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    The Thrombogenic Influences of Factor VIII and von Willebrand Factor

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    Date
    2015-04-02
    Author
    Golder, Mia
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    Abstract
    von Willebrand factor (VWF) and factor VIII (FVIII) circulate in the blood as a non-covalent complex. VWF plays an important role in primary hemostasis through its interactions with components of the extracellular matrix and platelet glycoproteins, as well as through its stabilization of FVIII. FVIII plays a crucial role in the intrinsic coagulation cascade and in the propagation of coagulation. The significant role of these two proteins in hemostasis is established, whereas little is known about the thrombotic effect of quantitative and qualitative variability in these proteins, particularly in the development of arteriolar thrombosis. Therefore, we established a ferric chloride induced arteriolar thrombosis injury model to evaluate the thrombotic effect associated with elevated FVIII levels and with gain of function mutations in VWF.

    The thrombotic effect of acute and extended elevations of FVIII level were evaluated using complementary in vitro and in vivo assays of thrombogenicity. Acute elevations in FVIII levels were associated with non-linear increase in thrombogenic potential as measured by our ferric chloride induced injury model. In addition, the elevation of FVIII levels for an extended time period did not further enhance the thrombogenic potential associated with elevated FVIII levels.

    Type 2B von Willebrand disease (2B VWD) is a bleeding disorder that arises as a result of gain of function mutations, leading to the enhanced affinity of the mutant protein for platelet glycoprotein Ibα (GPIbα). We created transient transgenic mouse models of 2B VWD and were able to reproduce the 2B VWD phenotype in mice. The circulating 2B VWF did not act as a prothrombotic stimulus: there was little or no thrombus formation after vascular injury and a marked failure of platelet accumulation at the sites of endothelial damage.

    Finally, modified transient transgenic models of type 2B VWD were created, in which the circulating VWF shows enhanced binding affinity for GPIbα and resistance to ADAMTS13 mediated proteolysis. This protein was hypothesized to act in as a prothrombotic stimulus, but instead it inhibited thrombogenicity; there was no vessel occlusion following vascular damage and platelet accumulation was similar to that seen in the injured arterioles of VWF-/- mice.
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    http://hdl.handle.net/1974/12798
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    • Department of Pathology and Molecular Medicine Graduate Theses
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