Three words are essential to science. Three words were missing from our leaders and pundits over the past thirty months. Three words inform patients of integrity. Those words: I Don’t Know.
During this crisis, it was easy for experts to pontificate about their knowledge of information about past phenomena. In many ways, this led to the belief that this information was predictive of the days and months ahead. As news media and governmental officials salivated for a drop of information that might help them understand the crisis, public health officials failed to inform them of the most important concept in the field of medicine and, more specifically, public health, uncertainty. As Michael Osterholm said in a recent California state Senate hearing, the three most important words he uses are: I Don’t Know.
Looking back over the past 24 months in assessing many of our public health authority’s responses as well as press conferences and interviews, the general public was given information constantly, and it was given with the certainty as if the sun was going to rise tomorrow. However, very few of our authorities attempted to transmit the certainty, validity, or reproducibility of this information.
Most of what was being relayed and broadcast was nothing more than consensus opinion or, for that matter, outright conjecture. Amid a crisis, especially with the outbreak of an entirely new disease, it is to be expected that much of the response is opinion based, and even with ‘expert’ modeling, the results are always just speculation. The problem lies in failing to communicate the truth, which is, that we don’t know.
In SARS-CoV-2-infected humans, disease progression is often associated with acute respiratory distress syndrome involving severe lung injury, coagulopathy, and thrombosis of the alveolar capillaries. The pathogenesis of these pulmonary complications in COVID-19 patients has not been elucidated. Autopsy study of these patients showed SARS-CoV-2 virions in pulmonary vessels and sequestrated leukocytes infiltrates associated with endotheliopathy and microvascular thrombosis. Since SARS-CoV-2 enters and infects target cells by binding its spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2), and there is evidence that vascular endothelial cells and neutrophils express ACE2, we investigated the effect of S-proteins and cell–cell communication on primary human lung microvascular endothelial cells (HLMEC) and neutrophils expression of thrombogenic factors and the potential mechanisms. Using S-proteins of two different SARS-CoV-2 variants (Wuhan and Delta), we demonstrate that exposure of HLMEC or neutrophils to S-proteins, co-culture of HLMEC exposed to S-proteins with non-exposed neutrophils, or co-culture of neutrophils exposed to S-proteins with non-exposed HLMEC induced transcriptional upregulation of tissue factor (TF), significantly increased the expression and secretion of factor (F)-V, thrombin, and fibrinogen and inhibited tissue factor pathway inhibitor (TFPI), the primary regulator of the extrinsic pathway of blood coagulation, in both cell types. Recombinant (r)TFPI and a thiol blocker (5,5′-dithio-bis-(2-nitrobenzoic acid)) prevented S-protein-induced expression and secretion of Factor-V, thrombin, and fibrinogen. Thrombomodulin blocked S-protein-induced expression and secretion of fibrinogen but had no effect on S-protein-induced expression of Factor-V or thrombin. These results suggests that following SARS-CoV-2 contact with the pulmonary endothelium or neutrophils and endothelial–neutrophil interactions, viral S-proteins induce coagulopathy via the TF pathway and mechanisms involving functional thiol groups. These findings suggest that using rTFPI and/or thiol-based drugs could be a viable therapeutic strategy against SARS-CoV-2-induced coagulopathy and thrombosis. View Full-Text