JULY 2022 | The Surgical Technologist | 305 FIGURE 2 | COVID-19-associated coagulopathy (CAC) and Fibrinolytic Shutdown. (1) The SARS-CoV-2 Spike protein binds with angiotensin converting enzyme 2 (ACE2), which causes internalization of the receptor and virus into the host cell. (2) In turn, ACE2 is not available for breakdown of angiotensin II (AT-II) leading to its build-up. AT-II causes subsequent lung injury and increases in plasminogen activated inhibitor 1 (PAI-1). Angiotensin I-7 (AT-I-7) and angiotensin I-9 (AT-I-9) are increased by other pathways involving activated platelets, but also lead to increased levels of PAI-1. (3) Increased circulating PAI-1 leads to fibrinolytic shutdown, a hypercoagulable state characterized by increased fibrin deposition and thrombus formation. (4) Among other mechanisms, widespread endotheliitis and microthrombosis can cause multi-organ injury in patients with severe COVID-19 illness. This exacerbates the acute inflammatory response, often causing a cytokine storm and worsening immuno-thrombosis. Inflammatory cytokines activate Factor XII (FXII), which subsequently increases bradykinin levels. Bradykinin increases tissue plasminogen activator (tPa) levels. (5) This subacute rebalancing of the fibrinolytic system predisposes the COVID-19 patient to both thrombosis and hemorrhage as a function of local endothelial derangement. This is particularly the case for hospitalized COVID-19 patients who are anticoagulated; these patients’ anticoagulant regimen must be judiciously titrated on a personalized basis (17, 29, 31). The spectrum of fibrinolysis is depicted as a balance whereby the predominate hypercoagulable fibrinolytic shutdown phenotype is portrayed as a balance with high levels of PAI-1, thrombin activatable fibrinolysis inhibitor (TAFI), fibrinogen, D-dimer, and lower levels of tPa and plasmin. The opposite occurs at the opposite end of the fibrinolysis spectrum when fibrinolysis predominates, which occurs much less frequently in CAC. Created using BioRender.com Bunch et al. COVID-19 Immuno-Thrombosis and Surgery Frontiers in Surgery | www.frontiersin.org 5 2022 | Volume 9 | Article 889999
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