Ex vivo effects of low dose delayed release rapamycin on agonist-induced platelet aggregation, activation and procoagulant platelet phenotypes in domestic cats

Cardiogenic arterial thromboembolism (CATE) is a complication of hypertrophic cardiomyopathy (HCM) with a high mortality rate. Despite anti-platelet drugs use, on-treatment recurrence rate remains high indicating a critical need to discover novel therapies. Studies in both humans and cats show that low dose delayed release rapamycin (LDDRR) can reduce the progression of left ventricular hypertrophy. However, its effect on platelets is unclear. In this study we assessed the ex vivo effects of LDDRR on platelet aggregation, alpha-granule secretion indicated by an increase in P-selectin, and procoagulant platelet phenotypes including loss of mitochondrial membrane potential (ΔΨm) and phosphatidylserine (PS) exposure. Cats were treated with 0.3 mg/kg LDDRR orally every 7 days for 4 consecutive weeks. Blood was collected at 3, 24 and 48 hours after the last dose. While LDDRR had no effect on aggregation, it significantly decreased P-selectin expression in thrombin + COL (3 hrs), and ADP (24, 48 hrs) samples. LDDRR had protective effects on ΔΨm in all agonists at all times. PS exposure was reduced at 24 hrs in thrombin ± COL samples. Our study indicated that LDDRR in cats can safely modulate platelet activation, procoagulant phenotypes and tendency in varying degrees making it an effective candidate to prevent CATE.