Von Willebrand Factor (VWF) is a multimeric plasma glycoprotein that mediates platelet adhesion and aggregation, a process critical for both hemostasis and thrombosis. Under normal conditions, VWF binds to platelets at sites of vascular injury or damage, leading to blood clot formation and wound healing. VWF contains four types of repeating domains in the following sequence: D1-D2-D’-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK (CK: cystine knot). It is synthesized and secreted into plasma by endothelial cells and megakaryocytes. Many newly-secreted VWF multimers are huge in size, thus they are termed ultra-large VWF (ULVWF). ULVWF is thrombogenic, so it is reduced to smaller VWF multimers by ADAMTS13, a metalloprotease that cleaves the Tyr1605-Met1606 bond in the A2 domain of VWF. Proper ULVWF cleavage and subsequent VWF cleavage result in appropriate size distribution of VWF in plasma, which is required for its hemostatic function. On the one hand, insufficient cleavage of ULVWF leads to thrombotic thrombocytopenic purpura (TTP), a disease characterized by microvascular thrombosis; on the other hand, excessive cleavage of VWF leads to Von Willebrand disease (VWD), a potentially-fatal bleeding disorder manifested by lack of large VWF multimers in plasma [1]. Therefore, understanding VWF cleavage by ADAMTS13 is crucial for understanding VWF function and its related diseases.