title: Platelet transfusion reverses bleeding evoked by triple anti-platelet therapy including vorapaxar, a novel platelet thrombin receptor antagonist.
abstract: Vorapaxar is a novel protease-activated receptor-1 (PAR-1) antagonist recently approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Patients who received vorapaxar in addition to standard of care antiplatelet therapy had an increased incidence of major bleeding events compared with placebo. To assess whether platelet transfusion can restore hemostasis in primates on triple antiplatelet therapy, template bleeding times were assessed concurrently in the buccal mucosa, finger pad, and distolateral tail of anesthetized cynomolgus macaques to evaluate bleeding with vorapaxar as either monotherapy or in combination with aspirin or aspirin and clopidogrel. Aspirin (5mg/kg, IV) or vorapaxar (1mg/kg, PO) alone had no significant effect on bleeding times in the three vascular beds examined. A modest (<2-fold) increase in bleeding time was achieved in the three beds with the dual combination of aspirin and vorapaxar. Major increases in bleeding time were achieved in the three beds with the triple combination of aspirin (5mg/kg, IV), vorapaxar (1mg/kg, PO), and clopidogrel (1mg/kg, PO). Transfusion of fresh human platelet rich plasma, but not platelet poor plasma, reversed the increase in bleeding time in the triple therapy group. Transfusion of human platelets may be a viable approach in situations requiring a rapid reversal of platelet function in individuals treated with triple anti-platelet therapy that includes vorapaxar.
authors: In Vivo Pharmacology, Kenilworth, NJ, USA. Electronic address: tianquan_cai@merck.com.
authors: Tian-Quan
authors: TQ
authors: Cai
authors: In Vivo Pharmacology, Kenilworth, NJ, USA.
authors: L Alexandra
authors: LA
authors: Wickham
authors: Safety, West Point, PA, USA.
authors: Gary
authors: G
authors: Sitko
authors: Safety, West Point, PA, USA.
authors: Maria Strainer
authors: MS
authors: Michener
authors: Biostatistics, Kenilworth, NJ, USA.
authors: Richard
authors: R
authors: Raubertas
authors: Safety, West Point, PA, USA.
authors: Larry
authors: L
authors: Handt
authors: Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ, USA.
authors: Madhu
authors: M
authors: Chintala
authors: Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ, USA.
authors: Dietmar
authors: D
authors: Seiffert
authors: In Vivo Pharmacology, Kenilworth, NJ, USA.
authors: Michael
authors: M
authors: Forrest
mesh_terms: D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects*; D001760:Bleeding Time; D000077144:Clopidogrel; D004359:Drug Therapy, Combination / Q000009:adverse effects*; D006470:Hemorrhage / Q000139:chemically induced / Q000628:therapy*; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects*; D008252:Macaca fascicularis; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D017713:Platelet Transfusion; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin; C530299:vorapaxar
keywords: Aspirin; Blood platelets; Clopidogrel; Hemorrhage; Vorapaxar