Elevated Blood Viscosity is the Primary Cause of Thrombotic Complications of COVID-19
The high incidence of thrombosis in COVID-19 patients is caused by elevated blood viscosity due to hyperfibrinogenemia. 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. 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). 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.
Fibrinogen and other acute-phase reactants act like glue and foster erythrocyte aggregation. This increases blood viscosity exponentially at low shear (slow flow). 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.
As noted by the famous pathologist Rudolph Virchow in the 19th century, areas of sluggish blood flow are prone to thrombosis. Sluggish blood flow is simply a manifestation of increased blood viscosity. Shear-mediated endothelial production of antiplatelet molecules such as nitric oxide and prostacyclin is decreased in these areas. The influx of fibrinolytic activity and dilution of activated coagulation factors is also reduced.4
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. 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.5
For this reason, reducing blood viscosity should be a goal in preventing or treating thrombotic complications of viscosity in COVID-19. In addition to decreasing the propensity for thrombosis, reducing blood viscosity will increase oxygen delivery because perfusion is inversely proportional to 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.
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 pioneering hemorhologist Prof. Holger Schmid-Shoenbein envisioned the relationship of elevated blood viscosity to thrombosis like an accumulation of kindling in a forest. One spark is all that is necessary to set off a conflagration. Low molecular weight heparin will prevent the spark but will not remove the kindling.
The cause of the massive inflammation seen in COVID-19 is hyperstimulation of the innate immune system. 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). 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 thrombophilia in COVID-19 patients is aggravated by hypofibrinolysis. Investigators recently reported that a complete lack of fibrinolytic activity in thirty minutes on thromboelastography correlated with thrombotic events and the need for hemodialysis.9 This finding is explained by the depletion of plasmin. Like fibrinogen, alpha-2-macroglobulin is an acute phase reactant. Alpha-2-antiplasmin, the primary physiological inhibitor of plasmin activity, and alpha-2 macroglobulin are suicide inhibitors of plasmin, meaning they irreversibly bind it, forming a circulating complex which is removed by the mononuclear phagocyte system. For this reason, a drug with direct fibrinolytic activity such as nattokinase may be useful in thrombotic complications of COVID-19.10
Thrombotic complications of infectious disease and active immunization are well-described.11 COVID-19 is unusual because of the frequency with which they occur. This is because of the intense inflammatory response elicited by SARS-CoV-2 superimposed on chronically elevated blood viscosity. Appropriate therapies including plasmapheresis, administration of plasma, and therapeutic phlebotomy will reduce hyperviscosity, improve tissue perfusion and oxygenation, and reduce thrombotic complications.
1. Wise J. Covid-19 and thrombosis: what do we know about the risks and treatment? BMJ 2020;369:m2058
2. Maier CL, Truong AD, Auld SC, et al. COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia? The Lancet Published online May 25, 2020, https://doi.org/10.1016/ S0140-6736(20)31209-5
3. Rosenson RS, McCormick A, Uretz EF. Distribution of blood viscosity values and biochemical correlates in healthy adults. Clin Chem 1996; 42(8): 1189-95
4. Sloop GD, Pop G, Weidman JJ, St. Cyr JA. Why atherothrombosis is in principle a hematologic disease: the effect of disorders and drugs which affect thrombosis on the development of atherosclerotic plaques. Int Arch Cardiovasc Dis 2018, 2:012 DOI: 10.23937/iacvd-2017/1710012
5. Sloop GD, Weidman JJ, St. Cyr JA. Perspective: The systemic vascular resistance response: a cardiovascular response modulating blood viscosity with implications for primary hypertension and certain anemias. Ther Adv Cardiovasc Dis 2015; 9(6): 403-11 DOI: 10.1177/1753944715591450
6. Li Y, Chen M, Cao H, et al. Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response. Microbes Infect 2013; 15(2): 88-95
7. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet 2020; 395: 565–74
8. Giannis D, Ziogas IA, Gianni P. Coagulation Disorders in Coronavirus Infected Patients: COVID-19, SARS-CoV-1, MERS-CoV and Lessons from the Past. J Clin Virol 2020 Jun;127:104362. DOI: 10.1016/j.jcv.2020.104362. Epub 2020 Apr 9
9. Wright FL, Vogler TO, Moore EE, et al. Fibrinolysis Shutdown Correlates to Thromboembolic Events in Severe COVID-19 Infection. J Am Coll Surg doi.org/10.1016/j.jamcollsurg.2020.05.007
10. Chen H, McGowan EM, Ren N, et al. Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases. Biomarker Insights 2018 Jul 5;13:1177271918785130. DOI: 10.1177/1177271918785130. eCollection 2018
11. Sloop GD, De Mast Q, Pop GA, Weidman JJ, St. Cyr JA. The role of blood viscosity in infectious diseases. Cureus 12(2): e7090. DOI:10.7759/cureus.7090
Gregory D. Sloop, Associate Professor of Pathology, Idaho College of Osteopathic Medicine, firstname.lastname@example.org
Gheorghe A. Pop, retired cardiologist, Nijmegan, NL
Ralph Holsworth, emergency Room physician, Miners’ Colfax Medical Center, Raton, New Mexico
Joseph J Weidman, independent Researcher, Gaithersburg, Maryland
John A. St. Cyr, retired cardiothoracic surgeon
Competing interests: No competing interests