The VWF performs this important homeostatic task through a specific protein-protein interaction between the VWF A1 domain and the platelet receptor glycoprotein Ib α (GPIB α). Two naturally occurring VWF A1 domain mutations near the GPIBα binding sites G1324A and G1324S induce a dramatic decrease in platelet adhesion, resulting in hemorrhagic disease classified as 2 MvWD type. The intact VWF A1 domain is required for VWF-dependent platelets binding to collagen 4 under flow conditions. Reduced binding to collagen 4 is associated with specific VWF A1 domain sequence variants in type 1 and 2M VWD, the VWF A1 domain where exposed collagen interacts with the A3 and A1 domains of VWF, leaving the VWF anchored to the vessel wall. Subsequently, the VWF A1 domain binds to the GP Ibα of platelets, triggering platelet activation and adhesion. The binding of the VWF A1 domain to GP Ibα not only promotes platelet adhesion but further triggers platelet activation and aggregation. With blood flow shear forces, the VWF molecules are stretched and unfolded, exposing more A1 domains, thereby enhancing the binding capacity to platelets. This binding effect promotes platelet aggregation and thrombus formation at the site of vascular injury.