VWF-targeted thrombolysis to overcome rh-tPA resistance in experimental murine ischemic stroke models

Recombinant human tissue plasminogen activator (rh-tPA) is an important thrombolytic agent for treatment of acute ischemic stroke. 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 2 randomized blinded acute ischemic stroke mouse models. Thrombosis was induced in the middle cerebral artery 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 = .001 39.3 +/- 13.1%; P < .0001; 15.6 +/- 7.5%, respectively, vs vehicle). In addition, both thrombolytic agents reduced cerebral lesion volume (determined by magnetic resonance imaging) after 24 hours (18.9 +/- 11.2 mm(3); P = .033; 16.1 +/- 13.9 mm(3); P = .018; 26.6 +/- 5.6 mm(3), respectively, vs vehicle). In the platelet-rich model, neither rh-tPA nor Microlyse increased cortical reperfusion 10 minutes after therapy (7.6 +/- 8.8%; P = .216; 16.3 +/- 13.9%; P = .151; 10.1 +/- 7.9%, respectively, vs vehicle). However, Microlyse, but not rh-tPA, decreased cerebral lesion volumes (13.9 +/- 11.4 mm(3); P < .001; 23.6 +/- 11.1 mm(3); P = .188; 30.3 +/- 10.9 mm(3), respectively, vs vehicle). These findings support broad applicability of Microlyse in ischemic stroke, irrespective of the thrombus composition.

Automated summary

Recombinant human tissue plasminogen activator (rh-tPA) and Microlyse are both important thrombolytic agents for the treatment of acute ischemic stroke, but they have different mechanisms. rh-tPA activates plasminogen by binding to fibrin, while Microlyse activates plasminogen by binding to von Willebrand factor (VWF). The study results show that both thrombolytic agents can increase cortical reperfusion and reduce cerebral lesion volume in different types of thrombus models. However, only Microlyse can reduce cerebral lesion volume in the platelet-rich model.