One of the extraordinary medical aspects of the COVID-19 pandemic is the high rate of blood clotting in critically ill patients. In one study, blood clots, or more properly “thrombi,” developed in 49% of patients in intensive care units. Clotting in COVID-19 is also unusual because it occurs in younger patients and despite the preventative measures which had largely controlled abnormal clotting in intensive care units prior to COVID-19.
As evidenced by Ebola and dengue, bleeding, not clotting, was the most common blood problem in severe viral infections before COVID-19. Clotting by viruses mainly occurred in science fiction books like The Andromeda Strain. COVID-19 also perplexed physicians with unusual syndromes like “silent hypoxemia,” also referred to as “silent hypoxia,” and “complete fibrinolysis shutdown.” Physicians were nonplused by COVID-19, like Bones whenever his patient was a nonhuman.
These complications of COVID-19 are caused by an unappreciated feature of extreme immune responses, thickened blood. The virtually unprecedented magnitude of the immune response in some COVID-19 patients thickens their blood so that its flow slows and focally stops. Anyone who has seen blood clot in a test tube knows blood needs to flow to remain fluid. Our group has studied the role of thickened blood in infectious diseases.
The technical term for the thickness of fluid is “viscosity.” Honey is more viscous than water.
If the viscosity of motor oil in a car is too high, the engine may have difficulty turning over in winter. The risk of clotting caused by increased blood viscosity has been likened to the accumulation of deadwood in a forest. Preventing a spark decreases the risk of a conflagration, but normalizing the risk requires removing the deadwood. Preventative measures in intensive care units decrease the risk of clotting, but the risk remains elevated until blood viscosity is reduced.
Fluids thicken as more molecules are dissolved in them. Muddy water is thicker and more viscous than tap water. The cause of increased blood viscosity is COVID-19 is astronomical elevations of molecules produced in response to infection and trauma called “acute phase reactants.” One of the most prominent of these is fibrinogen, a molecule that helps stop bleeding.
In COVID-19, fibrinogen concentrations increase five-fold or more, levels that would qualify for a world record if medical nonpareils were cataloged. Consequently, the viscosity of plasma, the liquid part of blood, can be greater than normal whole blood viscosity, which includes the contributions of its solid components to total viscosity. Red blood cells are the major solid parts in blood and normally constitute about 40% of blood volume.
Elevations of plasma viscosity of this degree are also unprecedented in my experience. Recently, a study has shown that plasma viscosity which is greater than that of normal whole blood is always associated with clotting. Although blood viscosity was not measured in that study, the presence of red blood cells would necessarily make it much higher than plasma viscosity, probably to a life-threatening degree.
Blood clotting in COVID-19 most commonly occurs in the legs and is called “deep vein thrombosis.” This can cause sudden death if the clot detaches and blocks blood flow to the lungs, which is called pulmonary embolism. Thrombosis of the arteries supplying the brain causes a stroke. Thrombosis of the coronary arteries causes a heart attack. All are seen in COVID-19.
Health is like a fabric woven from a warp of actions and a weft of reactions, both intended to maintain the status quo. In coagulation, the process of forming a clot or thrombus, one molecule cleaves fibrinogen to form fibrin, the molecule which forms the clot. Other molecules dissolve fibrin and eliminate the clot. Still other molecules inhibit that reaction.
One of these is another acute-phase reactant, alpha-2-macroglobulin. Like a bee that can only sting once, alpha-2 macroglobulin is a “suicide inhibitor” of the most important molecules which dissolve fibrin, irreversibly inactivating both. Eventually, the supply of molecules capable of dissolving a clot is exhausted, resulting in another unusual syndrome, complete fibrinolysis shutdown. Without intervention, thrombosis is inevitable at that point.
To physicians, perhaps the scariest syndrome seen in COVID-19 is silent hypoxemia. In this syndrome, patients present with exceptionally low oxygen concentrations in their blood, i.e., hypoxemia, but have no idea of how sick they are. Incredibly, patients don’t feel short of breath or the accompanying distress and anxiety. Before COVID-19, hypoxemia in a conscious patient was always associated with dyspnea, the reflex perception of labored, difficult breathing. Being a reflex, it probably occurred to very few that hypoxemia without dyspnea was even possible.
Silent hypoxemia alarms physicians because the lack of distress may cause patients to present later than they otherwise might. Also, it is unsettling when a symptom that was perceived to be as reliable as sunrise is revealed to be less so for reasons which were not immediately obvious.
Silent hypoxemia is also caused by increased blood viscosity. It decreases blood flow through the lungs, decreasing oxygen uptake. The nerves which cause reflex dyspnea fire when blood flow to the lungs increases, not decreases. Only when the work of breathing increases because of pneumonia or fluid in the lungs causes these nerves to fire do patients feel dyspnea. Just as importantly, elevated blood viscosity decreases oxygen (and glucose) delivery to the entire body.
The cause of the extreme immune response in COVID-19 is the unique genetic code of SARS-CoV-2, its cause. Its code contains an extraordinary number of pairings of the molecules guanine and uracil. This sequence stimulates an inflammatory pathway that elevates concentrations of certain cytokines, a type of inflammatory molecule.
Profound stimulation of this pathway causes another aspect of the extreme immune responses in COVID-19, “cytokine storm syndrome” which first received media attention when the introduction of superabsorbent tampons resulted in toxic shock syndrome in the 1970s. One of these cytokines signals the liver to manufacture fibrinogen and other acute phase reactants, causing the astounding elevations in COVID-19.
It appears that one unusual syndrome in COVID-19, “COVID toes,” cannot be explained solely by elevated blood viscosity. The cause of this condition, called “chilblains” when it develops after exposure to cold, is not understood. It can develop because of mutations in genes involved in a different inflammatory pathway which is activated by inflammatory molecules called “interferons.” The concentration of these is also increased in viral infections.
COVID-19 has challenged physicians in the front lines more than any viral illness since AIDS. Regarding the unusual presentations of COVID-19, Yale School of Medicine cardiologist Harlan Krumholz, M.D. said “Our ignorance is profound.” Much of this mystery stems from ignoring blood viscosity. Because blood viscosity is inversely related to blood flow, elevated blood viscosity increases the risk of clotting and causes hypoxemia. AIDS spurred medical science to advance, as will COVID-19.