VWF-targeted thrombolysis to overcome rh-tPA resistance in experimental thrombotic stroke models.

Recombinant human tissue plasminogen activator (rh-tPA) is an important thrombolytic agent for treatment of acute ischemic stroke (AIS). It requires fibrin binding for plasminogen activation. In contrast, Microlyse, a novel thrombolytic agent, requires von Willebrand factor (VWF) binding for plasminogen activation. We compared rh-tPA with Microlyse, administered 20 minutes after inducing thrombosis, in two randomized blinded AIS mouse models. Thrombosis was induced in the middle cerebral artery (MCA) with different experimental triggers. Where thrombin infusion generates fibrin-rich thrombi, topical FeCl3-application generates platelet-rich thrombi. In the fibrin-rich model, both rh-tPA and Microlyse increased cortical reperfusion (determined by laser-speckle imaging) 10 minutes after therapy administration (35.8±17.1%; p=0.001; 39.3±13.1%; p<0.0001; 15.6±7.5%, respectively vs vehicle). In addition, both thrombolytic agents reduced cerebral lesion volume (determined by magnetic resonance imaging; MRI) after 24 hours (18.9±11.2mm3; p=0.033; 16.1±13.9mm3; p=0.018; 26.6±5.6mm3, respectively vs vehicle). In the platelet-rich model, rh-tPA nor Microlyse increased cortical reperfusion 10 minutes after therapy (7.6±8.8%; p=0.216; 16.3±13.9%; p=0.151; 10.1±7.9%, respectively vs vehicle). However, Microlyse, but not rh-tPA, reduced cerebral lesion volumes (13.9±11.4mm3; p<0.001; 23.6±11.1mm3; p=0.188; 30.3±10.9mm3, respectively vs vehicle). These findings support broad applicability of Microlyse in ischemic stroke irrespective of the thrombus composition.