Deficiency of high‐molecular‐weight von Willebrand factor mitigates thrombo‐complement injury in an LPS‐induced TMA‐like mouse model

Abstract Complement‐mediated thrombotic microangiopathy (CM‐TMA) and thrombotic thrombocytopenic purpura (TTP) arise from distinct triggers, yet converge on a final common pathway of von Willebrand factor (VWF)‐mediated platelet adhesion within the microvasculature. Current complement component 5 (C5) inhibition therapies effectively halt complement amplification but leave a therapeutic gap regarding the acute resolution of existing endothelial activation and VWF strings. To determine whether the type 2A von Willebrand disease (VWD) phenotype, characterized chiefly by loss of high‐molecular‐weight (HMW) VWF multimers, limits microvascular thrombosis, complement accumulation, and organ injury in a lipopolysaccharide (LPS)‐induced TMA‐like model. Using a type 2A VWD murine model with constitutively reduced prothrombotic HMW VWF multimers, we induced TMA‐like injury with LPS. Histologic injury, fibrin deposition, complement activation, shear‐dependent thrombosis, and inflammatory responses were evaluated in comparison with wild‐type (WT) mice. Compared with WT controls, type 2A VWD mice showed substantially reduced microvascular thrombosis and tissue injury after LPS challenge, accompanied by decreased fibrin deposition and complement accumulation in affected organs. Microfluidic assays confirmed reduced platelet adhesion and thrombus formation under high shear stress in type 2A VWD mice. Alternative‐pathway hemolytic activity was lower in VWD mice at 24 h, whereas circulating inflammatory mediators did not differ between genotypes. In this LPS‐induced TMA‐like model, the type 2A VWD phenotype was accompanied by reduced microvascular thrombosis, complement accumulation, and organ injury, implicating VWF multimer composition and function in the propagation of thrombo‐complement microvascular injury.