Fig. 3

SARS-CoV-2 and relevant biological processes that involve ACE, PGR, FXIIIB, and tPA. SARS-CoV-2 uses ACE2 as a receptor for cell entry, facilitated by androgen-regulated TMPRSS2. SARS-CoV-2 can cause tissue and endothelial cell damages, activating the intertwined intrinsic and extrinsic blood coagulation pathways. ACE and ACE2 are two essential regulatory components in the RAAS. ACE can promote vasoconstriction through antagonizing the regulatory role of ACE2 in the RAAS and acting as a bradykininase in the KKS additionally activated by the intrinsic coagulation pathway. ACE2 is locally downregulated by SARS-CoV-2 entry and excessive ACE signaling. Progesterone can upregulate ACE2 via binding to the intracellular progesterone receptor. The result of hemostasis is the conversion of fibrin monomers to polymers catalyzed by Factor XIII, which, in circulation, is a heterotetrameric protein composed of FXIIIA and FXIIIB subunits. D-dimers constitute one of the fibrinolysis degradation products generated as plasmin catalyzes fibrinolysis. Plasminogen is the zymogen of plasmin; the transition can be facilitated by kallikrein and tPA among other molecules. Both plasmin and FXIIIB can activate the complement system in addition to their function as catalysts. The functions of proteins encoded by the ACE, PGR, PLAT, and F13B are integrally essential to the RAAS, KKS, and fibrinolytic systems; Alu variants in these genes likely contribute to the spectrum of symptoms observed in COVID-19 cases. ACE, angiotensin-converting enzyme; FXIII, Factor XIII; KKS, kallikrein-kinin system; PGR, progesterone receptor; RAAS, renin-angiotensin-aldosterone system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane protease, serine 2; tPA, tissue plasminogen activator