The Washington Post today ran a piece entitled Young and middle aged people, barely sick with COVID-19, are dying from strokes.

“Doctors sound alarm about patients in their 30s and 40s left debilitated or dead. Some didn’t even know they were infected.”

From the article: Sherry H-Y Chou, an intensive care physician, said “one question is whether the clotting is because of a direct attack on the blood vessels, or ‘a friendly-fire problem’ caused by the patient’s immune response.”

“In your body’s attempt to fight off the virus, does the immune response end up hurting your brain?” she asked.

Good question indeed.

Why does this happen? Why does COVID-19 cause blood clotting that leads to strokes and heart attacks, and pulmonary emboli?

COVID-19 causes a marked inflammatory response. As Chou alludes in the Washington Post article, it is well established that inflammation and blood clotting go together. This is why neurologists worried about strokes, and cardiologists worried about heart attacks in their patients measure C-reactive protein (CRP), an inflammatory biomarker. Higher CRP levels in the blood are associated with increased risk for having a heart attack.

What are the evolutionary explanations for why clotting and inflammation are linked?

One clue comes from the horseshoe crab. From Fiusa et al (2015):

“Evidence that hemostasis and inflammation evolved from a single-triggered mechanism can be traced back more than 450 million years, based on studies with the horseshoe crab (Limulus polyphemus)”

The Horseshoe Crab

The horseshoe crab  is a phylogenetically ancient arthropod that has an open circulatory system within its hard exoskeleton. Injury to the exoskeleton of Limulus causes both the loss of internal fluids and provides a site of entry for pathogens. Limulus responds to injury by activating its sole blood element – the hemocyte – inducing both phagocytosis and the initiation of clotting. Coagulation initiates repair of the damaged exoskeleton. Clotting also is a host defense against pathogens in the injured area. They become sealed away from the remainder of the open circulation. The hemocyte also phagocytoses pathogens thus trapped. This evolutionary legacy has echoes in the innate immune system of vertebrates. Vertebrates – while having separate cellular elements for clotting and phagocytosis – still often activate both systems at the same time.

Pathogens activate the hemocyte in Limulus, a feature that makes horseshoe crab blood useful for test kits used in biomedicine to detect lipopolysaccharide, (LPS)  the cell wall building block in gram negative bacteria, e.g. E. coli. In vertebrates, LPS also triggers the toll-like factor 4 and the inflammatory transcription factor NF-kappa B, which then activates clotting, and innate immune activation.

Invading pathogens trigger clot formation which promotes pathogen clearance in a process that Andrew Brainard and I termed “hemostatic containment.”

From Fiusa et al 2015

Pathogens, including bacteria, viruses, and even malignant cells, trigger hemostatic containment. As we proposed as part of the hemostatic containment hypothesis, clotting not only prevents blood loss, it also has an anti-infection function.

In line with this framework, lethal viruses also trigger blood clotting that carry benefits (pathogen clearance) and serious costs (strokes, heart attacks, and pulmonary emboli). Natural selection would have been expected to maximize the those benefits and minimize costs. The evolutionary calculus does not always result in the best outcomes, as we see in those unfortunate COVID-19 patients suffering strokes. Does this mean that all COVID patients should be anticoagulated? Possibly. But we do not know.  Many hospitalized patients are indeed anticoagulated, and powerful clot-busting fibrinolytic drugs have been used for those critically ill with COVID-19 on ventilators. We assume these interventions help. But we should be clear eyed about the possibility of unintended consequences of these medicines, and they should ideally be tested in a randomized controlled trial.

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine