Plasmin could be the link between COVID-19 comorbidities and serious illness

September 02, 2020

BIRMINGHAM, Ala. - Why is the COVID-19 virus more dangerous in people with comorbidities?

Sadis Matalon, Ph.D., of the University of Alabama at Birmingham and colleagues in Texas and San Francisco asked that question in a hypothesis paper published online in Physiological Reviews. This study was made available online in March 2020 ahead of final publication in issue on July 1, 2020. They reviewed, in detail, research literature for comorbidities like hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease and kidney dysfunction, as well as many viral studies, studies of COVID-19 pathology and clinical presentation, and literature on the life-threatening acute respiratory distress syndrome.

Twelve days later, UAB Professor Emeritus Timothy Ness, M.D., Ph.D., posted plans on ClinicalTrials.gov for an exploratory COVID-19 outpatient study to test Matalon's hypothesis and prevent worse clinical outcomes.

In the Physiological Reviews paper, the researchers noted that all those comorbidities feature elevated levels of the extracellular protease plasmin. Plasmin is able to nick proteins at amino acid sequences called furin sites. For many viruses, this nicking at furin sites increases their infectivity. Both SARS and MERS -- the two virulent coronaviruses that are related to the COVID-19 virus -- "have evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population," the researchers wrote.

They noted that the COVID-19 virus, SARS-CoV-2, also has a furin site on its spike protein, the vital, viral protein for viral attachment to a lung cell. The researchers proposed that plasmin may cleave that furin site in the spike protein to increase its infectivity and virulence, and they hypothesized that, "the plasmin system may prove a promising therapeutic target for combating COVID-19."

Ness already knew there is an inexpensive, commonly used drug -- tranexamic acid, or TXA -- that targets plasmin by inhibiting its conversion from the inactive precursor, plasminogen, to the active protease, plasmin.

TXA is approved by the U.S. Food and Drug Administration for treatment of heavy menstrual bleeding because having lower plasmin levels allows better clotting. TXA has a long track record of safety and is commonly given off-label. At UAB Hospital, TXA is used perioperatively as a standard-of-care for orthopedic and cardiac bypass surgeries; it is commonly used for hemorrhaging trauma patients and also has been used for spinal surgery, neurosurgery and corrective jaw surgeries. It is currently being studied for perioperative use in Cesarean section surgeries.

For the clinical trial, Ness and colleagues have started a double-blind study, giving either TXA or a placebo pill to COVID-19 outpatients who were recently diagnosed with COVID-19. Patients also receive an anticoagulant. The overall goal of the exploratory study is to assess both safety and efficacy of five days of TXA versus placebo in the COVID-19 population. Enrollment is ongoing.

Ness and colleagues hypothesize that the TXA treatment will reduce the infectivity and virulence of the virus, as measured by reduced need for hospitalization within a week if a patient's condition deteriorates. Adults 19 years old and older are eligible, and all patients -- whether in the control group or the TXA group -- receive standard care as directed by their primary caretakers.
-end-
To learn more about the study, "TXA and Corona Virus 2019 (COVID19) in Outpatients," patients and physicians can contact Timothy Ness, M.D., Ph.D., at tness@uabmc.edu. Patients who have recently tested positive for COVID-19 can call 205-934-6777 to see if they qualify for the study.

Other principal investigators for the trial are Sonya Heath, M.D., professor in the UAB Department of Medicine Division of Infectious Diseases; and Brant Wagener, M.D., Ph.D., associate professor, and Sadis Matalon, Ph.D., distinguished professor, both in the UAB Department of Anesthesiology and Perioperative Medicine. Ness is professor emeritus in that department.

Authors of the Physiological Reviews paper, "Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility," are Hong-Long Ji and Runzhen Zhao, University of Texas Health Science Centre at Tyler; Michael A. Matthay, University of California, San Francisco; and Matalon.

Matalon says the paper has been widely noticed. "Since its publication online, it has been downloaded 26,565 times and cited 55 times," he said.

At UAB, Matalon holds the Alice McNeal, M.D., Endowed Chair in Anesthesiology, and he is a Distinguished Professor and vice chair for Research

University of Alabama at Birmingham

Related Coronary Heart Disease Articles from Brightsurf:

Women with coronary artery wall thickness at risk for heart disease
The thickness of the coronary artery wall as measured by MRI is an independent marker for heart disease in women, according to a new study.

E-cigarettes linked to heart attacks, coronary artery disease and depression
Concerns about the addictive nature of e-cigarettes -- now used by an estimated 1 out of 20 Americans -- may only be part of the evolving public health story surrounding their use, according to data being presented at the American College of Cardiology's 68th Annual Scientific Session.

Coronary calcium levels a better predictor of patients at risk for coronary heart disease
A new study presented at the American Heart Association Scientific Session conference found that testing a patient's coronary calcium levels is a better predictor of blocked coronary arteries at risk for a heart attack and the need for revascularization than standard risk-assessment equations used in medical practice today.

Coronary heart disease: DMP could be extended by two topics
Almost all health care aspects need to be updated. The already third search update for guidelines shows that their number and quality have increased notably in 10 years.

Learning about coronary heart disease from women
While many risk factors of CHD, such as smoking, high blood pressure and age, are common among men and women, some metabolic risk factors, such as being diabetic, are more strongly associated with increased risk of CHD in women than in men.

Cardiorespiratory fitness is essential to reduce risk of coronary heart disease
Coronary heart disease (CHD) is a leading cause of death for men in the US.

New study highlights smoking intensity in coronary heart disease risk
Increased relative risks for coronary heart disease (CHD) have long been associated with smoking, and traditionally they have been dependent on the number of cigarettes smoked a day, smoking intensities, and total exposure over time.

Pessimism associated with risk of death from coronary heart disease
Pessimism seems to be a strong risk factor for death from coronary heart disease, while optimism does not protect from it, according to a study published in the open-access journal BMC Public Health that involved 2,267 middle-aged and older Finnish men and women.

Study finds large decrease in coronary heart disease in US
The incidence of coronary heart disease in the US declined nearly 20 percent from 1983 to 2011, according to a study appearing in the Nov.

Americans are getting heart-healthier: Coronary heart disease decreasing in the US
Coronary heart disease is one of the leading causes of death in the United States.

Read More: Coronary Heart Disease News and Coronary Heart Disease Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.