Antiplatelet Effects of Inhibiting Coagulation Factor XI in a Diet-Induced Obesity Model of Early Atherosclerosis

Background: Atherosclerosis-associated cardiovascular disease (CVD) remains the leading cause of non-communicable death worldwide. In the setting of atherosclerosis, platelets facilitate monocyte trafficking and drive inflammatory pathways. Previous studies have shown that coagulation factor (F) XI can interact directly with multiple pathways that are complicit in CVD, including platelet activation. Therefore, the objective of this study was to investigate the effects of pharmacologically inhibiting FXI on systemic platelet function in a diet-induced obesity model of early atherosclerosis.

Methods: Five rhesus macaques on a high-fat diet for ≥2 years with detectable carotid intimal thickening were administered a FXI function-blocking antibody, h1A6 (2 mg/kg). Blood was collected at baseline, one, and seven days after treatment. Flow cytometry studies were performed to asses platelet function in lean rhesus macaques on a standard chow diet, as well as obese rhesus macaques a high fat diet before and after treatment with h1A6. Platelet reactivity and platelet-leukocyte aggregate (PLA) formation in response to platelet hemostatic agents against GPVI (collagen-related peptide, CRP-XL) and PAR-1 (thrombin analog, TRAP-6) were measured by P-selectin expression. The coagulability of platelets in response to CRP-XL or TRAP-6 was measured by phosphatidylserine (PS) exposure.

Results: Obese NHPs demonstrated increased P-selectin expression and phosphatidylserine exposure in response to GPVI and PAR-1 agonists relative to lean NHPs. This suggests that diet-induced obesity may increase platelet sensitivity, PLA formation, and platelet coagulability. Administration of a FXI function-blocking antibody resulted in prolonged clotting times, decreased GPVI- and PAR-1 mediated platelet sensitivity, and reduced PLA formation compared to basal levels. Phosphatidyl serine exposure was not affected by FXI inhibition.

Conclusions: Pharmacological inhibition of FXI reversed the elevated platelet sensitivity and PLA formation observed in the diet-induced obesity model. Taken together, this suggests that coagulation FXI may modulate the exacerbated platelet function that is associated with atherosclerosis.

Shatzel:Aronora, Inc.: Consultancy. Wallisch:Aronora, Inc.: Current Employment. Tucker:Aronora, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Lorentz:Aronora Inc: Current Employment, Current holder of stock options in a privately-held company.