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Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility
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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.
1. Elevated plasmin(ogen) is a common feature in people with underlying medical conditions, including hypertension, diabetes, cardiovascular disease, cerebrovascular disease, and chronic renal illness, who are susceptible to SARS-CoV-2 infection.
2. Plasmin enhances the virulence and infectivity of SARS-CoV-2 virus by cleaving its spike proteins.
3. Extremely increased D-dimer in COVID-19 patients results from plasmin-associated hyperactive fibrinolysis.
4. D-dimer and viral load are independent risk factors of disease severity and mortality.
5. Antiproteases targeting plasmin(ogen) may be a promising approach to combat COVID-19.
Patients with preexisting hypertension, diabetes, coronary heart disease, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), and kidney dysfunction (comorbidities) have worse clinical outcomes when infected with SARS-CoV-2. The only treatment of COVID-19 is supportive (51), and registered clinical trials are ongoing. The mechanisms for high morbidity and mortality of patients with comorbidities are unknown. The existence of significantly increased fibrin degradation products (FDPs) and reduced platelets in severe COVID-19 patients is consistent with the presence of hyperfibrinolysis. This opinion is supported by the presence of hemorrhage in multiple organs and a positive correlation between fibrinolysis and mortality. Plasmin, a key player in fibrinolysis, enhances the virulence and pathogenicity of viruses containing a furin site in their envelope proteins, as is the case with the SARS-CoV-2. The purpose of this review is to summarize the clinical and preclinical evidence for the existence of elevated plasmin(ogen) in these comorbid conditions of COVID-19 and to highlight the importance of plasmin-induced proteolytic cleavage of the SARS-COV-2 S protein and fibrin in the development of COVID-19.
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Targeting hyperfibrinolysis with a broad spectrum or specific anti-plasmin compounds may prove to be a promising strategy for improving the clinical outcome of patients with comorbid conditions.
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The body produces plasmin. Plasmin is a protease, meaning that it breaks up protein. Plasmin excess in people leads to diseases which are comorbidities to COVID-19. Ivermectin is a protease inhibitor. Protease inhibitors have been shown to be effective against various viruses. In studies Ivermectin has been shown to be effective against COVID-19. Does Ivermectin work against COVID-19 because it counteracts excess plasmin?
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