VWF-targeted plasmin generation by Microlyse. TTP is a devastating thrombotic syndrome characterized by the deposition of VWF and platelets in the microvasculature. Plasmin generation occurs during acute episodes of TTP and can degrade VWF, suggesting that the fibrinolytic system may serve as a potential bypassing pathway for the treatment of TTP. Microlyse is a fusion between the protease domain of urokinase and a nanobody targeting VWF. Exogenous plasmin converts Microlyse into its active form. Activated Microlyse catalyzes plasminogen activation in the presence of VWF, leading to a burst of plasmin activity. Plasmin degrades VWF and dissolves the thrombus. Microlyse and plasmin are rapidly inhibited by PAI1 and α2-antiplasmin, respectively, thereby limiting systemic thrombolytic activity.