You are here

Blood Viscosity, Anemia of Chronic Disease, and Homeostasis

Anemia of chronic disease is characterized by decreased production of erythrocytes in the setting of chronic diseases such as chronic inflammatory conditions, plasma cell dyscrasias, congestive heart failure, and chronic renal failure.  Patients with anemia of chronic disease typically have abnormally low levels of erythropoietin, the growth factor which stimulates erythropoiesis (the production of red blood cells), and a subset of these patients are resistant to erythropoietin supplementation.  The cause of the anemia is still unknown.   

Erythropoietin circulates from its site of synthesis in the kidney to the bone marrow where it binds to membrane bound receptors on erythroid precursors.  Binding prevents apoptosis of these cells, allowing them to generate new erythrocytes.  Erythropoietin activity is antagonized by soluble erythropoietin receptor, which binds circulating erythropoietin, preventing it from acting in the bone marrow.  Soluble erythropoietin receptor is a truncated form of the membrane bound receptor, which lacks the transmembrane and cytosolic domains.

Erythropoiesis and Viscosity

Plasma viscosity is increased in chronic inflammation and plasma cell dyscrasias because of the increased level of immunoglobulins.  Erythropoietin levels are inversely proportional to plasma viscosity in anemic patients with plasma cell dyscrasias.1  In an animal model, increased plasma viscosity also decreased transcription of erythropoietin mRNA.1 Plasma viscosity is also increased in chronic renal failure.2 According to another study, “Hemodialysis patients … have a high incidence of rheological abnormalities although the degree of anemia associated with chronic renal failure compensated for these changes.”3

Along with hematocrit and erythrocyte deformability, plasma viscosity is a major determinant of blood viscosity.  Appreciation of blood viscosity has provided important insights into the pathogenesis of other cardiovascular diseases, such as atherosclerosishypertension, and the metabolic syndrome. Is anemia of chronic disease a compensatory response to normalize blood viscosity in the presence of increased plasma viscosity?    

If so, pharmacological correction of anemia, as with erythropoiesis stimulating agents, should have adverse consequences.4 The adverse effects of supplemental erythropoietin were demonstrated in a meta-analysis of anemic patients with chronic renal disease. In erythropoietin treated patients, those with higher hematocrits had higher all-cause mortality, increased arteriovenous access thrombosis, and poorly-controlled blood pressure, all of which can reasonably be attributed to elevated blood viscosity.

These observations lead me to suspect that the anemia of chronic disease may actually be a compensatory response to normalize blood viscosity and that blood viscosity is subject to homeostasis.  Under such a framework, because hematocrit is the strongest determinant of blood viscosity, modulation of erythropoietin activity would play a profound role in viscosity homeostasis.    

Increased levels of soluble erythropoietin receptor can be found in chronic renal failure patients before initiation of erythropoietin therapy.6 This is the probable cause of erythropoietin resistance.  Erythropoietin resistance is also present in chronic heart failure patients.7 These observations suggest a regulatory pathway for control of blood viscosity. 

Homeostasis of Blood Viscosity: A New Theory

Elevated blood viscosity directly increases systemic vascular resistance, which can be sensed by stretch receptors in the left ventricle.  Their signal causes cardiomyocytes to upregulate expression of soluble erythropoietin receptor, which intercepts circulating erythropoietin before it can act.  Animal models suggest there may also be down regulation of erythropoietin at the transcriptional level.  The end result of this pathway is decreased red cell mass, blood viscosity, and systemic vascular resistance.  An example of cardiac mechanotransduction that is familiar to all physicians is the Frank-Starling law of the heart, which states that the volume of blood ejected from the left ventricle is a function of left ventricular end diastolic volume.8 

Expression of soluble erythropoietin receptor has been shown in the rat heart.9  However, the level and control of expression are not known.  It is known that mechanotransduction pathways are active in the heart and that left ventricular expression of atrial natriuretic peptide is upregulated by increased afterload.10, 11  Atrial natriuretic peptide is a vasodilator, diuretic and reduces blood pressure.  It makes sense that this pathway would also be utilized by a parallel effector with the same homeostatic goal, to decrease systemic vascular resistance.   

Interestingly, cardiac expression of atrial natriuretic peptide is thought to be limited initially to those cardiomyocytes, which experience the most mechanical stress, but with continued stimulus, can involve  large areas of myocardium.12  Similarly, erythropoietin expression in the kidney is limited to a small population of cells under normal conditions, but can greatly expand with continued hypoxia.   

There is a widespread misconception that decreased erythropoietin production in chronic renal failure is due to decreased renal blood flow.   According to the online medical reference UpToDate:

The kidney is well suited to be the site of EPO [erythropoietin] production because it is able to dissociate changes in blood flow alone from those in oxygenation.  Reducing renal blood flow, for example, will also tend to diminish both the glomerular filtration rate and total tubular Na+ reabsorption.  Since active transport is responsible for most of renal oxygen consumption, the relation between oxygen delivery (reduced by hypoperfusion) and oxygen utilization (reduced by decreased reabsorption) is relatively well maintained, thereby preventing an inappropriate increase in EPO synthesis.  

If viscosity is indeed under homeostatic control, why are diseases caused by abnormal blood viscosity so prevalent?  Some diseases “fly under the radar” of homeostatic surveillance.  Examples are atherosclerosis, myocardial infarction, and deep venous thrombosis, all of which are caused by thrombosis due to increased blood viscosity.  These diseases occur in areas of low shear caused by eddy currents in arteries and veins, neither of which impact mechanical stretch receptors in the left ventricle. 

A second reason is that co-morbidities, particularly co-existent lung and heart disease in the case of blood viscosity, will limit the effectiveness of any homeostatic mechanism.  The hypoxia of co-existent lung disease will exert homeostatic pressure to increase oxygen-carrying capacity and hematocrit, opposing pressure to decrease blood viscosity.  Coronary artery disease will decrease myocardial perfusion and limit the ability of cardiomyocytes to express more protein. 

Three final remarks:  First, complications of erythropoietin therapy are due to hyperviscosity, not toxicity of the molecule itself.  Second, erythropoietin therapy should be guided by monitoring blood viscosity.  Third, the patients who are the most resistant to erythropoietin therapy may be those with the lowest hematocrit-to-viscosity ratio and the ones at highest risk for complications of therapy.  Overcoming erythropoietin resistance with more erythropoietin, increases the potential for harm and should be done cautiously with close monitoring of blood viscosity. 


References:

1. Increased plasma viscosity as a reason for inappropriate erythropoietin formation.  Singh A, Eckard KU, Zimmermann A, et al.  Journal of Clinical Investigation 1993; 91:  251-256.

2.  Abnormal blood rheology in progressive renal failure: a factor in non-immune glomerular injury? Gordge M P; Faint R W; Rylance P B; Neild G H   Nephrology, Dialysis, Transplantation 1988; 3(3):257-62.

3. Effect of hemodialysis and recombinant human erythropoietin on determinants of blood viscosity. Shand B I; Buttimore A L; Lynn K L; Bailey R R; Robson R A. Renal Failure 1994;16(3):  407-13.  

4.  Anemia of chronic disease:  a harmful disorder or an adaptive, beneficial response?  Zarychanski R, Houston DS.  Canadian Medical Association Journal 2008; 179(4):  333-337.

5. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treat with erythropoietin: a meta-analysis.  Phrommintikul A, Haas SJ, Elsik M, Krum H.  The Lancet 2007; 369 (9559):  381-388

6. Soluble Erythropoietin Receptor Contributes to Erythropoietin Resistance in End-Stage Renal Disease.  Khankin EV, MutterWP, Tamez H, Yuan H-T, Karumanchi SA, Thadhani R.  2010.  PLoS ONE 5(2): e9246. doi:10.1371/journal.pone.0009246

7. Erythropoietin resistance contributes to anaemia in chronic heart failure and relates to aberrant JAK-STAT signal transduction. Okonko DO, Marley SB, Anker SD, Poole-Wilson PA, Gordon MY.  Int J Cardiol. 2013 Apr 15;164(3):359-6

8. The Mechanosensory Heart:  A Multidisciplinary Approach.  Weckstrom M, and Tavi, P.  In:  Cardiac Mechanotransduction.  Springer Science + Business Media, New York, New York, U.S.A., 2007, p 2.

9. Role of alternative splicing of the rat erythropoietin receptor gene in normal and erythroleukemia cells. Fujita M, Takahashi R, Liang P, Saya H, Ashoori F, Tachi M, Kitazawa S, Maeda S. Leukemia. 1997 Apr;11 Suppl 3:444-5

10. Increased secretion of atrial natriuretic polypeptide from the left ventricle in patients with dilated cardiomyopathy.  Yasue H, Obata K, Okumura K, et al.  Journal of Clinical Investigation 1989; 83(1): 46.

11.  Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart.  Saito Y, Nakao K, Arai H, et al.  1989;(1):298.

12.  Developmental pattern of ventricular atrial natriuretic peptide (ANP) expression in chronically hypoxic rats as an indicator of the hypertrophic process.  McKenzie JC, Kelley KB, Merisko-Liversidge EM, Kennedy J, Klein RM.  J Mol Cell Cardiol. 1994 Jun;26(6):753-67

 

LAST UPDATED:  2014-12-30

 

Stay Connected