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Abstract

Without an active regulatory feedback loop, increased blood viscosity could lead to a vicious cycle of ischemia, increased erythropoiesis, further increases of blood viscosity, decreased tissue perfusion with worsened ischemia, further increases in red cell mass, etc. We suggest that an increase in blood viscosity is detected by mechanoreceptors in the left ventricle which upregulate expression of cardiac natriuretic peptides and soluble erythropoietin receptor. This response normalizes systemic vascular resistance and blood viscosity at the cost of producing ‘anemia of chronic disease or inflammation’ or ‘hemolytic anemia’ both of which are better described as states of compensated hyperviscosity. Besides its role in disease, this response is also active in the physiologic adaptation to chronic exercise. Malfunction of this response may cause primary hypertension.

Keywords

anemia blood viscosity cardiac mechanoreceptor erythrocyte deformability exercise adaption systemic vascular resistance

Introduction: why is control of blood viscosity necessary?

Hematocrit is the most powerful determinant of blood viscosity. Because blood viscosity is inversely proportional to perfusion, it is not surprising that the median survival of untreated polycythemia vera, a neoplastic proliferation of erythrocytes in which hematocrit is routinely increased to around 60%, is only 1.5–3 years, far worse than patients with primary hypertension or hypercholesterolemia. Blood viscosity is so important that a regulatory mechanism to normalize it over a range of hematocrits has evolved. Because blood viscosity is a determinant of systemic vascular resistance, this homeostatic pathway is referred to as the systemic vascular resistance response. This response can be envisioned as the long-term counterpart of the Frank–Starling reflex, in which changes in end diastolic volume cause beat to beat variation in cardiac output, for example, as in response to a premature ventricular contraction. We envision that the systemic vascular resistance response exerts its effect systemically and over the long term, given the lifespan of erythrocytes (100–120 days).

The systemic vascular resistance response also compliments the activity of the vasodilator nitric oxide, which at physiologic levels acts locally, given its short half life (seconds in the presence of hemoglobin) [Hakim et al. 1996]. Upregulation of endothelial nitric oxide production by increased shear stress is the most important factor in flow-mediated vasodilation, which will decrease vascular resistance [Paniagua et al. 2001]. In health, nitric oxide is generally synthesized by low-output pathways which produce enough nitric oxide to maintain homeostasis by matching blood vessel caliber with blood flow [Young, 2004]. However, endothelial nitric oxide production can be upregulated to the point that the resulting vasodilation will cause a paradoxical decrease in blood pressure despite modestly increased hematocrit and blood viscosity [Martini et al. 2005; Salazar Vasquez et al. 2011]. In certain conditions, such as benign familial erythrocytosis, cyanotic congenital heart disease, adaptation to high-altitude living, and secondary polycythemia due to chronic lung disease, extreme upregulation of erythropoietin and nitric oxide production appears to be an adaptation to maintain homeostasis in the face of extremely high hematocrits and blood viscosity. This strategy, which is costly in terms of energy, may be necessary when maximal oxygen delivery is necessary for survival.

A nitric oxide independent mechanism for long-term control of systemic vascular resistance is also probably necessary because excessive nitric oxide is toxic [Bateman et al. 2001; Young, 2004]. Nitric oxide binds to a wide range of metalloproteins, not just hemoglobin. Binding to heme-containing cytochrome oxidases might inactivate them, leading to a partial failure of oxidative phosphorylation and energy production. Excess nitric oxide production may be the cause of the systemic vasodilation and circulatory collapse in sepsis. Excess nitric oxide also decreases erythrocyte deformability, which deceases tissue perfusion. Furthermore, vasodilation in response to shear is markedly decreased in hypertension, even though the response of the involved vascular smooth muscle to sodium nitroprusside, a direct nitric oxide donor, is preserved [Paniagu et al. 2001]. This suggests that endothelial nitric oxide production can fail under the stress of prolonged hypertension, perhaps due to exhaustion of cytoplasmic L-arginine. Bioenergetically, it is more efficient to chronically decrease systemic vascular resistance by decreasing red cell mass rather than upregulating nitric oxide synthesis. This, coupled with the potential exhaustibility of the synthetic pathway and the toxicity of nitric oxide, especially when synthesized in sufficient quantities so that it is present in the systemic circulation, perhaps have provided the impetus for evolution of a second mechanism to control systemic vascular resistance.

A negative feedback loop to control blood viscosity is necessary to prevent hypoxia or anemia from initiating a cycle in which decreased oxygen delivery causes increased production of erythropoietin and red cell mass, increasing blood viscosity and decreasing perfusion, worsening hypoxia and further increasing erythropoietin production, red cell mass, and so on. It is a basic tenet of physiology that unrestricted positive feedback is incompatible with life.

Because hematocrit is the most powerful determinant of blood viscosity, a feedback mechanism to modulate blood viscosity would probably involve the regulation of erythropoietin activity. An elegant but sadly overlooked series of experiments by Kilbridge and colleagues in 1969 showed that increased blood viscosity results in a decrease in circulating functional erythropoietin, demonstrating the existence of such a mechanism [Kilbridge et al. 1969]. Mice were made hyperviscous by either transfusion or dehydration and then subjected to hypoxia. Despite hypoxia, this state of induced hyperviscosity led to a decrease in circulating functional erythropoietin to only 10% of controls after 4½ h. Upon rehydration, erythropoietin levels were fully restored.

In a dog model, the acute increase in cardiac output in response to anemia in normoviscous dogs was only 46% of the increase noted in hypoviscous dogs, despite similar hematocrits (19.9 ± 0.88% versus 18.1 ± 1.3%). In the same model, hyperviscosity acutely decreased cardiac output despite anemia. Cardiac output in anemic hyperviscous dogs was 82.0 ± 7.5 ml/kg/min, as opposed to 104.1 ± 9.8 ml/kg/min in controls. In anemic, hypoviscous dogs, cardiac output was 182.1 ± 93 ml/kg/min [Fowler and Holmes, 1975]. These data demonstrate the significant acute effect of blood viscosity on hemodynamics, and speak to the need for long-term control of viscosity.

The systemic vascular resistance response

Chronically increased blood viscosity can cause an increase in systemic vascular resistance and increased left ventricular end diastolic volume. This causes increased axial stretch of cardiomyocytes, resulting in upregulation of their paracrine secretory activity [Weckström and Tavi, 2007]. Stretch upregulates cardiomyocyte production of cardiac natriuretic peptides [Pikkarainen et al. 2007], producing a decrease in peripheral vascular resistance by diuresis and vasodilation of the microvasculature. Cardiac expression of atrial natriuretic peptide is limited initially to those cardiomyocytes which experience the most mechanical stress; however, with continued stimulation, larger areas of myocardium are recruited [McKenzie et al. 1994]. This observation is in keeping with paracrine activity.

We propose that an increase in left ventricular end diastolic volume also upregulates cardiomyocyte production of soluble erythropoietin receptors (Figure 1). Soluble erythropoietin receptor antagonizes erythropoietin activity by binding to circulating erythropoietin before it binds to erythroid precursors in the bone marrow, thereby decreasing red cell mass and blood viscosity [Khankin et al. 2010]. Alternative splicing of full-length mRNA to generate transcripts encoding only the soluble, extracellular domain, that is, ‘decoy receptors’, to modulate cytokine activity is a common motif in members of the class I cytokine receptor superfamily [Levine, 2008]. Production of erythropoietin receptor has been documented in adult human left ventricular tissue [Depping et al. 2005]. Increased levels of soluble erythropoietin receptor can be found in chronic renal failure with anemia [Khankin et al. 2010] and patients with anemia and chronic heart failure [Okonko et al. 2013], both of which are associated with increased intravascular volume. Antagonism by soluble erythropoietin receptors is the probable cause of erythropoietin resistance, in which increased doses of erythropoietin are required to achieve the desired therapeutic response [Khankin et al. 2010].

Figure 1.

The systemic vascular resistance response. Activities in red have not yet been demonstrated. HCT, hematocrit; LVEDV, left ventricular end diastolic volume; SVR, systemic vascular resistance.

A coordinated decrease in both plasma volume and red cell mass is necessary to maintain homeostasis. Therefore, both arms of the response, modulation of cardiac natriuretic peptides to control plasma volume and soluble erythropoietin receptor to control red cell mass, are necessary. A decrease in plasma volume without a commensurate decrease in red cell mass results in hemoconcentration, producing increased blood viscosity with the potential for the development of hypertension and thrombosis. Decreased plasma volume and normal red cell mass is a common finding in hypertension [Tarazi et al. 1968; Julius et al. 1971; Bing and Smith, 1981; Watts and Lewis, 1983; Kobrin et al. 1984; Lebel et al. 1989], as is increased hematocrit [Watts and Lewis, 1983; Barenbrock et al. 1993; Paul et al. 2012; Jae et al. 2014; Liu et al. 2015].

Compensatory anemia for potential hyperviscosity

The systemic vascular resistance response is manifest clinically in several anemias, including anemia of chronic disease or inflammation, sickle cell disorders, thalassemias, malaria, and possibly septic shock (multiple organ dysfunction syndrome, systemic inflammatory response syndrome). Many of these are considered hemolytic anemias, but are more accurately viewed as compensated hyperviscosity.

Several chronic diseases which are associated with anemia demonstrate increased plasma viscosity, and thus potential blood hyperviscosity. These diseases include rheumatoid arthritis, disseminated tuberculosis, and plasma cell dyscrasias such as multiple myeloma. Other diseases are characterized by increased plasma volume because of an increase in osmotically active molecules (e.g. glucose, urea, immunoglobulins). These osmotically active molecules may be present by design (polyclonal immunoglobulins in the presence of chronic infection or inflammation), or as a consequence of organ failure (urea), neoplasm (monoclonal immunoglobulins), or metabolic syndrome (glucose). In humans, increased intravascular volume results in increased systemic vascular resistance [MacAllister and Vallance, 1996]. Thus, these conditions trigger the systemic vascular resistance response in an effort to normalize left ventricular end diastolic volume at the cost of anemia.

A second cause of potential hyperviscosity is decreased erythrocyte deformability. Decreased erythrocyte deformability can be due to abnormal erythrocyte shape, especially a decreased ratio of cell surface to cell volume, altered viscoelastic properties of the cell membrane, and increased cytoplasmic viscosity [La Celle and Weed, 1971]. The latter two decrease erythrocyte deformability in sickling disorders [Chien et al. 1970], increasing vascular resistance and end diastolic volume. In sickle cell anemia, decreased deformability initiates the systemic vascular resistance response, resulting in normal or decreased blood viscosity and hematocrits typically ranging from 20% to 30% [Charache et al. 1982]. Quantitative blood viscosity data are also available for another hemolytic anemia, beta thalassemia minor. In this condition, decreased erythrocyte deformability results in a higher blood viscosity at any given hematocrit, but in vivo, the associated anemia results in normal blood viscosity [Crowley et al. 1992]. Sickle cell crises often occur for no known reason. However, case reports suggest that acute hyperviscosity may be an unrecognized cause of symptomatology (vide infra).

The systemic vascular resistance response operates in infectious diseases as well. Infection with Plasmodium falciparum leads to decreased erythrocyte deformability, both in parasitized and nonparasitized erythrocytes. In a study of 15 patients with renal failure due to falciparum malaria, blood viscosity was markedly increased at low shear rates upon hospital admission. During the recovery phase of the illness, blood viscosity decreased to normal, which was associated with a drop in hematocrit of 5.8% [Sitprija et al. 1977]. In their review of the hemorheology of malaria, Dondorp and colleagues also reported that blood viscosity in severe malaria is normal or only slightly increased as a consequence of increased plasma viscosity and anemia [Dondorp et al. 2000]. In falciparum malaria, the degree of erythrocyte deformability at high shear stress correlated with the nadir in hemoglobin level during hospitalization [Dondorp et al. 1999]. The anemia was due to decreased erythropoiesis and splenic clearance of both parasitized and nonparasitized erythrocytes. Removal of unparasitized erythrocytes was quantitatively most important, accounting for 90% of the reduction in hematocrit [Dondorp et al. 1999]. Thus, hemolysis served primarily to normalize blood viscosity, not eliminate infection.

Erythrocyte deformability, erythrocyte aggregation, plasma fibrinogen, and blood viscosity are increased in sepsis [Aird, 2003]. Although there are many potential causes for anemia in sepsis, several features suggest that it is also compensatory. The anemia in sepsis has many features in common with anemia of chronic disease or inflammation, such as decreased serum erythropoietin, decreased serum iron and transferrin saturation, increased ferritin, and normal or reduced iron-binding capacity [Aird, 2003]. Therapeutic transfusion in these patients is not associated with improved outcome, suggesting that the anemia is compensatory in order to maintain homeostasis (vide infra). In anemias associated with sepsis, studies have shown an association of transfusion with increased mortality in critically ill patients [Vincent et al. 2002; Taylor et al. 2002]. Decreased deformability of stored erythrocytes undoubtedly plays a role in the lack of benefit of transfusion. However, treating compensatory anemia with erythropoietin-stimulating agents is also associated with pathological consequences. As Aird noted, ‘a reduced hemoglobin level would be expected to offset the deleterious effect of altered red blood cell deformability, red blood cell aggregation, and increased plasma fibrinogen on blood viscosity’ [Aird, 2003, p. 874].

Intervention in anemias at homeostasis

Received wisdom suggests that ‘anemia of chronic disease’ or inflammation is caused by increased interleukin 6, an inflammatory cytokine which stimulates hepcidin production in the liver. Hepcidin binds iron, preventing its use by bacterial pathogens as well as erythropoiesis [Zarychanski and Houston, 2008]. This notion has not been dismissed despite the fact that even longstanding anemia of chronic disease or inflammation is typically normochromic and normocytic, while iron deficiency anemia is hypochromic and microcytic. If this notion is correct, in the absence of bacterial infection, transfusion should be beneficial treatment for an adverse consequence of chronic disease.

However, if these anemias are compensatory in order to maintain homeostasis, then intervention with transfusion, erythropoietin-stimulating agents, and splenectomy should be deleterious. Recognizing that at least some patients with ‘hemolytic anemias’ are in optimal homeostasis, Johnson wrote:

the native hematocrit might represent the optimal value, and simple transfusion might fail to improve or even worsen oxygen transport. This is consistent with observations that transfusion is not helpful in acute sickle pain and post transfusion hematocrits as low as 34% can be detrimental [Johnson, 2005, p. 834].

Similarly, Mohandas and colleagues wrote:

for patients with red cells of reduced deformability and high whole blood viscosity, lower than normal hematocrits are optimal (e.g., in hemoglobinopathies), since at these values the hemoglobin flow and oxygen delivery are maximized. Increasing hematocrits either by transfusion or by stimulating erythropoiesis will diminish oxygen delivery because their resultant increase in viscosity will reduce blood flow. [Mohandas et al. 1979, p. 96]

Numerous reports show that transfusion of patients with hemolytic anemia is associated with hypertension and neurologic events, some of which can be fatal [Royal and Seeler, 1978; Wasi et al. 1978; Rackoff et al. 1992]. Furthermore, a recent meta-analysis has shown that treating the anemia of chronic renal disease with erythropoietin-stimulating agents is associated with increased mortality, increased arteriovenous access thrombosis, and poorly controlled hypertension [Phrommintikul et al. 2007], all of which can be attributed to hyperviscosity.

Maintenance of normal viscosity and homeostasis in a state of decreased erythrocyte deformability requires balancing erythrocyte production in the bone marrow and erythrocyte removal by the spleen. Theoretically, removal of the spleen should therefore have an adverse effect on homeostasis in hemolytic anemias. Hemoglobin SC disease is another hemolytic anemia caused by decreased erythrocyte deformability. Markham and colleagues reported the case of a patient with Hemoglobin SC with excellent baseline functional status who developed a splenic infarction while at high altitude. After splenectomy, the patient developed a sustained increased in hematocrit, increased frequency of painful episodes, and new onset of dizziness and malaise, all of which responded dramatically to therapeutic phlebotomy [Markham et al. 2003]. This correlation between symptoms and hematocrit supports the importance of assessing blood viscosity to guide therapy.

The systemic vascular resistance response in chronic exercise

In addition to the clinical implications of the systemic vascular resistance response, this response should also be active in normal, physiologic states. This is seen in the hemorheological adaptations to exercise both acutely and long term. Intuitively, high blood viscosity should impair physical performance. Nevertheless, exercise acutely results in transiently increased blood viscosity and hematocrit, which is attributed to a reduction in plasma volume and a discharge of sequestered erythrocytes from the spleen [Brun et al. 1998; Stewart and McKenzie, 2002]. Plasma volume contraction is secondary to fluid loss and increased mean arterial pressure, resulting in extravascular fluid shifting. Although conflicting evidence exists, many studies have shown short-term increases of brain natriuretic peptide (BNP) in healthy adult athletes during and after prolonged, intense, and strenuous exercise [Huang et al. 2002; Scharhag et al. 2005, 2008]. Contraction of plasma volume results in increased concentrations of fibrinogen and other plasma proteins, which can result in an increased plasma viscosity [Vandewalle et al. 1988; Huang et al. 2002; Stewart and McKenzie, 2002; Ahmadizad et al. 2011]. Together, these alterations contribute to increased whole blood viscosity acutely, an effect which subsides with recovery from exercise [Stewart and McKenzie, 2002; Ahmadizad et al. 2011].

However, chronic exercise results in decreased blood viscosity, the so-called ‘sports anemia’ which we believe is a manifestation of the systemic peripheral resistance response. Training and chronic exercise typically reduce hematocrit and whole blood viscosity, an effect which has been correlated to improved measures of physical fitness, such as maximal oxygen consumption and endurance time [Brun et al. 1998; Romain et al. 2011]. A study of healthy male soccer players demonstrated that subjects with low hematocrits, less than 40%, had higher aerobic capacity than subjects with higher hematocrits [Brun et al. 2000]. In addition, those athletes with hematocrits greater than 44.6% were often overtrained and their whole blood viscosity was increased [Brun et al. 2000].

A meta-analysis by Romain and colleagues further highlighted the rheological benefits of exercise, showing reductions in RBC aggregation [–0.59; 95% confidence interval (CI) –0.72 to −0.46; p < 0.001], hematocrit (–0.296%; 95% CI −0.57 to −0.01; p < 0.04), and whole blood viscosity (–0.30; 95% CI −0.31 to −0.28; p < 0.001) in subjects who regularly exercised, although heterogeneity was present in the data [Romain et al. 2011]. Indeed, a phenomenon called ‘autohemodilution’ occurs in exercise-trained individuals at rest. Essentially, plasma volume is expanded while hematocrit is decreased, producing an increase in blood volume and cardiac output [Convertino, 1991; Brun et al. 1998]. Low baseline viscosity mitigates the acute hyperviscosity that would otherwise occur during exercise. Finally, Smith and colleagues demonstrated younger, more deformable erythrocytes in endurance athletes than controls [Smith et al. 1999].

According to the systemic vascular resistance response, natriuretic peptides should cause reduced plasma volume. To cause the observed increase in plasma volume, the effects of BNP may be opposed by a concomitant increase of aldosterone secondary to hemoconcentration [Huang et al. 2002]. Regardless, decreased baseline hematocrit in most athletes is not a ‘sports anemia;’ rather, it is a homeostatic adaptation and a marker of fitness [Eichner, 1985; Brun et al. 1998]. The beneficial effects of hemodilution, including reduced plasma viscosity, were experimentally demonstrated by Janetzko and colleagues who found improved submaximal physical working capacity at a heart rate of 130 bpm one day after 450 ml whole blood donation [Janetzko et al. 2001]. These effects were evident even in those who were unfit.

Therapeutic implications

The implications of the systemic vascular resistance response for the treatment of several anemias have been discussed above. It is also worthwhile mentioning that increased blood viscosity is easily treated with therapeutic phlebotomy [Holsworth et al. 2014]. This intervention has great potential because increased blood viscosity is seen in association with all major risk factors for atherosclerotic cardiovascular disease [Sloop et al. 2015]. Therapeutic phlebotomy is not an obsolete modality from medieval times. Sir William Osler used it in treating pneumonia at Johns Hopkins Hospital. This quote is from the 1921 edition of his classic textbook, The Principles and Practice of Medicine:

We employ [therapeutic phlebotomy] much more than we did a few years ago, but more often late in the disease than early. To bleed at the very onset in robust, healthy individuals in whom the disease sets in with great intensity and high fever is good practice. Late in the course marked dilatation of the right heart is the common indication [Osler and McCrae, 1921, p. 102].

The benefit observed by this eminent clinician was probably due to a decrease in elevated blood viscosity caused by the acute phase reactant fibrinogen, which would improve vascular congestion as well as decrease pulmonary vascular resistance in cor pulmonale. Therapeutic phlebotomy was used for angina pectoris at Charity Hospital in New Orleans in the 1960s [Burch and Depasquale, 1965]. Those patients reported a general feeling of improvement in wellbeing after phlebotomy. Additional reports of the efficacy of therapeutic phlebotomy in angina pectoris were published in 1970 [Parker et al. 1970] and 1994 [Piccirillo et al. 1994]. Most recently, a prospective, randomized trial of therapeutic phlebotomy in metabolic syndrome resulted in significant decreases in serum glucose and blood pressure [Houschyar et al. 2012]. Systolic blood pressure decreased from 148 ± 12.3 mmHg to 130 ± 11.9 mmHg in subjects and from 144.7 ± 14.4 mmHg to 143.8 ± 11.9 in controls. Serum glucose decreased from 110.7 ± 29.4 to 98.5 ± 24.0 mg/dl in subjects and from 109.1 ± 39.4 to 107.3 ± 33.6 mg/dl in controls. Furthermore, blood donation is also associated with a reduced risk of myocardial infarction [Salonen et al. 1998]. Although prospective data on therapeutic phlebotomy, blood donation and blood viscosity on the risk of atherosclerotic cardiovascular disease are still either limited or not widely appreciated, hemodynamics must obey the laws of physics: perfusion is inversely proportional to blood viscosity, and without a response to maintain homeostasis, blood viscosity will increase systemic vascular resistance. Reduced blood viscosity will increase blood flow to skeletal muscle, increase glucose utilization, and improve hyperglycemia. Therapeutic phlebotomy will decrease systemic vascular resistance and blood pressure, whatever the cause.

Conclusion

It appears that two strategies to maintain homeostasis in response to increased systemic vascular resistance have evolved: the first, dominated by the activity of erythropoietin and nitric oxide, and a second, postulated here, characterized by anemia and increased soluble erythropoietin receptor activity. Coexisting alternate strategies to respond to environmental stimuli are well described: in morphology, alternate pathways exist which result in either squamous or glandular differentiation, and in immunology, two distinct responses to pathogens, known as T helper 1 and 2, are described. In none of these three situations is it known what determines which program is implemented.

The new cardiovascular activity postulated here, which has great importance, is referred to as the systemic vascular resistance response. This has a comparable relationship to the Frank–Starling reflex in relationship to hematological and physiological importance. This response can have profound effects on bodily homeostasis and its effect on blood viscosity. Long-term increases in systemic vascular resistance and related increased left ventricular end diastolic volume affect cardiomyocyte expression of cardiac natriuretic peptides and soluble erythropoietin receptor. Elevation of these parameters creates a decrease in intravascular volume and blood viscosity. Studies have shown that this response can be reflected clinically in the development of several anemias, as well as its effect on exercise. A more in-depth analysis with additional investigations are needed in the future to further substantiate this response, which could be tailored toward more efficient treatment modalities.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

Notes

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The systemic vascular resistance response: a cardiovascular response modulating blood viscosity with implications for primary hypertension and certain anemias

Abstract

Keywords

Introduction: why is control of blood viscosity necessary?

The systemic vascular resistance response

Compensatory anemia for potential hyperviscosity

Intervention in anemias at homeostasis

The systemic vascular resistance response in chronic exercise

Therapeutic implications

Conclusion

Footnotes

Funding

Conflict of interest statement

Notes

References