This commentary provides a review of six different mechanisms responsible for hemorheologic (or blood flow) abnormalities and classifies a select number of disorders based on the mechanism. In some of these disorders, blood viscosity levels are actually reported to be normal because of homeostatic compensation, but a hemorheologic abnormality underlies them all.
I also discuss two case reports from the literature to demonstrate the clinical utility of classification based on these rheologic mechanisms, which emphasizes the presence or absence of compensation for normalizing hemorheologic abnormalities.
1. Anemia of Chronic Disease: Abnormal Plasma Volume With Compensation
The unifying factor in anemia of chronic disease is loss of control of plasma volume, not inflammation or chronic illness. This loss of control can be due to organ failure or increased concentrations of osmotically active molecules such as immunoglobulins1 or glucose2. Increased plasma immunoglobulins, whether due to chronic inflammation or neoplasm, also directly increase plasma and blood viscosity.
Both heart and renal failure result in loss of control of plasma volume. Congestive heart failure causes fluid overload, increased plasma volume, and increased end diastolic volume. The accompanying action of the renin-angiotensin-aldosterone system results in sodium and water retention, also increasing plasma volume. Chronic renal failure also leads to fluid overload and increased plasma volume.
The consequence of increased plasma volume, as well as increased blood viscosity, is increased total peripheral resistance and increased left end diastolic volume. These pathologic changes would result in hypertension in the absence of a homeostatic mechanism to decrease peripheral resistance.
mean arterial pressure = cardiac output x total peripheral resistance
Instead, increased left ventricular end diastolic volume is sensed by myocardial stretch receptors whose signal upregulates expression of cardiac natriuretic peptides, which decrease total peripheral resistance by vasodilation and diuresis. Their signal also upregulates myocardial expression of soluble erythropoietin receptor, which antagonizes erythropoietin activity, decreasing red cell mass.
The result is anemia of chronic disease, which I consider to be in homeostasis. In other words, I feel anemia of chronic disease is a compensatory process that is physiologic, not pathologic. Patients with anemia of chronic disease can benefit from erythropoiesis stimulating agents, however, these medications should be administered cautiously while monitoring hemodynamic parameters, such as blood viscosity, in order to prevent major complications of hyperviscosity, such as shunt thrombosis, cardiovascular events, and death.
Why does excessive dietary sodium not result in loss of control of plasma volume, when after all, sodium and its anions account for much of plasma osmolality. The answer is that homeostatic mechanisms maintain relatively tight control of serum sodium concentration despite variation in water and sodium intake.3 A marked sodium load triggers a transient increase in plasma volume, accounting for the marginal efficacy of dietary sodium restriction in the management of hypertension.
2. Abnormal Plasma Volume Without Compensation
There are at least four conditions in which hyperviscosity is caused by hemoconcentration: primary hypertension, secondary hypertension caused by alcoholism, cigarette smoking,4 and dehydration. In these conditions, hematocrit is elevated because of normal or increased red cell mass and decreased plasma volume. In primary hypertension, plasma volume is appropriately decreased, but red cell mass is not proportionately decreased for unknown reasons. Hence, hematocrit and blood viscosity are increased, resulting in hypertension.
Ethanol reduces secretion of antidiuretic hormone, resulting in water loss and contraction of plasma volume. Conditions which are associated with hypertension, such as cigarette smoking, obesity, diabetes mellitus, and metabolic syndrome are also associated with hyperviscosity and activate the homeostatic pathway to control blood viscosity. In those who are predisposed to partial failure of this pathway, the result is hypertension.
3. Increased Red Cell Mass With Compensation
Despite the adverse consequences of hyperviscosity, erythrocytosis is advantageous in chronic lung disease, cyanotic congenital heart disease, dwelling at altitude, benign familial erythrocytosis, and some cases of neonatal polycythemia. In contrast, polycythemia vera, in which hematocrit is similar to the aforementioned conditions, has a life expectancy of only 1 ½ to 3 years without treatment. The difference is that the former conditions are driven by erythropoietin, while polycythemia vera is not.
Erythropoietin has actions which are protective in the setting of erythrocytosis. It upregulates endothelial production of nitric oxide, which has antiplatelet activity. This should decrease the risk of thrombosis, which otherwise would be fostered by the decreased blood flow caused by hyperviscosity. Erythropoietin also has vasodilatory effects which mitigate the increased resistance caused by elevated blood viscosity. These actions allow prolonged survival despite elevated viscosity. I also consider these conditions to be compensated, and treatment with therapeutic phlebotomy is not routinely necessary.
4. Decreased Erythrocyte Deformability With Compensation
The importance of hemorheology in sickle cell anemia was recognized by Australian researcher Malcolm Horne, who noted that “Sickle cell anemia represents an aberration of blood rheology due to loss of normal red cell deformability. The characteristically low hematocrit compensates for the stiffness of the sickle cells, leaving the patient with approximately normal whole blood viscosity.”5
A leading group of sickle cell researchers at Johns Hopkins School of Medicine, Brown University, and Walter Reed Army Institute of Research previously wrote, “In a very real sense, patients are protected from hyperviscosity … by the hemolytic anemia, which is part of the disease.”6 This statement demonstrates the common view of sickling disorders as sometimes unpredictable episodes of crisis and hemolysis, rather than a fragile homeostasis, achieved at the cost of anemia, interrupted by episodic increases of blood viscosity, associated ischemia, and compensatory erythrocyte destruction in the spleen.
Indeed, many hemolytic anemias should be viewed through the lens of compensation for decreased erythrocyte deformability to normalize blood viscosity. Normalization of perfusion hinges on total peripheral resistance by balancing erythrocyte production in the bone marrow and destruction by the spleen. This homeostasis is inherently fragile because there is no compensation for impaired red cell passage through capillaries caused by decreased erythrocyte deformability, as well as autosplenectomy in sickle cell anemia patients.
The most quantitative examination of blood viscosity in a hemolytic anemia involved beta thalassemia minor. A Brown University research group led by hematologist James Crowley previously noted that for any given hematocrit, blood viscosity was higher in subjects with beta thalassemia minor, but because of anemia, there was no difference in low shear blood viscosity between subjects and normals.7
5. Decreased Erythrocyte Deformability Without Compensation
Erythrocyte deformability, erythrocyte aggregation, plasma fibrinogen, and blood viscosity are all increased in sepsis. Anemia has many possible causes in sepsis and is not unequivocally compensatory for elevated blood viscosity. Because of the emerging role of nitric oxide mediated impairments in erythrocyte deformability, I have included sepsis in this category.
However, as Harvard hematologist and vascular biologist William Aird wrote in 2003, “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.”8 Further, the anemia of patients with sepsis has many features in common with anemia of chronic disease, such as decreased serum erythropoietin, decreased serum iron and transferrin saturation, increased ferritin, and normal or reduced iron-binding capacity.
Is it possible that the physiologic mechanism to normalize blood viscosity and perfusion is so powerful that it is active in a syndrome in which multiple other systems fail?
Additional research is needed to validate the theory that decreased erythrocyte deformability and concomitant decreased tissue perfusion play a causal role in multiple organ dysfunction. It is noteworthy that transfusing the anemia associated with sepsis does not improve survival,8 supporting the idea that the anemia may be compensation for increased blood viscosity.
6. Erythrocyte Aggregation
Erythrocyte aggregation directly causes hyperviscosity in hypercholesterolemia, hyperfibrinogenemia, and the acute phase response, especially at low shear rates. Molecules or particles having a diameter large enough to simultaneously bind two erythrocytes, such as low density lipoprotein and fibrinogen, increases erythrocyte aggregation at low shear rates. High density lipoprotein is too small to simultaneously bind two erythrocytes, but decreases blood viscosity by competing with LDL for erythrocyte binding. This is the basis for the atheroprotective effect of high density lipoprotein. The increased viscosity at low shear rates caused by fibrinogen in the acute phase response may have evolved to facilitate neutrophil-endothelial interactions in the microvasculature, promoting diapedesis.
These cases of decreased erythrocyte deformability with compensation illustrate the consequences of hyperviscosity, the fragility of the homeostasis permitted by decreased erythrocyte deformability, and the hazard of intervening in conditions which are already in homeostasis, however fragile.
The case reported by Charache, de la Monte, and Macdonald6 illustrates the critical inverse relationship between viscosity and perfusion. A young female with sickle cell anemia presented with a typical pain crisis. Her hematocrit was 39% (typical for sickle cell patients is 20 to 30%), and reticulocyte count was 3.6%. During a two-day hospitalization, her hematocrit rose to 46%, her pain subsided, but she developed bizarre behavior and died. Autopsy revealed moderate cerebral edema and generalized vascular congestion containing numerous sickle cells.
Investigation revealed that the patient had been exposed to carbon monoxide for one week prior to admission. Crucially, the authors showed that blood viscosity progressively decreased with 13 to 20% carboxyhemoglobin, due to the anti-sickling effects of carbon monoxide. This allowed the hematocrit to increase (recall that increased blood viscosity inhibits erythropoietin production).9 However, the slow exchange of carbon monoxide for oxygen renewed the sickling potential of the erythrocytes, and combined with the increased hematocrit, resulted in hyperviscosity, decreased cerebral perfusion, bizarre behavior and death. The authors noted that therapeutic trials of carbon monoxide in sickle cell anemia were aborted because of mild toxicity, which they interpreted as being due to slowing of hemolysis, increased hematocrit and blood viscosity without increased oxygen delivery.
Hemoglobin S-C disease is another example of compensated decreased erythrocyte deformability. Markham et al. reported the case of a HbSC patient with excellent baseline functional status who developed a splenic infarction at high altitude. Following splenectomy, the patient developed a sustained increase in hematocrit, increased frequency of painful episodes, and new onset of dizziness and malaise. These symptoms responded dramatically to therapeutic phlebotomy. The authors noted that the correlation between symptoms and hematocrit supports the importance of blood viscosity in development of crises.10 The worsening of the patient’s condition following splenectomy supports the suggestion that the patient was in homeostasis prior to intervention.
LAST UPDATED: 2014-12-30