Session: 321. Coagulation and Fibrinolysis: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, drug development, Therapies, Biological Processes, molecular biology
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.
Disclosures: 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.
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