Fig. 2

Model of ADAM17 and extrinsic pathway of coagulation cascade activation by PtdSer externalization. a As a consequence of SARS-CoV-2 infection, ACE2 is internalized, increasing the Ang II/AT1R-axis. Both stimuli, ACE2 down-modulation and the high Ang II level trigger intracellular signals that culminate in Ca²⁺ influx, and TMEM16F-scramblase activation, leading to PtdSer externalization to the outer cell membrane. The interaction between the ADAM17 cationic conserved sequence domain with the negatively charged PtdSer head group on the outer leaf membrane, bring the protease in the right position for ACE2 processing, with detrimental effects. Additionally, the ADAM17 “shedasse” activity also release of proinflamatory cytokine TNF-α and IL-6R increasing inflammatory process. b Finally, the PdSer exposure on the outer membrane may also activate the extrinsic pathway of coagulation cascade by enhancing the activation of tissue factor, being able to contribute to disseminated intravascular coagulation—DIC observed in COVID-19 patients