Date

May 2009

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Science & Engineering

Institution

Oregon Health & Science University

Abstract

Thrombosis and hemostasis involve a complex interplay between coagulation factors, platelets, and their underlying microenvironment. During vessel injury, platelets become activated on exposed extracellular matrix proteins or on injured endothelium where they act as a surface for coagulation amplification. Ensuing fibrin formation and sustained platelet activation results in hemostatic platelet plug development which minimizes trauma-induced bleeding. This beneficial process can spiral out of control during diseased conditions, resulting in thrombotic vascular occlusion. Elements that differentiate thrombotic and hemostatic pathways include shear force and tissue factor(TF) exposure. Since vascular thrombo-occlusion occurs at increasing shear under low TF conditions rather than the more complex flow and high TF environment of the extravascular wound, it is now understood that these two processes utilize divergent mechanism to maintain growth and stability. In an effort to support the advancement of safer antithrombotic treatment strategies, the goal of my studies was to explore prothrombotic pathways in vivo to define the elements that favor thrombus development relative to those that are crucial for normal hemostasis. For these studies we utilized both baboon and mouse models of thrombosis. Using a mouse model of sepsis, which can result in infection related intravascular thrombosis, we found that mice lacking coagulation factor XI (FXI) had a significantly improved survival compared with wild type animals through a reduction in coagulopathy. In baboons, inhibiting FXI using a novel monoclonal antibody (aXIMab) decreased experimental thrombus formation and prevented vascular graft occlusion under high shear by destabilizing developing thrombi. FXI knockout mice and baboons treated with aXIMab showed no increased bleeding. Platelets also play a vital role in thrombus development. While normal platelet counts vary widely in the general population, low normal counts do not predispose patients to bleeding. By transiently reducing platelet count in baboons by targeting thrombopoietin we found a strong correlation between thrombus formation and platelet number. Indeed, occlusive thrombus formation was prevented at platelet counts that did not affect bleeding.

Identifier

doi:10.6083/M4P26W2N

Division

Div. of Biomedical Engineering

School

School of Medicine

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