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

David Stegner,Philipp Burkard,Christian Hackenbroch,Katherina Hemmen,Alma Zernecke,Viola Krenzlin,Guido Stoll,Michael K Schuhmann,Bernhard Nieswandt,Katrin G Heinze,Bernd J Pichler,Barbara F Schörg,Andreas Greinacher,Vanessa Göb,Sarah Beck,Frauke May,Peter Rosenberger,Jürgen Pinnecker

doi:10.1038/s44161-021-00017-1

Abstract

Cerebral venous (sinus) thrombosis (CVT) is an unusual manifestation of venous thrombosis causing severe neurological impairment and seizures1,2. Molecular mechanisms underlying CVT, potentially involving pathological platelet activation, are unknown. Here we show that antibody-(INU1-fab)-induced cooperative signaling of two platelet receptors, C-type lectin-like receptor-2 (CLEC-2) and GPIIb/IIIa, triggers 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, but no intracranial hemorrhages or edema formation. Transcranial intravital microscopy revealed rapidly progressing thrombosis in the superior sagittal sinus, a main site of CVT in humans. Interfering with CLEC-2 signaling or inhibition of GPIIb/IIIa completely blocked platelet activation and CVT. Blocking GPIIb/IIIa after onset of neurological symptoms protected mice from platelet consumption, CVT and death, which was not seen after treatment with heparin. These results point to aberrant platelet activation as a major trigger of CVT and potential target for treatment.

Highlights

Cerebral venous thrombosis (CVT) is an unusual manifestation of venous thrombosis causing severe neurological impairment and seizures[1,2]
We show that antibody-(INU1fab)-induced cooperative signaling of two platelet receptors, C-type lectin-like receptor-2 (CLEC-2) and GPIIb/IIIa, triggers within minutes a Cerebral venous (sinus) thrombosis (CVT)-like thrombotic syndrome in mice, characterized by tonic–myoclonic seizures, platelet consumption and death
While locally produced/released soluble agonists activate G protein-coupled receptors[6], macromolecular, mostly immobilized ligands activate immune-like receptors that signal through an immunoreceptor tyrosine-based activation motif (ITAM)

Summary

Introduction

Cerebral venous (sinus) thrombosis (CVT) is an unusual manifestation of venous thrombosis causing severe neurological impairment and seizures[1,2]. INU1-IgG/fab was administered intravenously during PET/MRI acquisition (Extended Data Fig. 2a). INU1-fab-treated mice at t = 20 min (Extended Data Fig. 3a).

Results

Conclusion