Cellular and Plasma Protein Crosstalk in Arterial and Venous Thrombosis

Coagulation is an enzymatic cascade culminating in the formation of a clot. Intravascular coagulation is termed thrombosis. Studies using platelet-rich plasma, whole blood, and animal models reveal the complex crosstalk between clotting factors and the cellular environment that promote thrombosis. Three distinct, yet related, studies included in this dissertation exemplify this crosstalk. First, the vascular bed-dependent prothrombotic effects of elevated prothrombin were examined. We found that elevated prothrombin increased venous, but not arterial, thrombosis in mice. The prothrombotic effects of elevated prothrombin were manifested by increased fibrin deposition but no significant increase in platelet accumulation. These data show that elevated prothrombin would not be expected to contribute to platelet-dominated arterial thrombosis. Second, the procoagulant properties of microparticles from different cell types were investigated. We found that monocyte-derived microparticles contributed to initiation and propagation of clotting via the extrinsic coagulation pathway, while platelet-derived microparticles contributed to primarily to propagation of clotting via the intrinsic coagulation pathway. These data suggest monocyte-derived microparticles may contribute to the initiation of a thrombotic event, while platelet-derived microparticles may propagate an existing thrombotic event. Third, the role of fibrinogen and factor XIII (FXIII) in venous thrombosis was studied. We discovered the binding site of FXIII on fibrinogen, the necessity for FXIII activity for red blood cell retention in clots, and that reduction or deficiency of FXIII activity reduces venous thrombus size. These data indicate a novel role for FXIII in the pathogenesis of thrombosis and implicate FXIII as a novel therapeutic target. Together, these studies emphasize the importance of complementary in vitro and in vivo studies of coagulation and thrombosis to properly elucidate the pathophysiological relevance of clotting factor and cell function.Doctor of Philosoph