Efficacy of Ex Vivo Autologous and In Vivo Platelet Transfusion in the Reversal of P2Y ₁₂ Inhibition by Clopidogrel, Prasugrel, and Ticagrelor

Abstract

T he addition of P2Y 12 receptor inhibiting drugs to aspirin therapy has resulted in improved clinical outcome secondary to reduced recurrent ischemic events in patients with acute coronary syndromes (ACS) or after percutaneous coronary intervention (PCI).1-3 The ischemic benefit is offset by significant morbidity and mortality associated with major bleeding complications in the both coronary artery bypass graft 4 and the nonoperative setting. 5 Indeed, the clinical benefit of systematic pretreatment with P2Y 12 receptor inhibitors (RI) has been recently challenged because of an increase in major Background-Allogenic platelet transfusions (PT) are administered to treat excessive bleeding in patients on P2Y 12 receptor inhibitors (RI). We assessed the effect of ex vivo and in vivo PT on platelet activation and aggregation in patients on dual antiplatelet therapy. Methods and Results-In the Antagonize P2Y 12 Treatment Inhibitors by Transfusion of Platelets in an Urgent or DelayedTiming After Acute Coronary Syndrome or Percutaneous Coronary Intervention Presentation-Acute Coronary Syndrome (APTITUDE-ACS) study, patients presenting with acute coronary syndrome or for elective percutaneous coronary intervention, receiving loading doses of clopidogrel (600 mg, n=13 or 900 mg, n=12), prasugrel 60 mg (n=10), or ticagrelor 180 mg (n=10) were included. PT was performed ex vivo by mixing platelet-rich plasma from blood sampling performed at baseline in increasing proportions with platelet-rich plasma sampled 4 hours after loading dose. The percentage restoration of residual platelet aggregation achieved with 80% proportion PT (residual platelet aggregation 80% PT mix/ residual platelet aggregation baseline×100) significantly decreased with increasing potency of P2Y 12 RI (83.9±11%, 73±14%, 66.3±15%, 40.9±19% for clopidogrel 600 mg, clopidogrel 900 mg, prasugrel, and ticagrelor, respectively; P for trend <0.0001). In the APTITUDE-Coronary Artery Bypass Graft (APTITUDE-CABG) study, vasodilator-stimulated phosphoprotein-platelet reactivity index, a specific marker of the P2Y 12 RI drug-effect, was assessed before and after in vivo PT administered for excessive bleeding in patients undergoing cardiac surgery while on a maintenance dose of aspirin and clopidogrel (n=45), prasugrel (n=6), or ticagrelor (n=3). When compared with baseline, there was a significant relative increase of 23.1% in platelet activation after PT transfusion (42.2±23.6% versus 56.6±18.2%; P=0.0008). Conclusions-PT restores platelet reactivity in patients with acute coronary syndrome/percutaneous coronary intervention and in patients undergoing cardiac surgery on P2Y 12 RI while bleeding with a less effect with increasing potency of P2Y 12 inhibition. Clinical Trial Registration

Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor‐treated patients

“…This is in line with results from previous studies, which showed no effect or only a minor effect of platelet transfusion on ADP‐induced aggregation8, 9, 10 and an improvement in AA‐induced aggregation8 in patients treated with ASA and ticagrelor. Platelet transfusions may therefore still be of clinical importance in patients with ongoing DAPT, as they markedly increase AA‐induced aggregation and can therefore treat the platelet inhibition induced by ASA.…”

“…In patients on ticagrelor, platelet transfusion has little or no effect,8, 9, 10 and there is no currently available antidote to ticagrelor. New alternatives are therefore needed to reduce the risk of excessive bleeding in ticagrelor‐treated patients who have ongoing bleeding or who are in need of emergent surgery.…”

2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS

“…If bleeding occurs during surgery, platelet transfusion has been shown to effectively counteract ASA effects. [166][167][168] This finding further supports the possibility of continuing ASA throughout the perisurgical period as ASA allows direct antiplatelet effect reversal if clinically indicated. The increased risk of bleeding complications if ASA and other antithrombotic drugs are not discontinued should be weighed against the potentially increased risk of thrombotic complications during the pre-operative cessation period.…”

Restoring Platelet Function in Patients on P2Y 12 Receptor Inhibitor Treatment

“…5 However, in interpreting the data, some issues and important aspects merit mentioning: First, in APTITUDE, various platelet function profiles were used as surrogate end points to assess the pharmacological characteristics of the currently available oral P2Y 12 receptor inhibitors in a setting of platelet transfusion for platelet function restoration. Although platelet function markers for this study were wisely chosen, the interplay of blood platelets, various signaling cascades, and the entire coagulation system to achieve hemostasis is complex and can hardly be explored entirely by ex vivo testing.…”

“…As long as this is not the case, we have to take the data coming from (in vitro) studies such as APTITUDE 5 and others [6][7][8][9][10] as the best available evidence for guidance of patient treatment. Second, the comparatively low sample size for prasugrel-treated patients (n=6) and ticagrelor-treated patients (n=3) in the APTITUDE-CABG cohort precludes from drawing definite conclusions on the feasibility of immediate and sustained platelet restoration after platelet transfusion with these 2 agents.…”