One of the things we know about COVID-19 so far is that people who already have certain conditions are more likely to have a severe form of the disease. New research helps to explain why and points to an impaired blood clotting system.

The conditions that raise the risk of COVID-19 severity are high blood pressure, diabetes, heart disease, cerebrovascular disease, respiratory conditions such as chronic obstructive pulmonary disease (COPD), and conditions affecting the kidneys.

Researchers are still investigating the precise reasons and mechanisms for why these conditions make COVID-19 outcomes so much worse.

The authors of a new review study — appearing in the journal Physiological Reviews — note that hemorrhage or bleeding disorders are among the leading causes of death for these patients.

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Dr. Hong-Long Ji, from the University of Texas Health Science Center at Tyler, and his colleagues further suggest in their study that the hyperactivity of the body’s anticoagulant response may be to blame for these bleeding dysfunctions.

An overactive anticlotting system, in other words, may be what causes excessive bleeding in COVID-19.

Why hyperfibrinolysis may be to blame

This overactivity of the body’s attempts to remove blood clots is known as hyperfibrinolysis. Fibrinolysis is “an enzymatic system […] that serves to localize and limit clot formation,” according to research.

In fibrinolysis, a clotting protein called fibrin is broken down, or degraded, through a process that two opposing “forces” drive. These opposite drivers “regulate pro and con the conversion of plasminogen to plasmin, the active enzyme that dissolves the fibrin clot into soluble fibrin degradation products.”

In their paper, Dr. Ji and team note that people with severe COVID-19 also present with fibrin degradation products and reduced platelets, which can be an indication of hyperfibrinolysis.

Hemorrhage in multiple organs together with a positive correlation between fibrinolysis and mortality, say the authors, further support the idea that hyperfibrinolysis may explain mortality in those with preexisting conditions.

Furthermore, COVID-19 patients with diabetes and heart, lung, and kidney preexisting comorbidities will often present high levels of plasminogen and plasmin.

Plasminogen is a nonactive substance in the blood. When substances found in blood vessels’ cells do activate plasminogen, it converts into plasmin — an enzyme that reduces blood clots. However, too much plasminogen and plasmin can cause hemorrhaging.

D-dimer levels also key

Additionally, according to studies that the authors reference, more than 97% of people who doctors admitted to hospital for COVID-19 have raised levels of another protein called D-dimer.

D-dimer forms in the blood when a blood clot dissolves. Researchers found raised D-dimer levels in patients with severe disease, explain the authors of the review.

The more severe COVID-19 becomes, the more D-dimer levels increase, particularly in the case of patients who develop acute respiratory distress syndrome (ARDS).

“In contrast, D-dimer levels decreased to control levels in [COVID-19] survivors or nonARDS patients,” write Dr. Ji and colleagues.

“The time [period] for the elevated D-dimer [to go] down in mild [cases] or survivors is dependent. Generally, it takes at least 1 week for mild [cases] but longer for severe patients,” says Dr. Ji, who is also the corresponding author of the study.

Therefore, conclude the authors, “The elevated plasmin(ogen) could be an independent factor for risk stratification of patients with COVID-19. Measurements of plasmin(ogen) levels and its enzymatic activity may be important biomarkers of disease severity in addition to resultant D-dimer.”

Studies that the authors reference used healthy mice and monkeys infected with SARS-CoV-2. The authors recommend that researchers carry out further studies in mice and monkeys with preexisting conditions and high plasmin levels to see if they go on to develop COVID-19, and to test potential new therapeutic agents.

“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.”

– Dr. Hong-Long Ji et al

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