Antiplatelet therapy: thrombin receptor antagonists

Abstract

Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. Multiple pathways contribute to platelet activation. Aspirin, an irreversible inhibitor of thromboxane A2 synthesis, in combination with clopidogrel, an inhibitor of P2Y12 adenosine diphosphate platelet receptors, represent the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations. Thrombin is one of the most important platelet activators. The inhibition of protease-activated receptor 1 showed a good safety profile in preclinical studies. In fact, phase II studies with vorapaxar (SCH530348) and atopaxar (E5555) showed no increase of bleeding events in addition to the current standard-of-care of antiplatelet therapy. Although the results of phase III trials for both drugs are awaited, this family is a promising new addition to the current clinical practice for patients with atherothrombotic disease, not only as an alternative, but also as additional therapy.

Targeting PAR1: Now What?

“…High throughput screening of compound libraries for platelet PAR1 inhibitors yielded several small molecules antagonists including SCH79797 [50], FR171113 [51], F16618 [52], E5555 ( atopaxar ) [53], and SCH530348 ( vorapaxar ) [54] (for overview see Table II). Although antithrombotic effects in animal models were observed for all these molecules, only vorapaxar and atopaxar were evaluated in large-scale clinical trials.…”

Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

“…18 PAR4 inhibition has a potential therapeutic advantage of inhibiting the maximal thrombin effect while minimizing bleeding because PAR1 signaling remains intact. 19 We recently demonstrated 3.7-fold increased PAR4-mediated aggregation kinetics and greater calcium mobilization in platelets from black individuals compared with white individuals and noted that phosphatidylcholine transfer protein partially accounted for this The online version of this article contains a data supplement.…”

Effect of Preoperative P2Y12 and Thrombin Platelet Receptor Inhibition on Bleeding After Cardiac Surgery

“…9 Thrombin is a powerful platelet activator, acting on the protease-activated human platelet receptors (PARs) PAR-1 and PAR-4. PAR activation is partially dependent on P 2 Y 12 inhibition, 10 and therefore it is possible that platelet aggregation remains within an acceptable range even in the presence of strong drug-induced inhibition of P 2 Y 12 receptors. However, evidence supporting the use of PFTs before surgery is based on assessment of P 2 Y 12 activity only.…”