Figure 3.

A schematic representation of the crosstalk between plasmin, complement, and platelet-activating systems in SARS-CoV-2 infection. Plasminogen conversion is mediated by either by tissue-specific plasminogen activator (T-PA) or urokinase plasminogen activator (U-PA), whose activities can be inhibited by the inhibitors, PAI-1 (SERPINE1) or PAI-2 (SERPINE2B). The conversion of plasminogen to active plasmin is critical for blood clot breakdown. Failure to breakdown the clots (fibrinolysis) leads to thrombosis. Fibrinolysis can be inhibited by complement component C3. The complement components C3 and C5 can be activated by plasmin in addition the classical, lectin, and alternative pathways. The anaphylatoxins, C3a and C5a, interact and stimulate mast cells to degranulate, releasing histamine, cytokines, granulocyte-macrophage colony-stimulating factor, leukotrienes, heparin, and several proteases that damage the tissues. Overstimulation of complement cascade leads to inflammation, cytokine storm resulting in epithelial damage, and airflow obstruction that manifests as the acute respiratory distress syndrome (ARDS). Also, C5a and Leukotriene-bound PAF are potent attractants of polymorphonuclear leukocytes (PMNs) to the site of damage. The recruited PMNs can release microbiocidal molecules and form the neutrophil extracellular traps (NETs). NETs are proinflammatory and promote tissue damage, thrombus formation, and activate platelets. PAF is also suggested to trigger pulmonary edema in models of acute lung injury. Degradation of the basement membrane/ ECM promote by matrix metalloproteinases further promote immune cell infiltration and tissue damage. NETs, tissue injury, platelets-activating factors (PAF), T-PA (if overexpressed), C3a and C5a activate platelets to aggregate on a fibrin scaffold to form clot. Clots and tissue injury lead to airflow obstruction that manifests as acute respiratory distress syndrome (ARDS). Double arrows indicate association.