Von Willebrand factor (vWF) orchestrates hemostasis through platelet activation, factor VIII stabilization, and inflammatory modulation, with emerging evidence highlighting its shear-dependent conformational dynamics as a critical regulator of thrombus formation. The protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) cleaves ultralarge vWF multimers under physiological conditions, although its efficiency declines sharply at supraphysiological shear forces characteristic of extracorporeal membrane oxygenation (ECMO) circuits. Beyond proteolytic regulation, cumulative evidence confirms that vWF self-association, autoregulatory domains, and inflammatory mediators collectively modulate vWF’s thrombogenic potential during ECMO support. Contrary to early assumptions that ECMO-associated vWF dysfunction solely reflects quantitative depletion, contemporary multimodal analyses reveal a biphasic trajectory: an initial prothrombotic phase mediated by shear-induced unfolding of high-molecular-weight multimers, which triggers platelet hyperreactivity in ECMO initiation, followed by a hemorrhagic phase due to progressive vWF multimer degradation and ADAMTS13 exhaustion, with acquired von Willebrand syndrome cases showing simultaneous platelet dysfunction. Post-ECMO removal, endothelial vWF surge then reignites thrombosis risk—a paradoxical rebound observed in survivors despite anticoagulation. Major bleeding and thrombotic events remain despite anticoagulation, underscoring the inadequacy of current anticoagulation and monitoring strategies. Although pulsatile flow modulation and vWF multimer monitoring show promise in preserving hemostatic balance, cohort data are conflicting on post-ECMO anticoagulation efficacy. This review synthesizes mechanistic insights from shear-stress models, clinical outcome studies, and emerging monitoring technologies, providing insights and references for establishing a temporal management framework aimed at maintaining vWF-ADAMTS13 homeostasis across ECMO phases.
