BLOOD VISCOSITY Earlier, More Accurate Prediction of Cardiovascular Event Risk
Pushpa Larsen ND
Ralph Holsworth, DO，最近和我分享了一个他多年前在科罗拉多的病人的故事。他在丹佛一家医院实习时，收治了一名被诊断为腿部血栓的病人。Holsworth博士开始给他进行低分子肝素皮下注射，同时给他注射华法林钠。他为病人治疗先天性血栓性血友病、癌症、甲状腺功能减退和其他疾病，并就这个病例咨询了血液肿瘤学家。当患者的凝血酶原时间-国际标准化比率超过2.0时，Holsworth医生按血液肿瘤学专家的医嘱安排病人出院。几分钟后，Holsworth博士的寻呼机嗡嗡作响。他的病人刚刚在停车场昏倒。他冲到急诊室，那里正在进行心肺复苏，并协助输入了代码。经过数次抢救，病人被宣布死亡。强制尸检显示病人有严重的肺栓塞，导致他的突然死亡。
血液粘度是衡量病人血液的稠度(Thickness)和黏度(stickness)的指标。这个重要的血液动力学生物标志物决定了与血管的摩擦量，心脏必须工作的程度，以及输送到组织和器官的氧气量。它是对血液“流动能力”的直接测量，可以通过现有的自然疗法进行治疗哦。血液粘度与心血管疾病的所有已知危险因素相关，包括年龄、性别、吸烟、肥胖、炎症、胰岛素抵抗、高血压、低密度脂蛋白胆固醇（LDL)、高密度脂蛋白胆固醇(HDL)等。血粘度升高是心血管事件的独立预测因子。在爱丁堡动脉研究(Edinburgh Artery Study)中，在控制了所有其他主要危险因素后，血液粘度升高是中风风险的最强预测因子
水和等离子体被认为是牛顿流体（Newtonic Fluid)。这意味着他们的粘度保持不变，无论他们流动的快或慢。另一方面，全血是一种非牛顿流体(Non-newtonic fluid)，它的粘度随速度而变化。这一点在临床监测血液粘度时变得很重要。
粘性血液是研磨性血液 (Abrasive blood)
血液向组织输送氧气的能力与血细胞比容（Hematocrit)直接相关。然而，它也与血液粘度成反比。这两个参数之间的关系用氧传递指数（oxygen delivery index)表示。在正常的男性和女性血细胞比容值范围内，改善氧传递指数与较低的血细胞比容水平相关。一个正常血细胞容量的女性实际上比一个正常血细胞容量高的男性更有能力向细胞输送氧气。高粘度血液的携氧能力下降会影响认知功能，也会影响任何组织的功能。鉴于向组织输送氧气的普遍重要性，血液粘度对健康维持和促进的相关性是显而易见的。
众所周知，任何年龄的男性都比绝经前的女性更容易患心血管疾病。女性的风险在绝经后显著增加，年轻切除子宫的女性风险也增加了，即使她们保留了卵巢(因此有能力维持雌激素水平)。这是为什么呢? 血液粘度的主要决定因素受女性每月失血的影响很大。对红细胞压积的影响是明显的:每月减少1 - 3盎司的血液会减少红细胞的体积。对红细胞变形能力的影响可能不那么明显。由于每月出血，女性比男性产生更多的新血细胞。她的血液中含有大约80%的年轻血细胞，比男性少大约85%的老年血细胞。较老的红细胞也比较年轻的红细胞更容易聚集，影响本文所述血液粘度的第三个决定因素。此外，较老的红细胞比年轻细胞更脆弱，更容易分裂，将高分子量蛋白质血红蛋白释放到血浆中。此外，无血浆血红蛋白与一氧化氮结合，降低了一氧化氮作为血管舒张剂和血小板聚集抑制剂的功能。甚至我们的第五个行列式的血液粘度、温度、可能导致绝经前女性的降低血液粘度,因为女性的基础体温在月经周期下半段的通是增加了0.5到1°C。
改善血液黏度的一个简单方法是通过献血或治疗性静脉切开术（放血疗法）将血细胞比容降至最佳范围。Holsworth博士估计，42%的血细胞比容最适合男性，38%最适合女性。献血转化为实际的生活结果。在Kuopio缺血性心脏病危险因素研究中，共有24名中年男性接受了平均9年的随访。在此期间，非献血者急性心肌梗死的发生率为12.5%，几乎是献血者0.7%的18倍(P < .001)。献血是一个双赢的解决方案，但一些血库不愿进行“治疗性”静脉切除术，许多血库不会接受同一个人的献血，频率高于每2到3个月。目前正在制定每月一次的静脉切开治疗方案，可以在医生办公室根据病人的体重、血细胞比容、收缩压和舒张压的血液粘度值来进行。
适当的水合作用最容易改善血浆粘度，也能降低红细胞比容。发表在《航空、航天和环境医学杂志》上的研究表明，脱水（Dehydrated, Dehydration)会使收缩压血液粘稠度增加9.3%，舒张压血液粘稠度增加12.5%。对于血液粘稠度度较高的患者，建议在静脉输液前用生理盐水进行静脉补液。处理血浆蛋白也很重要，特别是当病人的低剪切(（shear rate)舒张压)粘度升高时。纳豆激酶和其他补充剂可能会降低纤维蛋白。免疫球蛋白可以通过处理食物过敏和自身免疫而减少。
WBV的测量很少由初级护理医师进行，只能通过参考实验室进行。全血粘度通常是用粘度计测量的，粘度计是一种较老的技术，最初是用来测量室内涂料或机油的粘度。它产生的单一测量值大致相当于收缩压下血液的粘度，此时血液的流动性最强，黏度最低。然而，正如我们所见，血液粘度是动态的。在收缩压剪切速率(高剪切速率high shear rate)下显示正常粘度的血液，在舒张压剪切速率(低剪切速率)下可能会有不同的结果。
Pushpa Larsen, ND毕业于Bastyr大学(Kenmore，华盛顿)，接受自然疗法医学、自然疗法助产学、灵性、健康和医学方面的培训。她曾在Bastyr大学研究所担任研究临床医师，并在Bastyr大学担任附属临床教员，在她的诊所训练学生。她在华盛顿州西雅图实习了10年，直到3年前加入华盛顿州莱顿市的Meridian Valley 实验室（Meridian Valley Lab)，成为一名咨询医师。她每年都要向数百名医生咨询如何使用和解释Meridian Valley 实验室提供的检测方法。
BLOOD VISCOSITY Earlier, More Accurate Prediction of Cardiovascular Event Risk
Pushpa Larsen, ND
By Editor Posted October 8, 2012 In Cardiopulmonary Medicine
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.