Earlier, More Accurate Prediction of Cardiovascular Event Risk
Pushpa Larsen, ND
Ralph Holsworth, DO, recently shared a story with me about a patient he had in Colorado many years ago. He was an intern in a Denver hospital when he admitted a patient diagnosed as having a blood clot in his leg. Dr Holsworth started him on low-molecular-weight heparin subcutaneous injections concurrently with warfarin sodium. He worked the patient up for congenital thrombophilias, cancer, hypothyroidism, and other conditions, and consulted with hematology-oncology on the case. When the patient’s prothrombin time–international normalized ratio exceeded 2.0, Dr Holsworth was instructed by hematology-oncology to discharge the patient. A few minutes later, Dr Holsworth’s pager buzzed. His patient had just collapsed in the parking lot. He rushed down to the emergency department, where cardiopulmonary resuscitation was in progress and assisted in the code. The patient was pronounced dead after several attempts at resuscitation. A mandatory autopsy revealed that the patient had a major pulmonary embolism, resulting in his sudden death.
It was not until several years later that Dr Holsworth learned of the role of whole blood viscosity (WBV) in the formation of thrombi. Dr Holsworth recalled that his aforementioned patient had been discharged with normal vital signs and laboratory test results that provided no indication of the evolving danger. Dr Holsworth later became one of the world’s leading experts in the use of blood viscosity in a clinical setting and asked: “I wonder if this patient would be alive had I been able to evaluate his likely elevated WBV and treat him with antiviscogenic agents. Only then, after lowering his WBV to a safe range, would I have discharged this patient safely to home to his loved ones. I learned early on that a therapeutic international normalized ratio was not to be trusted.”
What Is Blood Viscosity?
Blood viscosity is a measurement of the thickness and stickiness of a patient’s blood. This important hemodynamic biomarker determines the amount of friction against the blood vessels, the degree to which the heart must work, and the quantity of oxygen delivery to the tissues and organs. It is a direct measure of the “flow ability” of blood and is modifiable with existing naturopathic therapies. Blood viscosity is correlated with all known risk factors for cardiovascular disease, including age, sex, smoking, obesity, inflammation, insulin resistance, high blood pressure, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, and others.1-5 Elevated blood viscosity is a strong independent predictor of cardiovascular events.6 In the Edinburgh Artery Study, elevated blood viscosity was the strongest predictor of stroke risk, after controlling all other major risk factors.7,8
It is important to understand the role of blood viscosity as a clinical marker. To do so, one must know something about how the physics of blood flow works and about what affects blood viscosity.
Factors Affecting Blood Viscosity
Five primary factors determine blood viscosity. These include hematocrit, erythrocyte deformability, plasma viscosity, erythrocyte aggregation, and temperature.1
Hematocrit is the most obvious determinant of WBV. A higher percentage of red blood cells (RBCs) results in thicker blood. Hematocrit accounts for about 50% of the difference between normal blood viscosity and high blood viscosity.
Erythrocyte deformability refers to the ability of RBCs to elongate at high velocity and to bend and fold themselves to pass through the slender passageways of the capillaries. More flexible RBCs result in less viscous blood, and young RBCs are more flexible than older RBCs. Erythrocyte deformability is the second most important determinant of blood viscosity, after hematocrit.
Plasma viscosity refers to the thickness of the fluid portion of blood (everything except for RBCs, white blood cells, and platelets). Plasma viscosity is highly affected by hydration and by plasma proteins, especially high-molecular-weight proteins such as immunoglobulins and fibrinogen.
Erythrocyte aggregation reflects the tendency of RBCs to be attracted to each other and to stick together. Red blood cell aggregation is complex, with both plasma proteins and RBC deformability having a role.
As with most fluids, blood flows more easily at higher temperatures. It is estimated that a 1°C increase in body temperature results in a 2% decrease in blood viscosity.9
The Physics of Blood Viscosity
Water and plasma are considered newtonian fluids. This means that their viscosity remains the same whether they are flowing fast or slowly. Whole blood, on the other hand, is a non-newtonian fluid, and its viscosity changes with its velocity. This point becomes important clinically when monitoring blood viscosity.
During diastole, blood is subject to lower pressures, or shear. Shear increases rapidly as the ventricles contract in systole and then decreases again as the ventricles relax. During these periods of low shear, the blood slows, cellular components of blood begin to aggregate, and viscosity increases. Blood at diastole can be anywhere from 5 to 20 times as viscous as the same blood at systole. In the next cardiac cycle, viscosity decreases as shear increases and blood components are dispersed, reaching its lowest viscosity at the height of systole (Figure 1).
Viscous Blood Is Abrasive Blood
Blood flows through the vessels in what is described as laminar flow. That is, the blood forms layers (lamina) that slide easily over each other. Looking at the blood vessel from the side, we would see the fastest flowing blood in the center layers, with slower moving blood in the outer layers near the wall of the vessel. Highly viscous blood does not slide as smoothly as less viscous blood, leading to turbulence that can damage the delicate intima of the blood vessel. Turbulence is also generated at curves and bifurcations in blood vessels, particularly the large vessels nearest the heart, which are subject to great changes in pressure with each heartbeat.
Clinical Implications of Altered Blood Viscosity
We see the consequences of hyperviscous blood primarily in damage to the blood vessels, in overwork of the heart, and in decreased delivery of oxygen to the tissues. Highly viscous blood pounding against the walls of the blood vessels leads to abrasion of the single-cell layer of the intima in the carotid, pulmonary, and coronary arteries. The body responds with a protective adaptation, creating a scab (plaque), which eventually calcifies in an effort to protect the blood vessel. The longer-term result, of course, is increased turbulence (because of the no-longer smooth wall) and an ever-narrowing channel for blood flow. This result requires the heart to work harder, pushing the viscous blood out at even higher pressures, further damaging the intimal layer. At the other extreme of the vascular tree, we see decreased perfusion of the tissues as the stiffened erythrocytes of viscous blood scour the capillary linings. The body responds by thickening the capillary walls, decreasing diffusion of oxygen and nutrients into the tissues. This effect is most pronounced in tissues where healthy capillaries are essential for unimpaired function such as the kidneys, eyes, fingers, and toes.
Blood Viscosity Explains Plaque Localization
The effects of blood viscosity, taken together with an understanding of the dynamics of blood flow in a closed circulatory system, explain why it is that atherosclerotic plaques are found only in specific locations in the body.1,10 If cholesterol or inflammation was the primary culprit, plaques would be evenly distributed throughout the body because cholesterol and inflammation are generalized rather than localized. Instead, plaques are found in the curves and bifurcations of the large arteries, and they are located in the exact places where blood flow investigations show that turbulence is the greatest. We all have these areas of turbulent blood flow because we share a common geometry of our vascular tree. Yet, not everyone develops artherosclerotic plaques. The difference lies in the viscosity of the blood traveling through those arteries. Cholesterol and inflammation are important because they contribute to blood viscosity.
Delivery of Oxygen to the Tissues Is Mediated by Blood Viscosity
The capacity of blood to carry oxygen to the tissues is directly correlated with hematocrit. However, it is also inversely correlated with blood viscosity. The relationship of these 2 parameters is expressed as the oxygen delivery index. Within the limits of normal hematocrit values for men and women, improved oxygen delivery index is associated with lower hematocrit levels. A woman with a normal hematocrit actually has a greater ability to deliver oxygen to cells than a man with a higher, but normal, hematocrit.11 The decreased oxygen-carrying capacity of higher-viscosity blood affects cognitive function, as well as the function of any tissue to which robust oxygen delivery is essential (such as the placenta). Given the universal importance of oxygen delivery to the tissues, the relevance of blood viscosity to health maintenance and promotion is clear.
All of this is borne out by hundreds of studies showing that elevated blood viscosity is associated with a host of conditions. A partial list includes diabetes mellitus, insulin resistance, preeclampsia, intrauterine growth retardation, stroke, transient ischemic attacks, atherosclerosis, myocardial infarction, peripheral artery disease, hypertension, headaches, visual field defects, glaucoma, retinopathy, Hodgkin disease, Raynaud disease, sudden deafness, nephrotic syndrome, Alzheimer disease, and more.12-22
The Sex Difference
It is well known that men of any age are at higher risk for cardiovascular events than premenopausal women.11,23 A woman’s risk increases significantly after menopause, and younger women who have hysterectomies are also at increased risk, even if they retain their ovaries (thus an ability to maintain estrogen levels). Why is this? The primary determinants of blood viscosity are highly affected by a woman’s monthly blood loss. The effect on hematocrit is obvious: the monthly loss of 1 to 3 oz of blood will decrease the volume of RBCs. The effect on RBC deformability may be less obvious. Because of monthly bleeding, a woman makes more new blood cells than a man. Her blood contains about 80% more young blood cells and about 85% fewer old blood cells.11 Older RBCs are also more likely to aggregate than are younger RBCs, affecting the third determinant of blood viscosity described herein. In addition, older RBCs are more fragile than younger cells and are more likely to break apart, releasing hemoglobin, a high-molecular-weight protein, into the plasma. Furthermore, plasma-free hemoglobin binds nitric oxide, reducing the ability of nitric oxide to perform its functions as a vasodilator and as an inhibitor of platelet aggregation. Even our fifth determinant of blood viscosity, temperature, may contribute to the lower blood viscosity of premenopausal women because a woman’s basal body temperature is normally increased by 0.5 to 1°C for the second half of her menstrual cycle.
Treatments for Hyperviscosity
We can use the 5 primary determinants of blood viscosity to guide our treatments for hyperviscosity. The objectives of therapy are to optimize hematocrit (Figure 2), improve RBC deformability, decrease plasma viscosity, reduce RBC aggregation, and normalize body temperature.
An easy way to improve blood viscosity is to decrease hematocrit to optimal ranges through blood donation or therapeutic phlebotomy. Dr Holsworth estimates that a hematocrit of 42% is optimal for men, while 38% is optimal for women. Blood donation translates into real-life results. In the Kuopio Ischemic Heart Disease Risk Factor Study,24 a total of 2862 middle-aged men were followed up for a mean of 9 years. During that time, the rate of acute myocardial infarction among non-blood donors was 12.5%, almost 18 times the 0.7% rate among blood donors (P < .001). Blood donation is a win-win solution, but some blood banks shy away from performing “therapeutic” phlebotomy, and many blood banks will not accept donation from the same individual more often than every 2 to 3 months. Protocols are being developed for monthly therapeutic phlebotomy that can be performed in the physician’s office based on a patient’s weight, hematocrit, and systolic and diastolic blood viscosity values.
Erythrocyte deformability is also improved by regular blood donation. New RBCs being produced in bone marrow will be more flexible than older RBCs. Other approaches to increasing RBC deformability include increasing membrane fluidity with nutrient supplementation (such as omega-3 fatty acids) and normalizing insulin sensitivity and blood glucose control. Blood glucose dysregulation results in fluctuations in osmolality that increase RBC rigidity. Evidence also shows that exercise can improve RBC deformability.25
Plasma viscosity is most easily improved with adequate hydration, which can also decrease hematocrit. Research published in the Aviation, Space, and Environmental Medicine journal demonstrated that dehydration increases systolic blood viscosity by 9.3% and diastolic blood viscosity by 12.5%.26 For patients with high blood viscosity, intravenous hydration with normal saline before phlebotomy is advised. It is also important to address plasma proteins, particularly if a patient’s low shear (diastolic) viscosity is elevated. Nattokinase and perhaps other supplements can reduce fibrin. Immunoglobulins can be decreased by addressing food allergies and autoimmunity.
Red blood cell aggregation is affected by RBC deformability and by plasma viscosity, as already noted. Inflammation increases cytokines that affect the polarity of RBCs, making them stickier and more attracted to each other. Infection also increases the tendency to aggregation. Our naturopathic toolboxes are filled with therapies that target inflammation and can improve these parameters.
Normalizing body temperature is just good naturopathic medicine. Increasing the body temperature with constitutional hydrotherapy, the use of daily contrast showers, and optimization of thyroid function are fundamental naturopathic therapies that may have significant effects on blood viscosity.
Several herbs and other natural substances have been shown to lower blood viscosity in animal and human studies.27-30 These include Trigonella foenum and bamboo shoot. The specific determinants of blood viscosity that these herbs affect are unclear, and as with many botanical treatments, more than 1 mechanism may be at play. There are many of these natural therapeutic possibilities, and they are worthy of an entire article by themselves.
Allopathic Antiviscogenic Therapies
Dr Holsworth’s patient described herein was treated with heparin and warfarin yet still developed a blood clot that killed him. We tend to think of warfarin as a blood thinner, but according to Dr Holsworth, he frequently sees patients receiving warfarin therapy who have elevated blood viscosity. Dr Holsworth likens warfarin to additives in concrete that slow down the time it takes for the concrete to set. They do not actually change the viscosity of the cement. Aspirin also does not decrease blood viscosity.
Statins, on the other hand, decrease blood viscosity, and that may be a reason for their effectiveness. Statins come with their own problems, of course. When weaning patients off statins, it would be prudent to monitor blood viscosity.
Until now, blood viscosity has been an overlooked parameter in clinical practice, despite the wealth of research on its importance and relevance to a wide range of conditions. Most viscosity testing has been for plasma viscosity, which has usefulness for a narrow range of specific conditions. Plasma, you will recall, is a newtonian fluid, and its viscosity is independent of shear.
The measurement of WBV, rarely ordered by primary care physicians, has been available only through reference laboratories. Whole blood viscosity is generally measured using a viscometer, an older technology originally developed to measure the viscosity of house paint or motor oil. It yields a single measurement that is roughly equivalent to the viscosity of the blood at systolic pressures, when blood is the most fluid and the least sticky. However, as we have seen, blood viscosity is dynamic. Blood that exhibits normal viscosity at systolic shear rates (high shear) may tell a very different story at diastolic shear rates (low shear).
The newest and most advanced testing uses an automated scanning capillary tube viscometer, which is capable of measuring viscosity over the complete range of physiological values experienced in a cardiac cycle (10 000 shear rates) with a single continuous measurement. It is subsequently simplified into 2 measurements, namely, a high shear (systolic) viscosity and a low shear (diastolic) viscosity. This terminology does not refer to the patient’s systolic and diastolic blood pressures but to shear rates that are typically found during systole and diastole. Those shear rates are well established in the blood viscosity research literature.
Who Should Be Tested?
Dr Holsworth believes that blood viscosity is another vital sign that should be monitored regularly just as one would monitor blood pressure. Certainly, when one looks at the number of conditions associated with elevated blood viscosity, it becomes clear that there are few patients for whom monitoring blood viscosity would be unreasonable. The most obvious patients to test for blood viscosity are those with clear cardiovascular risk factors, including smokers, obese individuals, patients with a history of blood clots, and those with insulin resistance, hypertension, or other elevated markers such as C-reactive protein, glycated hemoglobin, low-density lipoprotein cholesterol, fibrinogen, homocysteine, and others. Also included in this list would be women taking oral contraceptives that decrease the frequency of menses. These contraceptives are a double whammy. Not only do they attenuate the natural advantage of monthly blood loss, but the use of oral estrogens is associated with an increased risk for developing blood clots. To this list, I would add anyone with kidney disease, glaucoma, macular degeneration, changes in cognitive function, or autoimmune diseases. My final 2 personal picks are, first, pregnant women or women with any history of preeclampsia or intrauterine growth retardation and, second, young male athletes.
Why young male athletes? Recently, I consulted with a physician on a blood viscosity profile for a 23-year-old man. His blood viscosity values, both systolic and diastolic, were critically high. This young man was a long-distance runner, who took superb care of his body, generally stayed well hydrated, and had otherwise normal laboratory test values and blood pressure. I became curious about this because one hears periodically of young athletes dropping dead in the middle of a game or after a race. A little digging uncovered what to me was a surprising statistic: a young athlete dies of sudden cardiac arrest every 3 days in the United States.31 Ninety percent of those athletes are male.
Pregnant women would normally be considered at lower risk for blood viscosity issues because in pregnancy the increased blood volume is usually associated with hemodilution and with a mildly decreased hematocrit. However, complications of pregnancy (such as preeclampsia and intrauterine growth retardation) are associated with elevated blood viscosity. Dr Holsworth’s observation has been that blood viscosity starts to increase about 6 weeks before the development of hypertension and other signs of preeclampsia. That is a huge clinical window for intervention.
Why Not Just Treat?
A physician recently said to me, “I already know that my patient is likely to have high blood viscosity because of their risk factors. Why not just treat them? Why bother to test?” I test because I want to know how severe a problem I am dealing with. I test to know whether or not my treatments are working adequately or if we need to treat more aggressively.
Blood viscosity allows for earlier, more accurate prediction of cardiovascular event risk than any other risk factor. The predictive value of blood viscosity is made clear in looking at a study7 of 331 middle-aged men with hypertension. These men were stratified into 3 groups by blood viscosity and were followed up for a mean of 5 years. The men in the highest viscosity group had the most cardiovascular events during the study period. The men in the lowest viscosity group—remember that they also had high blood pressure—had the longest event-free survival. The Edinburgh Artery Study,8 as mentioned at the beginning of this article, found that blood viscosity had the highest predictive value for stroke.
Improving our patients’ blood viscosity holds great promise for reducing the risk for cardiovascular and cerebrovascular events, as well as improving health in any condition where perfusion is important. Would cardiologists do well to monitor their high-risk patients’ blood viscosity? Surely, they would. However, most patients see a cardiologist only after they have already had a heart attack or are experiencing symptoms. For naturopathic physicians and other primary care providers interested in preventing disease and helping our patients to thrive, blood viscosity is an invaluable tool that permits earlier detection of developing disease. This allows for sooner treatment, less damage, and improved outcomes. In this way, we come closer to fulfilling our precept to treat the cause.
Pushpa Larsen, ND graduated from Bastyr University (Kenmore, Washington), with training in naturopathic medicine, naturopathic midwifery, and spirituality, health and medicine. She has worked as a research clinician for the Bastyr University Research Institute and as an affiliate clinical faculty member at Bastyr University, training students in her clinic. She practiced in Seattle, Washington, for 10 years before joining Meridian Valley Lab, Renton, Washington, as a consulting physician almost 3 years ago. She consults with hundreds of physicians every year on the use and interpretation of tests offered by Meridian Valley Lab.
Kensey KR, Cho YI. Physical principles and circulation: hemodynamics. In: The Origin of Atherosclerosis: What Really Initiates the Inflammatory Process. 2nd ed. Summersville, WV: SegMedica; 2007:33-50.
Sloop GD, Garber DW. The effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis in humans. Clin Sci. 1997;92:473-479.
Solerte SB, Fioravanti M. Hemodynamic alterations in long-term insulin-dependent diabetic patients with overt nephropathy: role of blood hyperviscosity and plasma protein changes. Clin Nephrol. 1987;28:138-143.
Dintenfass L. Elevation of blood viscosity, aggregation of red cells, haematocrit values and fibrinogen levels with cigarette smokers. Med J Aust. 1975;1:617-620.
Fossum E. Hoieggen A, Moan A, et al. Whole blood viscosity, blood pressure and cardiovascular risk factors in healthy blood donors. Blood Press. 1997;6:161-165.
Koenig W, Sund M, Filipiak B, Döring A, Löwel H, Ernst E. Plasma viscosity and the risk of coronary heart disease: results from the MONICA-Augsburg Cohort Study, 1984 to 1992. Arterioscler Thromb Biol. 1998;18:768-772.
Ciuffetti G, Schillaci G, Lombardini R, Pirro M, Vaudo G, Mannarino E. Prognostic impact of low-shear whole blood viscosity in hypertensive men. Eur J Clin Invest. 2005;35:93-98.
Lee AJ, Mowbray PI, Lowe GD, et al. Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study. Circulation. 1998;97:1467-1473.
Rand PW, Lacombe E, Hunt HE, Austin WH. Viscosity of normal human blood under normothermic and hypothermic conditions. J Appl Physiol. 1964;19:117-122.
Sloop GD. A unifying theory of atherogenesis. Med Hypotheses. 1996;47:321-325.
Kameneva MV, Watach MJ, Borovetz HS. Gender difference in rheologic properties of blood and risk of cardiovascular diseases. Clin Hemorheol Microcirc. 1999;21:357-363.
Hobbs JB, Oats JN, Palmer AA, et al. Whole blood viscosity in preeclampsia. Am J Obstet Gynecol. 1982;142:288-292.
Zondervan HA, Oosting J, Smorenberg-Schoorl ME, et al. Maternal whole blood viscosity in pregnancy hypertension. Gynecol Obstet Invest. 1988;25:83-88.
Coull BM, Beamer N, de Garmo P, et al. Chronic blood hyperviscosity in subjects with acute stroke, transient ischemic attack, and risk factors for stroke. Stroke. 1991;22:162-168.
Ernst E, Resch KL, Matrai A, Paulsen HF. Hyperviscosity: an independent risk factor after a survived stroke. Acta Med Austriaca. 1991;18(suppl 1):32-36.
Ernst E, Matrai A, Marshall M. Blood rheology in patients with transient ischemic attacks. Stroke. 1988;19:634-636.
Coppola L, Caserta F, De Lucia D, et al. Blood viscosity and aging. Arch Gerontol Geriatr. 200;31:35-42.
Ciuffetti G, Mercuri M, Mannarino E, et al. Peripheral vascular disease: rheologic variables during controlled ischemia. Circulation. 1989;80:348-352.
Klaver JH, Greve EL, Goslinga H, et al. Blood and plasma viscosity measurements in patients with glaucoma. Br J Ophthalmol. 1985;69:765-770.
Dintenfass L. Blood viscosity factors in severe non-diabetic and diabetic retinopathy. Biorheology. 1977;14:151-157.
Akhtar N, Thompson J, Durrant ST, et al. The clinical relevance of plasma viscosity in Hodgkin’s disease. Clin Lab Haematol. 1991;13:1-8.
de la Torre JC. Critical threshold cerebral hypoperfusion causes Alzheimer’s disease? Acta Neuropathol (Berl). 1999;98:1-8.
Fowkes FG, Pell JP, Donnan PT, et al. Sex differences in susceptibility to etiologic factors for peripheral atherosclerosis: importance of plasma fibrinogen and blood viscosity. Arterioscler Thromb. 1994;14:862-868.
Salonen JT, Tuomainen TP, Salonen R, Lakka TA, Nyyssönen K. Donation of blood is associated with reduced myocardial infarction: the Kuopio Ischemic Heart Disease Risk Factor Study. Am J Epidemiol. 1998;148:445-451.
Carroll S, Cooke CB, Butterly RJ. Physical activity, cardiorespiratory fitness, and the primary components of blood viscosity. Med Sci Sports Exerc. 2000;32:353-358.
Doi T, Sakurai M, Hamada K, et al. Plasma volume and blood viscosity during 4 h sitting in a dry environment. Aviat Space Environ Med. 2004;75(6):500-504.
Pais E, Alexy T, Holsworth RE Jr, Meiselman HJ. Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell aggregation and whole blood viscosity. Clin Hemorheol Microcirc. 2006;35(1-2):139-142.
Xue WL, Li XS, Zhang J, Liu YH, Wang ZL, Zhang RJ. Effect of Trigonella foenum extract on blood glucose, blood lipid and hemorheological properties in streptozotocin-induced diabetic rats. Asia Pac J Clin Nutr. 2007;16(suppl 1):422-426.
Fu X, Wang M, Li S, Li Y. The effect of bamboo leaves extract on hemorheology of normal rats [in Chinese]. Zhong Yao Cai. 2005;28(2):130-132.
Woodcock BE, Smith E, Lambert WH, et al. Beneficial effect of fish oil on blood viscosity in peripheral vascular disease. Br Med J (Clin Res Ed). 1984;288)6417:592-594.
Section on Cardiology and Cardiac Surgery. Pediatric sudden cardiac arrest. Pediatrics. 2012;129(4):e1094-e1102. http://pediatrics.aappublications.org/content/129/4/e1094.long. Accessed July 29, 2012.