**4. Pathophysiology**

COVID-19 and other viral infections generate a hypercoagulable state and thus predispose to thromboembolism. This is caused by activation of systemic inflammatory response syndrome which creates an imbalance between pro and anticoagulant effects. Coagulation and body immune system pathways are essentially interlinked, Thrombin and platelets play an important role in coagulation and immune system stimulation. Blood clot formation limits the loss of immune and blood components, as well as causing slowdown of the microorganisms' invasion of circulation [9]. Endothelial injury in COVID-19 infection leads to loss of vasodilatory, fibrinolysis and anti-aggregation properties. Endothelial injury induced by the local viral load and penetration into the endothelium, releases cytokines and von Willebrand factors, inducing the thrombosis initiation in medium and smaller vessels [9].

Further in the process, release of pro-inflammatory cytokines causes vascular endothelial apoptosis, increases adhesion molecules causing pro-adhesive and proinflamatory effects. Endothelial damage also causes imbalance between ADAMTS-13 (A disintigrin and metalloproteinase with thrombospondin type1 motif memeber13) and excessive generation of ultra large von Willebrand factor multi lumen (ULVWF) from the endothelial cells, the ULVWF adheres to the endothelium surface and recruits platelets causing micro thrombi generation [10].

Secondly the endothelial injury with elevated von Willebrand factor (vWF), toll-like receptor activation and tissue pathway activation induce pro-inflammatory and pro-coagulant state through complement activation and cytokines release resulting in dysregulation of the coagulation process with formation of intraalveolar and systemic clots [11].

Moreover, the release of higher amount of proinflammatory cytokines causes 'cytokine storm' leading to secondary development of hemophagocytic lymphohistiocytosis and activation of blood clotting with increased risk of micro thrombosis. The final interaction between various blood cells (microphages, monocytes, platelets, lymphocytes, endothelial cells) plays an important role in the pro-coagulant effect in COVID-19 infection. Platelet activation by viral invasion facilitates pathogen clearance by white blood cells and clot formation [12].
