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

Date:
September 2, 2020
Source:
University of Alabama at Birmingham
Summary:
A drug that inhibits the protease plasmin is hypothesized to reduce
the infectivity and virulence of the virus, as measured by reduced
need for hospitalization within a week.



FULL STORY ==========================================================================
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.

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.


========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeff
Hansen. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hong-Long Ji, Runzhen Zhao, Sadis Matalon, Michael
A. Matthay. Elevated
Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility.

Physiological Reviews, 2020; 100 (3): 1065 DOI: 10.1152/
physrev.00013.2020 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200902131911.htm

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