Determining the role of platelets in the pathogenesis of venous thrombosis

Platelets are critical in hemostasis and a major contributor to arterial thrombosis (AT), i.e., in situations involving severe insult to the vascular system and elevated shear stress. Preclinical and clinical studies also suggest a role for platelets in venous thrombosis (VT), triggered by vascular inflammation and disturbed/reduced blood flow, but the mechanisms are unknown. We hypothesized that in VT, platelets utilize signaling machinery distinct from those known to mediate platelet activation/adhesion in hemostasis or AT. Our studies aimed to investigate the contribution of platelet signaling to VT pathogenesis. To that end, we used transgenic and wild-type (WT) mice treated with specific inhibitors to selectively inhibit platelet signaling pathways. VT was induced by inferior vena cava stenosis, and thrombus weight was determined 48 hours after flow restriction. Intravital microscopy was performed in the saphenous vein to study platelet-leukocyte interactions 2 hours after flow restriction. In in vitro studies, we used whole blood ex vivo to study clot contraction, thrombin generation and clot lysis. These studies revealed important contributions of platelets to the pathogenesis of VT, some of which have the potential to inform drug discoveries that may alleviate VT while keeping the hemostatic function of platelets intact.