin assay and ADP is used in the P2Y12 assay. TRAP is used in the GPIIb/IIIa assay and also in the P2Y12 assay as a separate channel to measure the expected aggregation response if the patient was not on a P2Y12 inhibitor, so that the percentage of inhibition of the ADP response could be estimated. The VerifyNow system is used to tailor antiplatelet therapy for better ischemic outcomes. The use of the system in a bleeding patient or patient undergoing an urgent procedure might be of some help with the timing of the procedure or the need to transfuse platelets. Since the PFA-100 could easily be used to evaluate the antiplatelet effect of aspirin, the P2Y12 assay could be used for measuring the effect of P2Y12 inhibitors in the urgent scenarios mentioned above. A P2Y12 reaction unit (PRU) ≥ 240 would be suggestive of a lack of significant P2Y12 inhibition [20]. Platelet-mapping assay Thrombelastography Platelet Mapping assay (TEG-PM) (Haemoscope Corporation, Niles, IL) is another point of care assay used to monitor platelet function [21]. TEG-PM, which uses citrated whole blood, could be used to detect the antiplatelet effect of aspirin and ADP receptor antagonists. This is more time intensive than the above-mentioned point of care testing methods and is seldom used

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for clinical decision-making regarding platelet transfusions in emergent situations. Platelet transfusions to reverse the effect of antiplatelet therapy There is a very limited in vivo data for the efficacy of platelet transfusion in patients on antiplatelet therapy with clinical outcomes as the endpoint. Most of these studies, as summarized in the following sections, are on healthy volunteers undergoing autologous platelet transfusions with ex vivo platelet function testing as an endpoint, while some studies focused on patients with arterial thrombotic disorders or healthy subjects on antiplatelet therapy where donor platelets were added to their blood ex vivo to study the reversal of platelet inhibition. In addition, there are some studies where the blood from healthy subjects was spiked with an APA ex vivo and donor platelets were added to the sample to evaluate if the platelet reactivity was restored. It is difficult to get clinically meaningful data from most of the above-mentioned studies since there was so much heterogeneity in the dose and timing of the antiplatelet agents used, study population, dose of platelets transfused or added to the ex vivo blood sample, the type of platelet function assay used and time points after platelet transfusion at which the effects on platelet reactivity were assessed. Though aspirin alone is used in a vast majority of patients with arterial thrombotic disorders for primary and secondary prophylaxis, dual antiplatelet therapy (DAPT) has become the standard of care for acute coronary events. Clopidogrel, prasugrel or ticagrelor are added to aspirin as a part of the DAPT. The current guidelines from American College of Cardiology Foundation/American Heart Association recommend discontinuation of the P2Y12 receptor antagonists a minimum of 24 hours prior to an urgent coronary artery bypass graft (CABG) surgery or 5 days prior to an elective CABG [22]. Since this approach could put the patients at high risk of recurrent thrombotic events and there are no reversal agents currently available for P2Y12 receptor antagonists, studies focusing on restoration of platelet reactivity with platelet transfusions are important in the peri-operative scenario apart from the situations where patients are experiencing a life-threatening bleed. In a systematic review and meta-analysis that included more than 30 000 patients undergoing non-cardiac surgeries (general, thoracic, abdominal, major urologic, orthopedic and vascular) while on APAs (aspirin,

clopidogrel or DAPT), though the risk of transfusion was increased, there was no increase in the requirement for a repeat procedure for bleeding [23]. The stronger the platelet inhibition by the APA regimen (DAPT N clopidogrel N aspirin), higher the risk for a transfusion. Studies with clinical endpoints with a focus on aspirin (Table 3) The Platelet transfusion in Cerebral Hemorrhage (PATCH) trial was the only phase 3 randomized controlled trial to study the efficacy of platelet transfusion in patients with bleeding on anti-platelet therapy using clinical outcomes as an endpoint [24]. This multicenter, openlabel study enrolled 190 adult patients with non-traumatic supratentorial intracranial hemorrhage (ICH) who presented within 6 hours of symptom onset. APAs for a minimum of 7 days prior to presentation and a Glasgow coma scale ≥8 were among the inclusion criteria. The primary outcomes were death or change in the level of dependence based on the modified Rankin Scale at 3 months. About 71% of the patients in the platelet transfusion group were on a COX inhibitor alone and another 19% of the patients in the group were on a COX inhibitor and dipyridamole combination. Only 7% of the patients in the platelet transfusion group were on P2Y12 receptor antagonists alone or a DAPT in combination with aspirin. The patients in the platelet transfusion group had worse outcomes compared to the group that did not receive platelet transfusions. Though there was no significant increase in ICH with platelet transfusion, there was a trend towards that effect and thromboembolic phenomenon. Because ASA is a mild APA, and there was no laboratory assessment of ASA effect performed, we would not know how many patients really had ASA effect after discontinuing ASA for a few days. Since the PATCH trial only included 9 patients receiving a P2Y12 inhibitor, it is not clear if the outcomes with platelet transfusion seen with aspirin will be applicable to patients with a spontaneous ICH on P2Y12 inhibitors. The PATCH trial did not include patients who needed a neurosurgical intervention, so the question of transfusing platelets in this situation to reverse the platelet inhibition by APAs still remains. In a single center retrospective cohort study of patients with gastrointestinal bleeding (GIB) on APAs (aspirin, clopidogrel and DAPT), platelet transfusions did not decrease the rebleeding rate and were associated with a higher mortality, though there is always a risk for

Table 3 Studies with clinical endpoints where platelet transfusions were used to reverse the effect of APAs Year of Reference Publication

Study type

Summary

Results

2016

Baharoglu et al [24]

Multicenter Phase 3 RCT

The patients in the platelet transfusion group had worse primary outcomes of death and dependence based on the modified Rankin Scale at 3 months compared to the group that did not receive platelet transfusions.

2017

Zakko et al Single center [25] retrospective cohort study Li et al Single center, [27] randomized, double-blind, randomized controlled trial

The study population involved 190 adult patients with non-traumatic supratentorial intracranial hemorrhage (ICH) who presented within 6 hours of symptom onset, on APAs (71% ASA, 19% ASA plus dipyridamole, 7% P2Y12 receptor antagonists alone or a DAPT in combination with aspirin) for a minimum of 7 days prior to presentation and a Glasgow coma scale ≥8. 204 patients with gastrointestinal bleeding (GIB) on APAs (aspirin, clopidogrel and DAPT) were compared to 204 matched controls The efficacy of platelet transfusions was studied in 780 patients on ASA who presented with acute hypertensive basal ganglia hemorrhage and underwent an emergent craniotomy for hematoma removal. The patients were divided into five groups with one of the groups not receiving aspirin at the time of enrollment (no platelet transfusions in this group). Among the patients receiving aspirin, the patients were defined as aspirin sensitive, resistant or semi-responsive using light transmittance aggregometry immediately upon admission to the hospital. The aspirin resistant/semi-responsive group did not receive platelet transfusions. The aspirin sensitive group was divided into a no transfusion group, one dose of platelets transfused group and 2 doses of platelets transfused group.

2012

95

RCT- randomized controlled trial; APAs-Anti-platelet agents; ASA-aspirin; DAPT-dual anti-platelet therapy;

Platelet transfusions did not decrease the rebleeding rate and was associated with a higher mortality. The primary outcome of postoperative hemorrhage and secondary outcome of mortality rate in the platelet transfusion groups were similar to the group of patients not on aspirin and better than the group of patients who were aspirin sensitive and did not receive platelets, suggesting some benefit from transfusion.

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bias with a retrospective study [25]. There are very few studies on the current topic with clinical endpoints as the primary outcomes. Based on the data so far, there is no evidence for the use of platelet transfusions to reverse the platelet inhibition due to APAs after a spontaneous ICH or GIB. Patients on aspirin presenting with spontaneous ICH actually did worse with platelet transfusion. The question of platelet transfusion to reverse the APA induced platelet inhibition in a patient undergoing an emergent/urgent surgery is something clinicians deal with on a daily basis. The maximal platelet inhibitory effect of aspirin is reached within 60 minutes after ingestion and there are no active metabolites; the ex vivo platelet reactivity in a subject on aspirin is readily restored with 1 or 2 U of apheresis platelets [26]. Li et al studied the question of efficacy of platelet transfusions in patients on ASA who presented with acute hypertensive basal ganglia hemorrhage and underwent an emergent craniotomy for hematoma removal [27]. This was a single-center, randomized, double-blind, randomized controlled trial with 780 patients meeting the inclusion criteria. The patients were divided into five groups with one of the groups not receiving aspirin at the time of enrollment (no platelet transfusions in this group). Among the patients receiving aspirin, the patients were defined as aspirin sensitive, resistant or semi-responsive using light transmittance aggregometry immediately upon admission to the hospital. The aspirin resistant/semi-responsive group did not receive platelet transfusions. The aspirin sensitive group was divided into a no transfusion group, one dose of platelets transfused group and 2 doses of platelets transfused group. The primary outcome of postoperative hemorrhage and secondary outcome of mortality rate in the platelet transfusion groups were similar to the group of patients not on aspirin and better than the group of patients who were aspirin sensitive and did not receive platelets, suggesting benefit from transfusion. The study with a clinical endpoint as the primary and secondary outcome provides guidance on platelet transfusion in neurosurgical patients on aspirin requiring an emergent procedure. The study also highlights the benefit of using an assay for assessing platelet function in tailoring the need for platelet transfusion. Point of care testing with a quick turnaround time could save on unnecessary platelet transfusions even in patients undergoing urgent/emergent procedures. Studies with non-clinical endpoints with a focus on P2Y12 inhibitors and DAPT Studies involving coronary artery disease patients As mentioned previously, ticagrelor is an oral reversible P2Y12 inhibitor that directly inhibits the receptor without the need for activation. Ticagrelor and aspirin DAPT was better than clopidogrel/aspirin in terms of the primary composite endpoint of MI, stroke and death from vascular causes without a significant increase in major bleeding in a Phase 3 trial [28]. In an open label prospective cohort study of 20 stable coronary artery disease patients, Zafar et al studied the effect of adding platelets at increasing dosage in vitro to the blood from the patients receiving DAPT with aspirin and ticagrelor [29]. The blood was drawn at 4, 6, 24 and 48 hours after the loading dose (LD) of ticagrelor 180 mg and aspirin 325 mg. The patients were then continued on the maintenance therapy (MT) of ticagrelor 90 mg twice daily and aspirin 81 mg daily for 5 to 7 days followed by serial blood collection at time points similar to LD. Donor platelets were mixed in vitro to blood samples obtained at various time points on LD and MT DAPT regimens at 25%, 50% and 75% of the platelet counts in the blood samples (if the sample platelet count was 200 × 109/L, then donor platelets were added to get a final mix platelet count of 250 × 10 9/L when using 25% donor platelets). Whole blood ADP-induced platelet aggregation was assessed by Multiplate and VerifyNow assays to determine the degree of reversal of inhibition of platelet aggregation (IPA). There was no significant reversal of platelet inhibition both in the LD and MT patient blood samples in the first 24 hours, irrespective of the dose of donor platelets mixed. The IPA was similar between the LD and MT samples at 48 hours, and

furthermore, the IPA improved by 60% of baseline at 48 hours without any intervention. The reversal of IPA was b36% at 4 and 6 hours, even with the highest platelet concentrate supplementation of 75% in both the LD and MT samples. Thus, for all practical clinical scenarios, platelet transfusions seem ineffective to reverse ticagrelor-induced IPA in the first 24 hours after the discontinuation of the drug. By 24 hours, 25% platelet supplementation (equivalent to 1 platelet apheresis unit transfusion in a patient with 200 × 109/L platelet count) caused more than 50% reversal of IPA by multiplate assay in both the LD and MT samples. The short half-lives of ticagrelor and the active metabolite (Table 2) would provide the reason for the above observations, along with the reversible nature of the drug so that it could be redistributed to the freshly added platelets. At 48 hours, given the fact that new platelets are synthesized and the anti-platelet effect of the drug is fading, there was spontaneous recovery in IPA. Based on the in vitro data from this study, 2 to 3 U of apheresis platelet transfusion might help with the complete recovery of IPA in vivo. O'Connor et al evaluated the effects of platelet transfusion on the reversal of IPA by aspirin and various P2Y12 receptor antagonists in both the ex vivo and in vivo settings using a variety of platelet function assays [30]. The APTITUDE-ACS study evaluated the ex-vivo restoration of platelet reactivity upon mixing platelet rich plasma obtained from the patients 4 hours after the loading dose of APA with autologous platelets collected pre-APA. The restoration of platelet reactivity was inversely proportional to the potency of the APA (platelet reactivity: clopidogrel N prasugrel N ticagrelor). APTITUDE-CABG study patients received donor platelets for bleeding during CABG while on DAPT with aspirin and one of the P2Y12 receptor antagonists (clopidogrel n = 45, prasugrel n = 6, ticagrelor n = 3). Overall, taking into account all the DAPT regimens, there was a significant improvement in platelet reactivity with platelet transfusion in clopidogrel group, but there was no significant improvement in platelet reactivity in the small subgroup of prasugrel and ticagrelor (n = 9) patients. Studies using in vitro or ex vivo effect should be interpreted cautiously. Studies involving healthy subjects In an open-label, single center, randomized, cross-over trial by Teng et al, the efficacy of 1 unit of autologous platelet transfusion on improvement of IPA (ADP-induced platelet aggregation by LTA) and PRU (VerifyNow) in healthy subjects who were administered one loading dose of Ticagrelor 180 mg was studied. The ticagrelor was administered 24 or 48 hours prior to the platelet transfusion [31]. The platelet apheresis was performed 72 hours prior to the transfusion and the subjects were also on aspirin 81 mg after apheresis until 24 hours prior to platelet transfusion. Blood samples were collected starting day 2 before the ticagrelor dosing and was continued at various time points until 96 hours after the drug administration in both the ticagrelor 24 hour and 48 hour groups. There was no significant difference in the IPA and PRU after the platelet transfusion compared to no platelet transfusion in the ticagrelor group that received the drug 24 hours prior to the transfusion. There was a difference in the IPA and PRU between the platelet transfusion and no platelet transfusion groups when the loading dose of ticagrelor was administered 48 hours earlier. The lack of difference in the IPA and PRU at the later time points is due to the loss of anti-platelet effect due to the half-life of the drug and generation of new platelets resulting in spontaneous recovery of platelet function. The same study also evaluated the reversal of clopidogrel-induced platelet inhibition by 1 unit of autologous platelet transfusion 48 hours after one loading dose of clopidogrel 600 mg. Though there was no immediate difference in the improvement of IPA in subjects receiving platelet transfusions versus no platelet transfusions at 12 hours, the 24- to 48-hour time points showed small but statistically significant improvement in IPA with platelet transfusions. There was a similar improvement in PRU with platelet transfusions from the 12- to 48-hour time points.

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The finding of non-reversal of IPA with platelet transfusions in patients on ticagrelor and aspirin was also demonstrated in multiple case studies [32-34]. Godier et al demonstrated the inefficacy of platelet transfusions, in reversing the anti-platelet effect of ticagrelor, in a patient who developed an intracranial hemorrhage after undergoing thrombolysis for a non-hemorrhagic stroke. The platelet transfusions did not help to control the hemorrhage or in the reversibility of ticagrelor-induced IPA with 2 different P2Y12 assays [33]. Unlike ticagrelor, the above-mentioned studies suggest that the IPA by clopidogrel could be reversed to some extent by platelet transfusion, although it is difficult to ascertain the benefits of platelet transfusion in an acute bleeding situation while on clopidogrel. Another study done in 6 healthy subjects evaluated the efficacy of platelet transfusion on reversing the IPA by aspirin and clopidogrel [35]. The study subjects received a loading dose of aspirin 300 mg and clopidogrel 300 mg on day 1, followed by aspirin 100 mg and clopidogrel 75 mg for 2 consecutive days. The subjects underwent platelet apheresis prior to receiving the loading dose of the APAs. The autologous platelets (2 U) were transfused on day 4. Platelet reactivity was measured using LTA and vasodilator-stimulated phosphoprotein phosphorylation (VASP phosphorylation). Though platelet reactivity index measured by VASP phosphorylation improved significantly 2 hours after the platelet transfusion, AA and ADP-induced platelet aggregation by LTA did not increase until 24 hours later. The improvement in the IPA seen at 24 hours in the above study and Teng et al study could be attributed to the generation of new platelets and the loss of anti-platelet effect of clopidogrel based on the half-life of the drug and active metabolite. In conclusion, the data on efficacy of platelet transfusion in clinical practice based on either a few clinical trials or in vitro/ex vivo studies seem insufficient to make practice decisions to transfuse platelets to reverse anti-platelet effect in a given patient. Further studies are required to address this important topic. Newer agents in development might be able to reverse the effect of some of the APAs in the near future [36]. Conflict of interest None of the authors declare any relevant conflict of interest. References [1] Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e89S-119S. [2] Ghoshal K, Bhattacharyya M. Overview of platelet physiology: its hemostatic and nonhemostatic role in disease pathogenesis. ScientificWorldJournal 2014;2014: 781857. [3] Thon JN, Italiano JE. Platelets: production, morphology and ultrastructure. Handb Exp Pharmacol 2012:3–22. [4] Shattil SJ, Newman PJ. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood 2004;104:1606–15. [5] Weber AA, Zimmermann KC, Meyer-Kirchrath J, Schror K. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999; 353:900. [6] Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998;38:97–120. [7] Borgdorff P, Handoko ML, Wong YY, Tangelder GJ. COX-2 inhibition by use of Rofecoxib or high dose aspirin enhances ADP-induced platelet aggregation in fresh blood. Open Cardiovasc Med J 2010;4:198–205. [8] Kahner BN, Shankar H, Murugappan S, Prasad GL, Kunapuli SP. Nucleotide receptor signaling in platelets. J Thromb Haemost 2006;4:2317–26. [9] Nguyen T, Frishman WH, Nawarskas J, Lerner RG. Variability of response to clopidogrel: possible mechanisms and clinical implications. Cardiol Rev 2006;14: 136–42. [10] Floyd CN, Passacquale G, Ferro A. Comparative pharmacokinetics and pharmacodynamics of platelet adenosine diphosphate receptor antagonists and their clinical implications. Clin Pharmacokinet 2012;51:429–42. [11] Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet

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