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

Abstract Cerebral venous (sinus) thrombosis (CVT) is an unusual manifestation of causing severe neurological impairment and seizures 1,2 . Molecular mechanisms underlying CVT, potentially involving pathological platelet activation, are unknown. Here we show that antibody-(INU1-fab)-induced cooperative signaling two receptors, C-type lectin-like receptor-2 (CLEC-2) GPIIb/IIIa, triggers within minutes a CVT-like thrombotic syndrome in mice, characterized by tonic–myoclonic seizures, consumption death. Brain autopsy showed thrombi mainly the cortical venules, but no intracranial hemorrhages or edema formation. Transcranial intravital microscopy revealed rapidly progressing superior sagittal sinus, main site CVT humans. Interfering with CLEC-2 inhibition GPIIb/IIIa completely blocked activation CVT. Blocking after onset symptoms protected mice from consumption, death, which was not seen treatment heparin. These results point to aberrant as major trigger potential target for treatment.