Mien Vu

Introduction: In the United States, stroke is the leading cause of disability and the fifth leading cause of death^1,2. It is estimated 60-80% of stroke cases are ischemic^1,2. Current treatment guidelines as recommended by American Heart Association include intravenous thrombolysis with tissue Plasminogen Activator (tPA) and mechanical removal of clots⁹. However, availability of endovascular treatment remains an issue as some hospitals lack the resources or personnel necessary⁹. tPA treatment screening is extensive and carries the risks of severe cerebral hemorrhage⁹. Vascular injury and subsequent thrombus formation have been identified as the primary underlying cause of ischemic stroke¹. Following vascular injury, von Willebrand factor (VWF) released from endothelial cells initiate platelet adhesion which follow the coagulation cascade to form thrombus¹. ADAMTS13 is a metalloprotease that cleaves VWF into smaller and less active molecules, therefore reducing clot burden in acute ischemic stroke (AIS)³. Studies have found that low ADAMTS13 level is associated with higher incidence of strokes⁶. Other studies show ADAMTS13:VWF ratio could predict severity and progression of cardiovascular diseases⁷. These findings suggest a potential role for anti-thrombotic treatment of ADAMTS13. Research is aimed at creating a minimal necessary functional construct of recombinant ADAMTS13 to serve as a pharmacotherapeutic agent. Methods: Wild-type ADAMTS13 and two truncation variants that either lacked the C-terminal thrombospondin motif-7 to the CUB domain (MP-TSP6) or contained only the two CUB domains (CUB) were characterized for interactions with coiled VWF, flow-elongated VWF, and a VWF A1A2A3 tridomain³. Atomic force microscopy was used to assess the interaction of each set of ADAMTS13 and VWF³. Results: VWF assumes coiled conformation under static condition and extended form under shear flow that mimics hemodynamic condition. Coiled VWF binds more tightly to CUB domain whereas flow-extended VWF binds to MP-TSP 63³. Presence of calcium is required for binding³. ADAMTS13 contains 2 binding sites for VWF, one calcium dependent on MPTSP6 and 1 calcium independent on CUB³. Conclusions: Thrombus formation is the leading pathogenesis of acute ischemic stroke. Imbalance of ADAMTS13:VWF ratio can cause hemodynamic dysregulation. ADAMTS13 interacts with VWF via multiple domains and is subjected to high flow shear force of blood under physiological condition. ADAMTS13 could provide a possible alternative to the current guideline treatment of tPA. Human trials are needed to provide efficacy and safety of this novel approach.

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