Blood viscosity is increased by elevated concentrations of acute phase reactants and hypergammaglobulinemia in inflammation. These increase blood viscosity by increasing plasma viscosity and fostering erythrocyte aggregation. Blood viscosity is also increased by decreased erythrocyte deformability, as occurs in malaria. Increased blood viscosity contributes to the association of acute infections with myocardial infarction (MI), venous thrombosis, and venous thromboembolism. It also increases vascular resistance, which decreases tissue perfusion and activates stretch receptors in the left ventricle, thereby initiating the systemic vascular resistance response. This compensates for the increased vascular resistance by vasodilation, lowering hematocrit, and decreasing intravascular volume. This physiological response causes the anemias associated with malaria, chronic inflammation, and other chronic diseases. Since tissue perfusion is inversely proportional to blood viscosity, anemia may be beneficial as it increases tissue perfusion when erythrocyte aggregating factors or erythrocytes with decreased deformability are present in the blood.

The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities. Accordingly, the risk of turbulence, which is dictated by the Reynolds and Dean numbers, also varies. Relatively high blood viscosity is needed to prevent turbulence in the left ventricle and aorta, where high-velocity blood changes direction several times. Low blood viscosity is needed in the capillaries, where erythrocytes pass through vessels with a diameter smaller than their own. In addition, higher blood viscosity is necessary when the cardiac output and peak blood velocity increase as a part of a sympathetic response or anemia, which occurs following significant hemorrhage. Blood viscosity, as reflected in systemic vascular resistance and vascular wall shear stress, is sensed, respectively, by cardiomyocyte stretching in the left ventricle and mechanoreceptors for wall shear stress in the carotid sinus. By controlling blood volume and red blood cell mass, the renin-aldosterone-angiotensin system and the systemic vascular resistance response control the hematocrit, the strongest intrinsic determinant of blood viscosity. These responses provide gross control of blood viscosity. Fine-tuning of blood viscosity in transient conditions is provided by hormonal control of erythrocyte deformability. The short half-life of some of these hormones limits their activity to specific vascular beds. Hormones that modulate blood viscosity include erythropoietin, angiotensin II, brain natriuretic factor, epinephrine, prostacyclin E2, antidiuretic hormone, and nitric oxide.

A 76-year-old female followed closely for five years with IgM monoclonal gammopathy of uncertain significance developed anemia, worsened plasma creatinine concentration, and markedly elevated serum viscosity. This case illustrates the scope of pathology that can be caused by elevated blood viscosity. Our patient's anemia was a homeostatic response to normalize systemic vascular resistance and resulted from activation of the systemic vascular resistance response. The elevated plasma creatinine resulted from decreased renal perfusion because of elevated blood viscosity. Recent insights in hemorheology (the study of blood flow) are discussed, namely the recent identification of preferential blood flow patterns and erythrocyte autoregulation of deformability. These insights confirm that blood viscosity is part of the "milieu intérieur."

Viscosity is inversely related to temperature. The circulatory system of Antarctic icefish may have been designed to prevent high blood viscosity at low temperatures by taking advantage of the increased solubility of oxygen at low temperatures, allowing use of hemoglobin-free blood. This necessitates a high-output, high-velocity, low-pressure, low-resistance circulation. High-velocity flow requires adequate viscosity to minimize loss of laminar flow and increased friction. This creates an interesting design problem: in other animals, hemoglobin determines blood viscosity via the hematocrit, whereas in icefish, blood viscosity is produced largely by antifreeze glycoproteins. The effect of inappropriate blood viscosity on maximal cardiac output is seen in experiments with a related fish, Pagothenia borchgrevinki . In this species, acclimation to a particular temperature involves tailoring blood viscosity to cardiac power, which varies with the availability of oxygen and temperature. The factorial scope for cardiac output—i.e., the ratio of maximal to basal cardiac output—is greater in acclimated than unacclimated fish despite the similar availability of oxygen. Experiments also suggest that blood viscosity determines the maximum tolerable temperature in Antarctic fish. Those experiments demonstrate that blood viscosity is actively controlled. It is part of what the physiologist Claude Bernard called the milieu intérieur . The hemoglobinless phenotype requires simultaneous customization of the heart, vasculature, and blood, including its viscosity

BackgroundThe copy number of the oligonucleotide 5'-purine-uridine-uridine-purine-uridine-3' (purUUpurU) motif in a viral genome was previously shown to correlate with the severity of acute illness. This study aimed to determine whether purUUpurU content correlates with virulence in other single-strand RNA (ssRNA) viruses that vary in clinical severity.MethodologyWe determined the copy number of purUUpurU in the genomes of two subtypes of human respiratory syncytial virus (RSV), respiratory syncytial virus A (RSV-A), and respiratory syncytial virus B (RSV-B), which vary in clinical severity. In addition, we determined the purUUpurU content of the four ebolaviruses that cause human disease, dengue virus, rabies virus, human rhinovirus-A, poliovirus type 1, astrovirus, rubella, yellow fever virus, and measles virus. Viral nucleotide sequence files were downloaded from the National Center for Biotechnology Information (NCBI)/National Institutes of Health website. In addition, we determined the cumulative case fatality rate of 20 epidemics of the Ebola virus and compared it with that of the other human ebolaviruses.ResultsThe genomic purUUpurU content correlated with the severity of acute illness caused by both subtypes of RSV and human ebolaviruses. The lowest purUUpurU content was in the genome of the rubella virus, which causes mild disease.ConclusionsThe quantity of genomic purUUpurU is a virulence factor in ssRNA viruses. Blood hyperviscosity is one mechanism by which purUUpurU causes pathology. Comparative quantitative genomic analysis for purUUpurU will be helpful in estimating the risk posed by emergent ssRNA viruses.

Background Coronavirus disease 2019 (COVID-19) can be associated with pathologic inflammation. The authors hypothesize that a high copy number of a purine-uridine-rich nucleotide motif is present in the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hyperactivates innate immunity. Methods The number of purine-uridine-uridine-purine-uridine (purUUpurU) motifs was counted in the genomes of SARS-CoV-2 and other single-strand RNA viruses. The nucleotides of SARS-CoV-2 in random order were used as a control. Results PurUUpurU occurred 2.8 times more often in the actual SARS-CoV-2 genome than the randomized genome. The number of purUUpurU motifs correlates with the potential severity of acute illness caused by these viruses, except for influenza A. Conclusion The large number of purUUpurU in SARS-CoV-2 may hyperactivate innate immunity, potentially causing the markedly increased concentrations of cytokines, acute phase reactants, and blood viscosity that can be seen in COVID-19.

Many of the complications of severe coronavirus disease-2019 (COVID-19) are caused by blood hyperviscosity driven by marked hyperfibrinogenemia. This results in a distinctive hyperviscosity syndrome which affects areas of high and low shear. A change in blood viscosity causes a threefold inverse change in blood flow, which increases the risk of thrombosis in both arteries and veins despite prophylactic anticoagulation. Increased blood viscosity decreases perfusion of all tissues, including the lungs, heart, and brain. Decreased perfusion of the lungs causes global ventilation-perfusion mismatch which results in silent hypoxemia and decreased efficacy of positive pressure ventilation in treating pulmonary failure in COVID-19. Increased blood viscosity causes a mismatch in oxygen supply and demand in the heart, resulting in myocarditis and ventricular diastolic dysfunction. Decreased perfusion of the brain causes demyelination because of a sublethal cell injury to oligodendrocytes. Hyperviscosity can cause stasis in capillaries, which can cause endothelial necrosis. This can lead to the rarefaction of capillary beds, which is noted in "long-COVID." The genome of the virus which causes COVID-19, severe acute respiratory syndrome coronavirus 2, contains an extraordinarily high number of the oligonucleotide virulence factor 5'-purine-uridine-uridine-purine-uridine-3', which binds to toll-like receptor 8, hyperactivating innate immunity. This can lead to a marked elevation in fibrinogen levels and an increased prevalence of neutrophil extracellular traps in pulmonary failure, as seen in COVID-19 patients.

Inflammation causes hyperviscosity. This phenomenon is fully expressed in coronavirus 2019. The cardiac complications of coronavirus 2019 are most commonly caused by hyperviscosity, not viral invasion of endothelial cells or cardiomyocytes. This hyperviscosity is caused by high concentrations of acute phase reactants, especially fibrinogen, and immunoglobins. These increase erythrocyte aggregation which causes sludging of blood in areas of low shear in the coronary circulation, veins and microvasculature. This can lead to thrombosis. Coronary thrombosis occurs in association with several infectious diseases and even immunization. In the early twentieth century, Osler noted right ventricular dilation, a common complication of coronavirus 2019, in response to hyperviscosity caused by infection. Perfusion is inversely proportional to blood viscosity. Diastolic dysfunction, another common complication of coronavirus 2019, is a consequence of this hypoperfusion. Therapeutic plasmapheresis is the therapy of choice for reducing blood viscosity and restoring normal perfusion. All tissues are underperfused when blood viscosity is elevated. This reduces delivery of metabolic substrates needed to maintain cellular function. Post-covid syndrome may be the result of torpid recovery after prolonged hypoperfusion. D-ribose is a versatile metabolic substrate which may hasten improvement of post-inflammatory illness.

Blood viscosity is increased by elevated concentrations of acute phase reactants and hypergammaglobulinemia in inflammation. These increase blood viscosity by increasing plasma viscosity and fostering erythrocyte aggregation. Blood viscosity is also increased by decreased erythrocyte deformability, as occurs in malaria. Increased blood viscosity contributes to the association of acute infections with myocardial infarction (MI), venous thrombosis, and venous thromboembolism. It also increases vascular resistance, which decreases tissue perfusion and activates stretch receptors in the left ventricle, thereby initiating the systemic vascular resistance response. This compensates for the increased vascular resistance by vasodilation, lowering hematocrit, and decreasing intravascular volume. This physiological response causes the anemias associated with malaria, chronic inflammation, and other chronic diseases. Since tissue perfusion is inversely proportional to blood viscosity, anemia may be beneficial as it increases tissue perfusion when erythrocyte aggregating factors or erythrocytes with decreased deformability are present in the blood.

Apolipoprotein(a) [apo(a)] is an apolipoprotein unique to lipoprotein(a) [Lp(a)]. Although it has no known function, Lp(a) is a risk factor for accelerated atherothrombosis. We hypothesize that LPA, the gene which encodes apo(a), is a heretofore unrecognized unprocessed pseudogene created by duplication of PLG, the gene which encodes plasminogen. Unprocessed pseudogenes are genes which were created by duplication of functional genes and subsequently lost function after acquiring various mutations. This hypothesis explains many of the unusual features of Lp(a) and apo(a). Also, this hypothesis has implications for the therapy of elevated Lp(a) and atherothrombosis theory. Because apo(a) is functionless, the diseases associated with elevated levels of Lp(a) are due to its impact on blood viscosity.

The authors hypothesize that thrombosis causes both the complications of atherosclerosis as well as the underlying lesion, the atherosclerotic plaque. Atherosclerotic plaques develop from the organization of mural thrombi. In this process, circulating progenitor cells trapped within the thrombus differentiate into myofibroblasts which synthesize collagen, and endothelial cells which form granulation tissue. Eventually, all or most of the thrombus is replaced by collagen. Thus, conditions and drugs which affect thrombosis also affect the development of atherosclerotic plaques, i.e., atherogenesis.

Deaths due to atherothrombosis are increasing throughout the world except in the lowest socio-demographic stratum. This is despite 60 years of study and expenditure of billions of dollars on lipid theory. Nevertheless, mainstream atherothrombosis theory persists even though it has failed numerous tests. Contrary data are ignored, consistent with the practice of science as envisioned by Thomas Kuhn. This paper examines defects in mainstream atherogenesis theory and the flawed logic which allows its persistence in the face of what should be obvious shortcomings.

The authors hypothesize that thrombosis causes both the complications of atherosclerosis as well as the underlying lesion, the atherosclerotic plaque, which develops from the organization of mural thrombi. These form in areas of slow blood flow, which develop because of flow separation created by changing vascular geometry and elevated blood viscosity. Many phenomena typically ascribed to inflammation or "chronic oxidative stress", such as the development of fatty streaks, "endothelial dysfunction," "vulnerable plaques," and the association of mild elevations of C-reactive protein and cytokines with atherothrombosis are better explained by hemorheologic and hemodynamic abnormalities, particularly elevated blood viscosity. Elevated blood viscosity decreases the perfusion of skeletal muscle, leading to myocyte expression of the myokine IL-6, decreased glucose uptake, insulin resistance, hyperglycemia, and metabolic syndrome. The hyperfibrinogenemia and hypergammaglobulinemia present in true inflammatory diseases foster atherothrombosis by increasing blood viscosity.

The authors hypothesize that consumption of interesterified fats may be the cause of the continuous increase in cardiovascular deaths in the United States which began in 2011. Interesterification is a method of producing solid fats from vegetable oil and began to supplant partial hydrogenation for this purpose upon recognition of the danger of trans fats to cardiovascular health. Long, straight carbon chains, as are present in saturated and trans fatty acids, decrease the fluidity of the erythrocyte cell membrane, which decreases erythrocyte deformability and increases blood viscosity. This decrease in cell membrane fluidity is caused by increased van der Waals interactions, which also solidify dietary fats. Elevated blood viscosity is favored as the pathogenic mechanism by which trans fats increase cardiovascular mortality because changes in lipoprotein levels do not account for all the mortality attributable to their consumption. The rapid changes in cardiovascular mortality noted with the introduction and withdrawal of trans fats from the food supply are reviewed. The evidence implicating elevated blood viscosity in cardiovascular disease is also reviewed. Data regarding the production and consumption of interesterified fats in the US should be released in order to determine if there is an association with the observed increase in cardiovascular deaths.

Uric acid may be a risk factor for atherosclerotic cardiovascular disease, although the data conflict and the mechanism by which it may cause cardiovascular disease is uncertain. This study was performed to test the hypothesis that uric acid, an anion at physiologic pH, can cause erythrocyte aggregation, which itself is associated with cardiovascular disease. Normal erythrocytes and erythrocytes with a positive direct antiglobulin test for surface IgG were incubated for 15 minutes in 14.8 mg/dL uric acid. Erythrocytes without added uric acid were used as controls. Erythrocytes were then examined microscopically for aggregation. Aggregates of up to 30 erythrocytes were noted when normal erythrocytes were incubated in uric acid. Larger aggregates were noted when erythrocytes with surface IgG were incubated in uric acid. Aggregation was negligible in controls. These data show that uric acid causes erythrocyte aggregation. The most likely mechanism is decreased erythrocyte zeta potential. Erythrocyte aggregates will increase blood viscosity at low shear rates and increase the risk of atherothrombosis. In this manner, hyperuricemia and decreased zeta potential may be risk factors for atherosclerotic cardiovascular disease.

Overview It is rare in the field of cardiovascular medicine that new data cause a rapid or decisive change in mainstream clinical practice, let alone one’s thought process. The failure of antioxidant supplementation to clearly impact cardiovascular disease [Vivekananthan et al. 2003] has not caused any decreased interest in their daily use for chronic oxidative stress. Besides this attention for a possible role in oxidative stress, other markers have continued to be explored for potential relationships in the development of cardiovascular disease. For example, continued interest in homocysteine as a risk factor for atherosclerosis persists, despite conflicting data. Likewise, it could be considered unusual that the failure of two inhibitors of cholesteryl ester transfer protein might have a positive impact in atherosclerotic cardiovascular disease. Despite significantly increasing serum high-density lipoprotein (HDL) levels by these inhibitors, there was generated doubt not only on the theory of ‘reverse cholesterol transport’, but also on 40 years of epidemiologic data suggesting that HDL protects against atherosclerosis. In 2013, the National Lipid Association concluded that HDL is not a therapeutic target at present [Toth et al. 2013].

Normal aortic compliance allows cardiac output to be distributed throughout the cardiac cycle, resulting in lower peak blood velocity. Loss of compliance with aging, hypertension, and possibly other risk factors for atherosclerosis increases peak blood velocity, creating eddy currents in areas of changing vascular geometry, as well as creating adverse patterns of diastolic flow. In the resulting areas of low flow, increased blood viscosity creates the potential for thrombosis. Occlusive thrombi may cause death; parietal or mural thrombi may organize to form atherosclerotic plaques.