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

Discover this publication with TargED Biopharmaceuticals on VWF-targeted thrombolysis to overcome rh-tPA resistance in experimental murine ischemic stroke models, in which studies were performed by STROK@LLIANCE on our MCA occlusion by FECl3 application in vivo model, as well as analysis. Published in Blood (2022) 140 (26): 2844–2848. Brief Report, THROMBOSIS AND HEMOSTASIS. December 29, 2022.

Significant milestones since the publication:

• TargED entered clinic with Phase 1 trial of its groundbreaking thrombolytic TGD001 (December 19, 2024).
• The first patients have been successfully dosed in Phase 1b/2a proof-of-concept clinical study evaluating TGD001 as a potential treatment for acute ischemic stroke (July 16, 2026).

Read the full article: DOI: https://doi.org/10.1182/blood.2022016342

Keypoints:

• Microlyse is noninferior to rh-tPA when AIS is driven by fibrin-rich thrombi, but superior in AIS driven by platelet-rich thrombi.
• VWF-targeted plasminogen activation overcomes the intrinsic resistance of platelet-rich thrombi against rh-tPA–mediated thrombolysis.

Keywords: ischemic stroke; microlyse, thrombolytic agent, fibrin-rich thrombi, platelet-rich thrombi, cerebral reperfusion.

Authors: Marc V. A. van Moorsel 1 2, Steven de Maat 1 2, Kristof Vercruysse 2, Esther M. van Leeuwen 3, Charlène Jacqmarcq 4, Thomas Bonnard, Denis Vivien4 5, H. Bart van der Worp 6, Rick M. Dijkhuizen 3, Coen Maas 1 2.

Affiliated:

• 1. Central Diagnostic Laboratory Research, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.
• 2. TargED Biopharmaceuticals, Utrecht, The Netherlands.
• 3. Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.
• 4. UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C), Normandie University, Caen, France.
• 5. Department of Clinical Research, Caen Normandie University Hospital, Caen, France.
• 6. Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands

Acknowledgments: The authors thank Strok@lliance (Caen, France), and specifically Annelise Letourneur and Nicolas Violle for performing the in vivo experiments and analyses.

ABSTRACT:

Background

Microlyse, a Novel Thrombolytic Agent for Acute Ischemic Stroke

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.

Methods

Comparison of Microlyse and rh-tPA in Experimental Stroke Models

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.

Improved Reperfusion and Reduced Lesion Volume in Fibrin-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 mm³; P = .033; 16.1 ± 13.9 mm³; P = .018; 26.6 ± 5.6 mm³, respectively, vs vehicle).

Microlyse Shows Benefits in Platelet-Rich Thrombi

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 mm³; P < .001; 23.6 ± 11.1 mm³; P = .188; 30.3 ± 10.9 mm³, respectively, vs vehicle).