A macrophage attack culminating in microthromboses characterizes COVID 19 pneumonia, 2021, Bull et al

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A macrophage attack culminating in microthromboses characterizes COVID 19 pneumonia
Brian S Bull, Karen L Hay

Introduction: A neutrophilic infiltrate characterizes bacterial pneumonia. Macrophage infiltration is similarly characteristic of the viral pneumonia caused by SARS-CoV-2. These infiltrating macrophages, while phagocytic and capable of engulfing virus laden alveolar cells, are also rich in tissue factor - a thromboplastin. This prothrombotic aspect likely explains how a respiratory virus whose malign effects should be confined to the oropharynx, bronchi and lungs, can cause a panoply of extra-pulmonary organ disorders.

Elevated ferritin levels in ICU Covid 19 patients, and elevated acute phase proteins suggest immune overreaction. Elevated d-dimers implicate clotting as well. This evidence links hyperactive innate immunity (macrophage lung infiltrates) with the elevated levels of oligomeric fibrin present in the bloodstream of these patients.

Methods: An in-house assay measuring oligomeric (soluble) fibrin (also referred to as soluble fibrin monomer complexes or SFMC) in whole blood, previously developed for monitoring incipient disseminated intravascular coagulation (DIC) during liver transplantation, was made available to COVID ICU attendings. Since SFMC constitutes the input to intravascular fibrin clots and d-dimer reflects fibrin clot dissolution, it was thought that the two tests, run in tandem along with assays of immune activation, might clarify the frequency and possibly the cause of DIC in patients with severe COVID-19 pneumonia.

Results: Classical DIC with intravascular clotting and thrombocytopenia was documented only rarely. However, early in the pandemic shortly after the assay was made available, it identified three patients undergoing acute defibrination. In each patient virtually all of the body's fibrinogen was transformed into SFMC over 3-4 days and deposited somewhere in the vasculature without any gross clots being detected.

Conclusions: Three COVID-19 patients with evidence of a hyperactive immune response (elevated ferritin and acute phase proteins) defibrinated while blood levels of SFMC were being monitored. SFMC levels that were five times higher than normal appeared in the circulation during the defibrination process. SFMC at these levels may precipitate as showers of microclots, damaging heart, kidney, brain, and so forth.

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This paper relates to acute Covid (but does mention long Covid) and suggests microclots are forming in the lungs, rather than generally in the circulation. They used techniques devised to evaluate the early graft vasculature in liver transplantation.

It has been unclear whether the amyloid microclots reported in long Covid patients are ex vivo artifacts or whether they are truly circulating in vivo. Evaluating clotting outside of the body is prone to artifact. Some quotes from the paper.

In COVID‐19 patients, microscopic clots occur throughout the body. It is not unreasonable to assume that this procoagulant production in the alveoli and the occlusion of capillary networks throughout the body by tiny clots, are related as to cause and effect. Most often, the presence of these extra‐pulmonary clots will not be detectable during life. That they exist, however, has been confirmed in living, ventilator‐dependent, COVID‐19 ICU patients. Eleven of 13 such patients (85%) demonstrated evidence of sublingual microvascular thrombi, with 31% showing completely stagnated capillaries. In three of these patients, an abrupt thromboembolic obstruction was captured on video as it occurred.

From this point on, the pathophysiology of COVID‐19 pneumonia is no longer primarily that of a viral disease; it is now largely that of a clotting disorder and we can confirm that quantities of molecular aggregates between short‐chain fibrin and native fibrinogen molecules known as soluble fibrin monomer complexes (SFMC) appear in the circulation of such patients.

As short‐chain fibrin molecules lengthen by polymerization, they become too long to remain in solution. It is microclots of this size—on the boundary between soluble and insoluble fibrin—that first appear. These microclots are far too small to be detected by routinely available, noninvasive, diagnostic techniques.

We report on three patients who developed extremely high levels of SFMC shortly after the assay became available. In each patient, virtually all of the body's fibrinogen was transformed into SFMC over a 3‐ to 4‐day period and deposited somewhere in the vasculature. We report measurement of these oligomeric fibrin molecules and document that the process of SFMC formation may result in whole body defibrination with- out macroclots being identified clinically.

Quantification of SFMC was performed as previously described. Briefly, citrated whole blood was drawn by trauma‐free venipuncture or through a central line after appropriate clearing. Samples were at all times maintained at 37°C.

The fact that SFMC is mostly soluble does not mean it is innocuous. If fragile microclots are forming and dissolving throughout the circulation, then fragile microclots may temporarily occlude random portions of the microvasculature throughout the body.