Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility

Abstract

Patients with hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease, and kidney dysfunction have worse clinical outcomes when infected with SARS-CoV-2, for unknown reasons. The purpose of this review is to summarize the evidence for the existence of elevated plasmin(ogen) in COVID-19 patients with these comorbid conditions. Plasmin, and other proteases, may cleave a newly inserted furin site in the S protein of SARS-CoV-2, extracellularly, which increases its infectivity and virulence. Hyperfibrinolysis associated with plasmin leads to elevated D-dimer in severe patients. The plasmin(ogen) system may prove a promising therapeutic target for combating COVID-19.

Keywords: COVID-19; SARS-CoV-2; comorbidity; fibrinolysis; plasmin(ogen).

Graphical abstract

FIGURE 1.

Plasmin(ogen) increases the pathogeneticity of COVID-19. Plasmin cleaves the S protein of SARS-CoV-2 extracellularly, increasing its ability to bind with angiotensin converting enzyme 2 (ACE2) receptors of host cells, and probably facilitating virus entry and fusion. Plasmin proteolytically breaks down excess fibrin to elevate D-dimer and other fibrin degradation products in both bronchoalveolar lavage fluid and plasma, which decreases platelets and results in hemorrhage. Plasmin also cleaves epithelial sodium channel (ENaC) subunits, located at the apical membranes of epithelial cells in the airway, lung, and kidney. This increases the ability of Na⁺ ions to enter epithelial cells resulting in hypertension and dehydration of the fluid lining lung airways and alveolar cells.