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Foudroyant cerebral venous (sinus) thrombosis triggered through CLEC-2 and GPIIb/IIIa dependent platelet activation

1University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Biomaging University of Würzburg, Würzburg, Bayern, Germany, 2University Hospital and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Bayern, Germany, 3University of Mainz, Mainz, Rheinland-Pfalz, Germany, 4 University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Bayern, Germany, 5Rudolf Virchow Center, University of Würzburg, Würzburg, Bayern, Germany, 6University Hospital Würzburg, Würzburg, Bayern, Germany, 7Eberhard Karls University Tübingen, Tübingen, Baden-Wurttemberg, Germany, 8CSL Behring, Marburg, Hessen, Germany, 9University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Germany, Würzburg, Bayern, Germany, 10University Hospital Tübingen, Tübingen, Baden-Wurttemberg, Germany, 11University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany, 12Rudolf Virchow Center for Integrative and Translational Biomaging University of Würzburg, Würzburg, Bayern, Germany, 13Institute of Experimental Biomedicine, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Bayern, Germany

Abstract Number: OC 45.2

Meeting: ISTH 2022 Congress

Theme: Arterial Thromboembolism » Cerebrovascular Disorders

Background: Cerebral venous (sinus) thrombosis (CVST, CVT) is an unusual manifestation of venous thrombosis causing severe neurological impairment and seizures. Molecular mechanisms underlying CVT, potentially involving pathological platelet activation, are currently unknown.

Aims: Recent studies suggested a role for platelet ITAM signaling in venous thrombosis. Therefore, we investigated a potential role of the hemITAM receptor CLEC-2 in CVT.

Methods: Mice were monitored following the administration of the anti-CLEC-2 antibody, INU1, or its fab-fragment. Platelet count and activation were assessed by flow cytometry, and thrombus formation was analyzed intravitally or in tissue sections using different imaging modalities.

Results: Administration of INU1 fab-fragments, but not INU1-IgG, triggered within minutes a CVT-like thrombotic syndrome in mice, characterized by tonic/myoclonic seizures, platelet consumption and death. Brain autopsy showed thrombi mainly in the cortical venules. Transcranial intravital microscopy revealed rapidly progressing thrombosis in the superior sagittal sinus, a main site of CVT in humans. PET/MRI and light-sheet fluorescence microscopy confirmed that INU1-fab induced thrombosis is limited to cerebral veins.

Defective CLEC-2 signaling protected mice from INU1-fab induced symptoms and lethality. Lack of dense granule secretion or treatment with Aspirin or Clopidogrel delayed the onset of CVT but did not prevent thrombocytopenia or lethality. In contrast, prophylactic GPIIb/IIIa blockade abolished platelet consumption, CVT and death. Unlike heparin, the current first line treatment of CVT, GPIIb/IIIa blockade was also highly beneficial when applied therapeutically after symptom onset.

Conclusion(s): These results point to aberrant platelet activation as a major trigger of CVT and suggests targeting GPIIb/IIIa or CLEC2-ITAM signaling as a potential therapeutic option in foudroyant CVT.

Image

CLEC-2 dependent platelet activation results in cerebral venous thrombosis. The bivalent anti-CLEC-2 antibody INU1 triggers platelet activation in vitro, while this is not the case for the monovalent INU1-fab fragment. In vivo, however, INU1-fab leads in the rapid formation of thrombi in the cerebral veins, here shown for the superior sagittal sinus. As a result, mice suffer from neurological symptoms like seizures -parts of the figure were created in BioRender-.

To cite this abstract in AMA style:

Stegner D, Göb V, Krenzlin V, Beck S, Hemmen K, Schuhmann M, Schörg B, Hackenbroch C, May F, Burkard P, Pinnecker J, Zernecke A, Rosenberger P, Greinacher A, Pichler B, Heinze K, Stoll G, Nieswandt B. Foudroyant cerebral venous (sinus) thrombosis triggered through CLEC-2 and GPIIb/IIIa dependent platelet activation [abstract]. https://abstracts.isth.org/abstract/foudroyant-cerebral-venous-sinus-thrombosis-triggered-through-clec-2-and-gpiib-iiia-dependent-platelet-activation/. Accessed December 6, 2023.

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