SARS-CoV-2 vaccination induced cerebral venous sinus thrombosis: Do megakaryocytes, platelets and lipid mediators make up the orchestra?

The COVID-19 vaccines comprised of adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2 are highly effective but associated with rare thrombotic complications. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein expressed locally stimulates neutralizing antibody and cellular immune responses. These vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). S glycoprotein stimulates the expression of cyclooxygenase-2 (COX-2) and leads to massive generation of thromboxane A in COVID-19. Megakaryocytes express CAR and we postulate that S glycoprotein stimulated generation of thromboxane A leads to megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinuses express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses could be further activated by thromboxane A-dependent podoplanin-CLEC2 signaling, leading to CVST. A prothrombotic hormonal milieu, and increased generation of thromboxane A and platelet activation in healthy females compared to males is consistent with increased risk for CVST observed in women. We propose that antiplatelet agents targeting thromboxane A receptor signaling such as low-dose aspirin merit consideration for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to young adults at risk of thrombosis provided there are no contraindications.