The thrombophilia in COVID-19 patients is aggravated by hypofibrinolysis. Stimulation of the TLR8 pathway upregulates cytokine synthesis, including interleukin 6, which stimulates hepatic synthesis of acute-phase reactants, including fibrinogen.6 Hyperstimulation of this pathway results in a cytokine storm and extreme hyperfibrinogenemia. The genome of SARS-CoV, a single-stranded RNA virus, contains an extraordinarily high number of segments rich in guanine (G) and uracil (U).6 The genome of SARS-CoV-2 is 79% similar to SARS-CoV.7 SARS-CoV also causes cytokine storm and thrombotic complications, but at a lower frequency than COVID-19.8 GU-rich single-strand RNA fragments are the ligand for Toll-like receptor 8 (TLR8). The cause of the massive inflammation seen in COVID-19 is hyperstimulation of the innate immune system. Low molecular weight heparin will prevent the spark but will not remove the kindling. One spark is all that is necessary to set off a conflagration. Holger Schmid-Shoenbein envisioned the relationship of elevated blood viscosity to thrombosis like an accumulation of kindling in a forest. Plasmapheresis to reduce the level of acute-phase proteins, dilution with plasma or therapeutic phlebotomy (300-400 cc) are therapeutic options to reduce blood viscosity. The low oxygen saturations in COVID-19 patients might well be due to reduced tissue perfusion caused by high blood viscosity due to high concentrations of acute-phase reactants superimposed on a hematocrit which is inappropriately high for this intense inflammatory state. In addition to decreasing the propensity for thrombosis, reducing blood viscosity will increase oxygen delivery because perfusion is inversely proportional to blood viscosity. This is probably because these patients have elevated baseline blood viscosity.4 The acute phase reaction to COVID-19 superimposed on chronically elevated blood viscosity results in extreme elevations of blood viscosity because these patients have not had sufficient time to develop compensatory anemia, the “anemia of chronic disease or inflammation,” which is a homeostatic response to reduce blood viscosity caused by inflammation.5įor this reason, reducing blood viscosity should be a goal in preventing or treating thrombotic complications of viscosity in COVID-19. Males, smokers, those over age 65, and those with chronic obstructive pulmonary disease, hyperlipidemia, and diabetes have an increased risk of thrombotic complications of COVID-19. The influx of fibrinolytic activity and dilution of activated coagulation factors is also reduced.4 Shear-mediated endothelial production of antiplatelet molecules such as nitric oxide and prostacyclin is decreased in these areas. Sluggish blood flow is simply a manifestation of increased blood viscosity. Areas of low shear occur naturally in veins and in areas of changing arterial geometry, such as branches, curves, and dilatations, making these vascular regions prone to thrombosis.4 Blood viscosity is a more sensitive marker than plasma viscosity for the risk of thrombosis because it reflects changes caused by hemoconcentration and intrinsic erythrocyte abnormalities.Īs noted by the famous pathologist Rudolph Virchow in the 19th century, areas of sluggish blood flow are prone to thrombosis. This increases blood viscosity exponentially at low shear (slow flow). All patients with plasma viscosity > 3.5 cP had thrombosis.2 For comparison, normal whole blood viscosity at a high shear rate (100/s) is 3.26 ± 0.43 cP.3 Thus, blood viscosity has the potential to be extraordinarily high in COVID-19 patients.įibrinogen and other acute-phase reactants act like glue and foster erythrocyte aggregation. A recent report of 15 critically ill COVID-19 patients showed all had elevated plasma viscosity, ranging from 1.9 to 4.2 centipoise (cP) (normal range: 1.4-1.8 cP). As noted recently in BMJ, fibrinogen concentrations can be extraordinarily high in severe COVID-19, reaching 10-14 g/L.1 This is reflected in the markedly increased plasma viscosity of COVID-19 patients. The high incidence of thrombosis in COVID-19 patients is caused by elevated blood viscosity due to hyperfibrinogenemia.
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