Foudroyant cerebral venous (sinus) thrombosis triggered through CLEC-2 and GPIIb/IIIa dependent platelet activation
David Stegner, Vanessa Göb, Viola Krenzlin, Sarah Beck, Katherina Hemmen, Michael K. Schuhmann, Barbara F. Schörg, Christian Hackenbroch, Frauke May, Philipp Burkard, Jürgen Pinnecker, Alma Zernecke, Peter Rosenberger, Andreas Greinacher, Bernd J. Pichler, Katrin G. Heinze, Guido Stoll, Bernhard Nieswandt
Abstract
. 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.