Determination of ADAMTS13 Susceptibility in Type IIA von Willebrand Disease

von Willebrand Disease (vWD) is a bleeding disorder caused by a deficiency in von Willebrand Factor (vWF), a large glycoprotein that assists in coagulation. Specifically, large vWF multimers in the blood stream are key components in starting the coagulation cascade. vWF is cleaved by the metalloprotease ADAMTS13, regulating the multimers size, which hinders vWF’s ability to function properly. The three main types of vWD —Type I, II, and III— are not well defined, and as a result are all similarly treated with plasma-derived vWF replacement therapy. Plasma-derived vWF is a treatment that does not cure the problem but relieves the symptom of continual bleeding. vWD Type II, the second most common form of vWD, is sub-grouped further into four types: IIA, IIB, IIN and IIM. The objective of this project was to better understand the mutation(s) involved in vWD Type IIA and thus determine the mechanism of this specific vWF dysfunction. In vitro assays were optimized to determine ADAMTS13 susceptibility for uncharacterized vWD Type II mutations. Our findings suggest that Type IIA mutations that result in a loss of high molecular weight vWF multimers are associated with increased ADAMTS13 susceptibility. A better understanding of the various mechanisms behind vWD may lead to the development of more successful, targeted therapies.