The Concept of Vulnerable Blood in Cardiovascular Disease

by Jeremy Mikolai, ND

Cardiovascular disease (CVD) is still the number one killer of Americans.¹ Coronary heart disease, in particular, will be the ultimate demise of the majority of our patients. We have made great strides in our understanding of the atherosclerotic process over the last 60 years; and our understanding of that process continues to grow, develop, and be refined into a clinical ability to predict and reduce lifetime cardiovascular risk and acute cardiovascular injury. Yet we know that atherosclerosis is not the entire story of CVD.

Inflammation is appreciated as an important risk factor for CVD. Statistically and pathophysiologically, we have come to understand the adverse contributions of inflammation to CVD. Inflammation is associated with increased levels of low-density lipoprotein-cholesterol (LDL-c) and oxidized LDL-c.² Inflammation contributes to vascular injury, which causes, perpetuates, and exacerbates endothelial dysfunction and CVD pathogenesis.³ Inflammation has become well recognized enough as a contributor to CVD risk that high sensitivity C-reactive protein (hs-CRP) is one of the few nontraditional risk factors for CVD that the conventional medical community condones as an appropriate measurement for risk assessment beyond the standard lipid profile in intermediate risk asymptomatic adults.⁴ The contribution of hs-CRP to CVD risk is supported by enough high-quality evidence and research that it is incorporated into highly regarded and well-utilized risk stratification tools such as the Reynolds Risk score.⁵ Yet, we know that inflammation is not the entire story of CVD.

The pathophysiology of CVD and risk factors for CVD are complex and often not the result of any one particular risk factor or process. Certainly, there is some variability in risk and pathophysiology based on the specific type of CVD in question; but in nearly all instances, the contributions of atherosclerosis, inflammation, pathological processes of the vessels, and comorbidities (such as diabetes mellitus) can be appreciated. We must now cultivate our appreciation for the contribution of the blood itself, and the elements that comprise it, to the pathogenic process and the events of acute injury. This concept has been referred to as vulnerable blood.⁶

The meaning of the term vulnerable blood is largely self-explanatory. By it, we refer to all of the dysfunctional elements and processes of the blood that may contribute to the development of CVD and acute events. Blood may be vulnerable due to overt pathological processes such as atrial fibrillation, sickle cell disease, or others; but in these cases the vulnerabilities are known and largely quantifiable processes that are managed in and of themselves as well as for their potential contribution to further CVD and events. It is the more occult, functional, and insidious vulnerability of the blood with which we need to concern ourselves in the average patient in order to affect optimal primary or secondary CVD prevention. These more oblique risks are often the result of suboptimal function of the blood or the confluence of many mildly elevated risks or dysfunctional factors, rather than an overt process. What is worse is the fact that the first opportunity to appreciate this suboptimal function or vulnerability may not be until after a first event has transpired or disease has developed.

Famous 19th-century German pathologist Rudolf Virchow first elucidated the three core pathological dysfunctions that lead to thrombus formation: venous stasis, endothelial injury, and hypercoagulability; these three form the Virchow Triad.⁷ The concept of vulnerable blood is not separate or distinct from the elements of the traditional Triad of Virchow. Rather, it should be conceptualized as a constellation of physiologic mechanisms that may contribute to any one or more of the three aspects of the triad.

Venous stasis is a well-known and appreciated risk for the formation of acute thrombi. Whether that static blood comes as the result of an immobilized limb, a fibrillating atrium, prolonged positional confinement or any of several other scenarios, it creates an opportunity for blood to clot and thrombi to form. However, thrombi do not always form in the setting of venous stasis; in fact, they most often do not. Virchow would say that they form in this setting when hypercoagulability, endothelial injury, or both are also present. We would agree, but may choose to add or substitute the term vulnerable blood into the list of contributors.

Endothelial function, dysfunction, and injury are perhaps one of the great frontiers of modern vascular biology. On the one hand, our understanding of the role of endothelial injury in the activation of the blood clotting cascade and the formation of acute thrombi is well elucidated and has been so for many decades. On the other hand, our understanding of chronic endothelial dysfunction, its mechanisms, and its contributions to every manner of CVD from hypertension, to heart failure, to atrial fibrillation and beyond, is still in its infancy. Chronic endothelial injury and dysfunction resulting from the presence of atherosclerosis, and the inflammatory and metaplastic changes that it induces in the vascular subendothelial space, are central to our present understanding of vascular and atherosclerotic pathogenesis. Yet that process itself does not appear to become life-threatening until there is the involvement of vulnerable blood.

The process of vascular plaque rupture, hemorrhage, thrombosis, and healing is considered to be pathologically central to the chronic progression of plaque size and vascular obstruction. Most often, acute CVD events are the result of infarction resulting from the rapid formation of thrombi, embolization of those thrombi, or acute hemorrhage. Highly obstructive vascular lesions create narrowing and stenosis of arteries (typically greater than 70%), which can cause ischemic pain such as angina pectoris and intermittent claudication.⁸ In some circumstances, that obstruction can lead to lead to hypoxia sufficient to cause acute injury such as in critical limb ischemia or acute myocardial infarction (MI). Yet in many cases of MI, we know that it is the rupture of a nonobstructive lesion (less than 50% occlusive), a vulnerable plaque, which results in acute thrombus formation, the complete occlusion of the coronary artery and infarction. Much attention is given to the acute endothelial injury and exposure of the subendothelial space to the blood resulting from the plaque rupture as the pathogenic bad actor in acute thrombus formation and infarction. However, we understand that the vulnerability of the blood to thrombus formation is the necessary partner-in-crime in this process. This fact forms the foundation for the biological plausibility and the evidential efficacy of the use of drugs that inhibit platelet aggregation and the blood-clotting cascade in the setting of acute MIs and in the management of patients with unstable angina and other atherosclerotic diseases such as peripheral arterial disease. In effect, what we are describing here is closely akin to other types of “two-hit” hypotheses. A single bad actor may not be capable of major crimes, but when a team of bad actors join forces, a crime spree may ensue. While vulnerable blood alone, or any other state in and of itself, may not be sufficient to create or perpetuate CVD or vascular injury having one and acquiring the other may create the necessary circumstances for disease.

Hypercoagulability, or thrombophilia, is a general term which refers to a heterogeneous collection of conditions which predispose the blood to clot formation. These conditions include relatively common genetic disorders such as the factor V Leiden mutation, relatively uncommon defects in clot breakdown such as protein C and S deficiencies, metabolic conditions such as hyperhomocysteinemia, endocrine conditions such as hyperestrogenism, and many others. While each of these examples is an identifiable condition unto itself that results in thrombophilia, tipping the balance of the blood in favor of clot formation over clot breakdown can be a much more subtle and less identifiable circumstance resulting from suboptimal, nonpathologic conditions combined with vulnerable blood. Acute phase reactants such as fibrinogen and hs-CRP in the setting of other blood vulnerabilities can lead to a relative thrombophilia resulting in acute or chronic CVD. Moreover, use of particular substances such as tobacco, hormonal contraceptives, and exogenous hormone replacement as well as comorbid conditions such as diabetes mellitus and autoimmune diseases (especially lupus and the antiphospholipid syndrome) predispose individuals to a state of relative hypercoagulability. When combined with the presence of vulnerable blood, any of these states can constitute the milieu necessary to create acute thrombotic diseases, vascular injury, and the acute exacerbation of chronic CVD.

Blood is the single connective tissue that unites all bodily systems. Blood is the primary supplier of the nutrients that feed all body systems and the carrier responsible for the removal of waste from those systems. It is the responsible conduit for the transfer of messaging from the nervous, immune, and endocrine systems, which synchronize all body processes. As such, a full discussion of all of the elements that may contribute to the vulnerability of blood would be exhaustive; would need to include considerations toward inflammation, hormone balance, nervous system function, and several others; and would require more than a single article to describe each of these in detail and their critical interplay. Therefore, we will confine our remaining discussion to several key aspects of the formed elements of the blood itself.

Blood type itself has been correlated to risk of cardiovascular disease. In particular, when considering ABO blood type antigens, non-O blood is correlated with the highest risk of CVD. He et al. (2012) performed a meta-analysis of the data from two large prospective cohort studies, the Nurses’ Health Study (NHS), and the Health Professionals Follow-Up Study (HPFS). Both studies were conducted with more than 24 years of follow-up; the former a study of over 62,000 women and the latter over 27,000 men. These authors found a statistically significant increased risk for the development of coronary heart disease (CHD) based on ABO blood type. Specifically, their work demonstrated a 6.27% increase in the risk of CHD attributable to having a non-O blood type.⁹ While the ABO blood type is a nonmodifiable risk factor, it is interesting that these authors propose that a possible mechanism underlying this finding is the fact that the von Willebrand factor (vWF) levels in the blood of non-O blood types is known to be about one-quarter higher than their O-type counterparts. Increased levels of vWF are associated with increased risk of CHD.¹⁰ This fact helps to demonstrate the possible contribution of aspects of vulnerable blood to the pathogenesis and propagation of CVD. Even when risk factors are nonmodifiable, they can represent important components of risk assessment and potential guides to the relative importance of our work in disease prevention in individuals.

Modifiable lifestyle factors constitute issues of utmost importance to the integrative-medicine provider in the prevention of chronic disease. Certainly, modifiable risk factors such as tobacco use and obesity contribute heavily to the development of CVD and to the concept of vulnerable blood. Tobacco use is associated vasoconstriction and elevated levels of fibrinogen; it also increases vascular inflammation and hemostasis.¹¹ It could be by any one or more of these mechanisms that increases CVD risk and the vulnerability of blood. Likewise, obesity is a pro-inflammatory state that is associated with higher levels of inflammatory mediators such as the cytokine interleukin-6 (IL-6) and CRP, as well as with higher blood pressure, atherosclerotic burden, and CVD risk. Beyond these, there has been a long-held association between psychoemotional stress, so-called Type A personality traits, and the incidence of CVD. In the Normative Aging Study, anxiety characteristics such as psychasthenia, social introversion, phobia, manifest anxiety, and overall anxiety were associated with relative risk increases ranging from 1.31 to 1.43 for MI in older men.¹² Several studies have demonstrated increases in relative risk for heart disease of more than 3-fold for people who have the highest levels of stress, anger, anxiety and other negative emotions.¹³ Recent work by Mostofsky et al. (2013) has continued to help substantiate the risk of acute outbursts of anger for myocardial infarction demonstrating that in the two hours after such an outburst the relative risk of MI increases nearly 2.5-fold.¹⁴ While many possible mechanisms may be at play in these observations, the two-hit hypothesis involving existing risk factors combined with the acute vulnerability of the blood may be central. In CHD, endothelin-1 (ET-1), a potent vasoconstrictor, release has been shown to be increased resulting from the activation of the autonomic nervous system in response to laboratory-induced stress. The ET-1 increase leads to prolonged endothelial dysfunction.¹⁵ If that increase causes acute atherosclerotic plaque rupture it may be enough to trigger acute events by itself. If other aspects of vulnerable blood are present, such as high platelet reactivity, high blood viscosity, or others, there may be sufficient dysfunction present to result in acute thrombosis even without acute plaque rupture. More importantly, several studies demonstrate that interventions toward stress reduction, anger management, meditation, and forgiving attitude can significantly modify these increased risks.^16–18

The term viscosity refers to the relative ease with which two particles move around one another during the flow of fluid. To use an analogy, if you sit in a movie theater with only one other person and there is a fire, both of you will escape the theater with relative ease; there is low viscosity. On the other hand, if the theater is filled to capacity when the fire breaks out, the emergency exit will be filled with people trying to escape and it will be more difficult for you to move around and get out; the viscosity is higher. We often refer, inappropriately, to the “thickness” or “thinness” of the blood or to antiplatelet and anticoagulant medications as “blood thinners.” The reason that this reference is inappropriate is that “thickness” and “thinness” are issues of viscosity, which is not typically where antithrombotic therapies exert their action. The most straightforward example of truly high blood viscosity is polycythemia, an abnormally high number of red blood cells (RBCs). Like having too many people in a crowded theater, the most straightforward way to reduce viscosity is to decrease the number of people in the theater, or the number of RBCs in circulation.

A brief mention of the physics of fluids is also relevant here. Blood is a non-Newtonian fluid, meaning that its viscosity is different when it is at rest than when it is flowing. Water is the primary example of a Newtonian fluid; its viscosity is the same regardless of whether it is flowing or stationary. The importance of this fact becomes more obvious when we hearken back to our discussion of venous stasis. Even when blood is at an optimal viscosity during flow, its viscosity is higher when it is static.

Appreciation for the importance of blood viscosity is growing. Many laboratories now offer blood viscosity laboratory measurements. However, the clinical utility of the laboratory marker is still in its infancy. Blood viscosity is central to the concept blood vulnerability. Blood that is more viscous is more coagulable. Obstructed blood flow results in more stagnation and therefore higher viscosity; therefore increased risk of coagulation and greater blood vulnerability. For instance, a recent cross-sectional study performed by Li et al. (2013) demonstrated that whole blood viscosity is a novel indicator of silent cerebrovascular infarction beyond the classical risk factors for stroke.¹⁹ It has also been suggested that greater blood viscosity contributes to greater shear-stress within the vascular system and therefore to endothelial dysfunction.²⁰

RBC deformability and the other factors present in the blood also contribute to blood viscosity. To return to the movie theater analogy, it makes no difference whether the theater is occupied by members of the same family, or children, or pets, or furniture; the more “stuff” you have to get past in order to get out of the theater, the higher its viscosity. On the other hand, the more flexible you are, the easier it is for you to move around that “stuff,” whatever its composition. Likewise, the more flexible or deformable the RBCs, the better they can move around other “stuff” in the bloodstream. Cecchi et al. (2013) recently published a small study of stress-induced cardiomyopathy in women which demonstrated that those who had suffered cardiomyopathy had higher blood viscosity and that this fact likely contributed to their problems with getting blood flow and oxygen through the small blood vessels that feed the left heart wall.²¹ Going all the way back to 1984, research has demonstrated the ability of polyunsaturated fatty acids (PUFAs) to decrease blood viscosity by up to 15%.²² Given their relevant application in cardiovascular disease treatment and prevention, this element of vulnerable blood is likely to be yet another “bird” in the aviary of cardiovascular disease which can be “fed” with the single “seed” that is intervention with PUFAs.

Platelet reactivity is likely to become one of the most important aspects of our understanding of CVD progression in the years to come. At their core, platelets have essentially two functions: (1) to aggregate and form a platelet plug; (2) to trigger the reaction and aggregation of other platelets. Platelet reactivity is a term which describes the relative ease or difficulty with which thrombocytes go through the process of activation and aggregation as well as trigger the aggregation of others.

In the Thrombosis Risk Progression Study (TRIP), investigators demonstrated that fibrin-platelet clot strength increases significantly as CHD progresses from a stable asymptomatic condition, to stable angina, to unstable angina, and that a state of heightened hypercoagulability, inflammation, and platelet reactivity marks the progression to unstable CVD.²³ Dr. Paul Gurbel, the lead investigator on the study from Sinai Center for Thrombosis Research, has said, “A distinct pathophysiological state of heightened platelet reactivity to ADP, platelet activation, inflammation and hypercoagulability marks the development of symptomatic cardiovascular disease from chronic stable disease.”²⁴

The molecular biology of thrombus formation is a complex physiologic cascade. Yet at its core, the final steps in the process are to form a plug of platelets which bind together and then get stuck in a net of fibrin strands. Glycoprotein IIb/IIIa (GP IIb/IIIa) is the receptor on platelets which binds to fibrin. Adenosine diphosphate (ADP) receptors exist across the surface of platelets. Their binding with ADP triggers platelet activation and permits the binding of GP IIb/IIIa to fibrin. Thromboxane A2 (TXA2) is released from activated platelets. It causes increased GP IIb/IIIa expression as well as triggers platelet aggregation and the activation of neighboring platelets. These three molecular targets are all points of therapeutic interference with clot formation. Aspirin blocks the production of TXA2, clopidogrel and other P2Y12 inhibitors interfere with the ADP-dependent binding of platelets, and agents such as abciximab block GP IIb/IIIa and platelet aggregation. Platelet reactivity varies, as does the effect of drugs designed to decrease platelet reactivity. While the standard of care for years has been to deliver antiplatelet therapy and simply assume that it is working, the increased appreciation for clopidogrel-resistance (most often a caused by genetic polymorphism which results in loss of function of the CYP 2C19 cytochrome system) has led to a new era of interest in platelet function assays and the concept of vulnerable blood.

The platelet-activating factor (PAF) is another chemokine central to platelet reactivity, thrombus formation and vulnerable blood. PAF is a signaling molecule which is produced by several cell types including endothelial cells, platelets, and multiple types of white blood cells. While it promotes platelet activation and aggregation, it is also involved in triggering allergic reactions, increasing vascular permeability, production and release of oxidative defense mechanisms, inflammation, and other processes. While PAF is considered to be a weak activator of platelets, it is yet another contributor to blood vulnerability.

Blood vulnerability is a broad concept. It encompasses many mechanisms which may promote the pathogenesis or progression of CVD or provoke acute CVD events. Blood may be vulnerable due to high viscosity, high platelet reactivity, vascular stasis or it may contribute the second hit necessary to provoke disease when conditions such as endothelial dysfunction, hypercoagulability, inflammation, or atherosclerosis are already present. Vulnerable blood also presents us with an opportunity. Redress of the elements of blood vulnerability may be a place for integrative medicine to further contribute to CVD prevention. Natural medicine is already quite adept at addressing chronic inflammation. We must now work to find and further substantiate the evidence for the natural medicine interventions which can address the aspects of vulnerable blood.

This author has no financial conflicts of interest to declare.

Jeremy Mikolai, ND, is the NERC Integrative Cardiovascular Medicine Fellow for 2013–2015. Along with Drs. Tori Hudson, Sheryl Estlund, and Martin Milner and the Naturopathic Education and Research Consortium (NERC), he has designed the first-ever clinical fellowship program for naturopathic physicians to develop special expertise in areas of medical emphasis. Dr. Mikolai is an assistant professor of naturopathic medicine, clinical medicine, and research at the National College of Natural Medicine (NCNM) and adjunct faculty/professor of cardiology in the naturopathic medicine department at Universidad del Turabo in Gurabo, Puerto Rico. He is also a lead faculty member at the Heart and Lung Wellness Center of Excellence in Naturopathic Cardiovascular Medicine at NCNM and at the Naturopathic Institute of Cardiovascular and Pulmonary Medicine (NICVM).

To contact the author or for further information:

Jeremy Mikolai, ND

Heart & Lung Wellness Center of Excellence in Naturopathic Cardiovascular Medicine

Center for Natural Medicine Inc. (CNM)

1330 SE Cesar E Chavez Blvd.

Portland, Oregon 97214

503-232-1100

CNMWellness.com

drmikolai@cnmwellness.com

Notes

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