Abstract Number: OC 45.2
Meeting: ISTH 2022 Congress
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.
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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