Copyright

Annu. Rev. Biomed. Eng. 1999. 01:299329 1999 by Annual Reviews. All rights reserved

Fluid Mechanics of Vascular Systems, Diseases, and Thrombosis

David M. Wootton1 and David N. Ku
G.W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 303320405; e-mail: dwootton@bme.jhu.edu, david.ku@me.gatech.edu

Key Words platelets, shear, arteriosclerosis, stenosis, intimal hyperplasia Abstract The cardiovascular system is an internal ow loop with multiple branches circulating a complex liquid. The hallmarks of blood ow in arteries are pulsatility and branches, which cause wall stresses to be cyclical and nonuniform. Normal arterial ow is laminar, with secondary ows generated at curves and branches. Arteries can adapt to and modify hemodynamic conditions, and unusual hemodynamic conditions may cause an abnormal biological response. Velocity prole skewing can create pockets in which the wall shear stress is low and oscillates in direction. Atherosclerosis tends to localize to these sites and creates a narrowing of the artery lumena stenosis. Plaque rupture or endothelial injury can stimulate thrombosis, which can block blood ow to heart or brain tissues, causing a heart attack or stroke. The small lumen and elevated shear rate in a stenosis create conditions that accelerate platelet accumulation and occlusion. The relationship between thrombosis and uid mechanics is complex, especially in the post-stenotic ow eld. New convection models have been developed to predict clinical occlusion from platelet thrombosis in diseased arteries. Future hemodynamic studies should address the complex mechanics of ow-induced, large-scale wall motion and convection of semisolid particles and cells in owing blood. CONTENTS Introduction ..................................................................................... 300 Physiologic Environment.................................................................... 300 Flows in Specic Arteries................................................................... 302
302 303 304 305 Biological Responses to Hemodynamics ............................................... 305 Hemodynamics of Stenoses ................................................................ 308
1 Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The Carotid Arteries ......................................................................... The Aorta ...................................................................................... Flow at the Left Coronary Artery Bifurcation ........................................... Flows in the Heart and Great Vessels.....................................................

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Diagnosis of Disease......................................................................... 309 Shear-Dependent Thrombosis .............................................................. 310 Arterial Thrombosis .......................................................................... 310 Cellular and Molecular Mechanisms of Thrombosis.................................... 311 Hemodynamics and Thrombosis .......................................................... 312 Hemodynamics in Advanced Atherosclerosis............................................. 313 Hemodynamics and Thrombus Composition ............................................. 313 Shear and Platelet Accumulation .......................................................... 313 Shear-Linked Mechanisms .................................................................. 314 Modeling Clinical Thrombosis ............................................................ 317 Model Based on Ex Vivo Experiments .................................................... 318 Model Development .......................................................................... 318 A Model of Occlusion ........................................................................ 320 Future Directions............................................................................. 322 Conclusions ..................................................................................... 322

INTRODUCTION
Nutrient and waste transport throughout the body is the primary function of the cardiovascular system. The heart serves to pump blood through a sophisticated network of branching tubes. The ow is not steady but pulsatile. The blood vessels distribute blood to different organs while maintaining vessel integrity. The arteries are not inert tubes but adapt to varying ow and pressure conditions by growing or shrinking to meet changing hemodynamic demands. It is important to study blood ows during disease as well as under normal physiologic conditions. The majority of deaths in developed countries are from cardiovascular diseases. Most cardiovascular diseases are associated with some form of abnormal blood ow in arteries. This review focuses on some selected areas of importance to cardiology.

PHYSIOLOGIC ENVIRONMENT
The uid blood is a complex mixture of semisolid and liquid material. Blood is composed of cells, proteins, lipoproteins, and ions by which nutrients and wastes are transported. Red blood cells (RBCs) typically comprise 40% of blood by volume. In most arteries, blood behaves in a Newtonian fashion, and the viscosity can be taken as a constant 4 centipoise (cP) for a normal hematocrit. The nonNewtonian viscosity is extensively studied in the eld of biorheology and has been reviewed by others (e.g. 21, 89). Blood ow and pressure are unsteady. The cyclic nature of the heart pump creates pulsatile conditions in all arteries. The aorta serves as a compliance chamber that provides a reservoir of high pressure during diastole as well as systole. Flow is zero or even reversed during diastole in some arteries such as the external

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carotid, brachial, and femoral arteries. These arteries have a high distal resistance during rest, and ow is on/off with each cycle. Flow during diastole can also be high if the downstream resistance is low, as in the internal carotid or the renal arteries. Pulsatile ows dominate many of the problems in the cardiovascular system. The existence of unsteady ow forces the inclusion of a local acceleration term in most analyses. In contrast to unsteadiness, several features of biological ows may often be neglected as being of secondary importance for particular situations. These include vessel wall elasticity, non-Newtonian viscosity, slurry particles in the uid, body forces, and temperature. Although each of these factors is present in physiology, the analysis is greatly simplied if they can be justiably neglected, which is the case in most arterial ows. Biologists are often concerned with the local hemodynamic conditions in a particular artery or branch. The important uid mechanic parameter is often a detailed local description of the uid-wall shear stress in a blood vessel for a given pulsatile ow situation. The three-dimensional nature of many of these unsteady ows has provided an important challenge to computational methods, because the computational time required is enormous. The arterial system is tortuous and must branch many times to reach an end organ. The cross-sectional area along the axis may enlarge at branch points, sinuses, and aneurysms. However, if the area diverges, the ow must decelerate, and an adverse pressure gradient can exist. In this situation, ow separation is possible and typically occurs along the walls of the sinus. As blood ows across the endothelium, a shear stress is generated to retard the ow. The wall shear stress is proportional to the shear rate c (velocity gradient) at the wall, and the uid dynamic viscosity l: s lc. Shear stress for laminar steady ow in a straight tube is s 32lqp
1

where q is volume ow rate, and D is tube diameter. This approximation is a reasonable estimate of the mean wall shear stress in arteries. For situations in which the lumen is not circular or the blood ow is highly skewed, as it is at branch points, shear stress must be determined by detailed measurements of velocity near the wall. Shear stress is not easily measured for pulsatile ows. The velocity and velocity gradient must be measured very close to a wall, which is technically difcult. The gradient will depend highly on the shape of the velocity prole and the accurate measurement of distance from the wall. For blood ow, the viscosity very near a wall is not precisely known because the red cell concentration is reduced. Thus, arterial wall shear stress measurements are estimates and may have errors of 20%50%. At the lumenal surface, shear stress can be sensed directly as a force on an endothelial cell. In contrast, cells cannot sense ow rates directly. Determination of the ow rate would require knowledge of blood velocities far away from cells in the artery wall, as well as some way to integrate the velocities to give the

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volume ow rate. Thus, it is natural for endothelial cells to sense and respond to shear stress. Arteries will typically adapt to maintain a wall shear stress of 15 dyn/cm2 (41). This appears to be true for different arteries within an animal, between animal species, as well as after large changes within a single artery. The bloodwall shear stress modulates diameter adaptive responses, intimal thickening, and platelet thrombosis. The wall shear stress is thus central to the vascular response to hemodynamics. The other major hemodynamic force on an artery is the transmural pressure across the thickness of the wall. Arteries have a mean pressure of 100 mmHg, whereas veins have pressures of 10 mmHg. The hoop stress can be estimated by Laplaces Law as r 0.5PDt
1

where t is wall thickness, D is vessel inner diameter, and P is transmural pressure, for vessels with circular lumens that are not too thick (38). It is possible that the primary determinant of smooth muscle cell response is the local strain of these cells. The arterial wall may remodel in response to both static and cyclical loading conditions by secretion and organization of collagen and elastin, respectively (88).

FLOWS IN SPECIFIC ARTERIES

There are four major arteries that are subject to the most clinical disease. These include the carotid bifurcation, the abdominal aorta, the left coronary artery, and the heart and proximal aorta.

The Carotid Arteries

The carotid arteries are located along the sides of the neck. These arteries supply the brain and face with blood. Atherosclerosis, which develops right at the bifurcation, causes the majority of strokes in patients. The branch is unique in that there is an anatomic sinus or expansion at the origin of the internal carotid. The mean Reynolds number is 300, and the Womersley parameter is 4. The daughter branches are 25 off-axis of the parent artery, on average. Measurements of velocity have been made in machined plastic models of this bifurcation by laser Doppler anemometry (65). Secondary ows are produced downstream of the bifurcation (Figure 1). Velocity proles obtained by laser Doppler anemometry and computational uid dynamics quantify the extent of reverse velocities at the outer wall of the internal carotid sinus (Figure 2). A region of transient ow separation is created along the posterior wall of the carotid sinus, which is prominent during the downstroke of systole. The artery wall in the sinus region would experience oscillations in near-wall velocity and a low mean wall shear stress. Atherosclerotic plaque is highly localized to a small area

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FIGURE 1 Hydrogen bubble visualization of ow through a model carotid bifurcation illustrating the laminar ow at the ow divider and separation of ow at the posterior wall of the internal carotid sinus. The separation region of transient reverse velocities is also the site of secondary vortex patterns. (Reprinted with permission of the American Heart Association, Inc.)

within this sinus region and correlates with low wall shear stress with coefcients greater than 0.9, p 0.001. Comparison of the unsteady, three-dimensional in vitro results against in vivo measurements with Doppler ultrasound conrms that the assumptions of the modeling are valid (66). Several groups have recently used computational uid dynamics to study the effects of wall elasticity and nonNewtonian viscosity (4, 86). These effects are small in comparison with the anatomic and ow variations between patients (79, 83).

The Aorta
The aorta is the large vessel from the heart that traverses the middle of the abdomen and bifurcates into two arteries supplying the legs with blood. The renal arteries have a low resistance so that two-thirds of the entering ow leaves the abdominal aorta through these branches at the diaphragm. Curiously, atherosclerotic disease extends along the posterior wall of the relatively straight abdominal aorta downstream of the renal arteries in all people. Little disease is ever present in the upstream thoracic aorta. In vitro measurements in a glass-blown aorta model show that outow conditions combine with curvature to create an oscillation in velocity direction at the posterior wall of the aorta, with a corresponding low average wall shear stress (77). The area of low wall shear stress correlates very well with the location of

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FIGURE 2 a. Axial velocity proles in the sinus region of a three-dimensional model of the carotid bifurcation, using laser Doppler anemometry (LDA) and computational uid dynamics (CFD). b. Flow in the carotid sinus is unsteady with a transient reverse ow at the outer wall shown in this three-dimensional plot of velocity vs diameter position and time. (Reprinted from 65 with permission from Elsevier Science, Ltd.)

atherosclerotic plaque measured in autopsy specimens, p 0.001 (35, 77). As verication, measurements of in vivo ow in humans exhibit the same skewing and time-varying velocity proles as are produced in the model (76).

Flow at the Left Coronary Artery Bifurcation

Flow at the left coronary artery bifurcation is complicated by several important features (10). First, the left main coronary artery is quite short, leading to an entrance type ow at a small Womersley parameter of 3. Second, the ow waveform in the left coronary artery is reversed in comparison with that in most arter-

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ies, having more ow during diastole. Flow can be reversed during systole. The high pressure in the myocardium during systolic contraction causes the blood ow to reverse direction in the coronary arteries. Third, the bifurcation does not lie in a single plane but curves around the heart while branching. The curvatures likely set up secondary ows during part of the cardiac cycle. The actual uid dynamics have been characterized with large-scale experimental models (103) and spectral-element computational modeling (50, 51). Comparison of the ow eld with maps of atherosclerotic disease locations yields a strong correlation between oscillations in shear stress and probability of plaque (r 0.85, p 0.001) (51). Surprisingly, variations in branch angle do not alter the overall ow eld regimes in a dramatic way (50). However, changes in the coronary ow waveform affect the magnitudes of oscillation signicantly (50).

Flows in the Heart and Great Vessels

Flows in the heart and great vessels are dominated by inertial forces over viscous forces. Reynolds numbers at peak systole are 4000. The ow in the aorta and pulmonary trunk is similar to an entrance-type ow, which is not developed. Consequently, the core of the ow can be considered as an inviscid region away from a developing boundary layer at the wall. The pressure and velocity patterns in a complex chamber of the heart can be modeled in three dimensions, even including a moving boundary condition that develops tension (80, 113). The analysis of hemodynamics in this representative set of arteries enables one to develop a general understanding of the uid mechanics in the normal cardiovascular system. It should be remembered that arteries are not xed tubes. They are biological organs, which remodel over time.

BIOLOGICAL RESPONSES TO HEMODYNAMICS

The artery reacts to the dynamic changes in mechanical stress. Several physiologic responses are essential to the maintenance of normal functioning of the circulatory system. The responses of arteries to the hemodynamic environment may create normal adaptation or pathological disease. Hemostasis is the arrest of bleeding. Trauma is a common occurrence, and the body must be able to deal with this possibility. In this hemodynamic environment of high shear stresses, hemostasis is maintained primarily by platelet adherence and activation. Platelets pass quickly over the injury site, and adherence must occur in milliseconds. On a longer time scale, an artery can respond to minute-to-minute changes in hemodynamics. The blood vessels must adapt to differing physiologic demands and conditions from changes in blood pressure and ow. This response is typically governed by the need to control systemic vascular resistance, venous pooling, and intravascular blood volume.

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Arteries adapt to long-term increases or decreases in wall shear stress. The response to increased wall shear stress is to vasodilate and then remodel to a larger diameter with the same arterial structure. This situation is commonly seen with the creation of an arteriovenous stula for hemodialysis access. Decreased ow rates will cause a thickening of the intimal layer to reestablish a normal wall shear stress (41). Eventually, the artery may maintain a thickened intima or remodel to a normal artery of smaller diameter. On an even longer time scale of weeks to months, arteries will remodel their intima and media layers. The medial thickness is inuenced by the local amount of hoop stress and nutrition. As described above, as the blood pressure increases, the hoop stress will proportionally increase (22). Because the formation of a lamellar unit requires the proliferation of smooth muscle cells and the creation of a highly organized extracellular structure, the process may take several days. Alterations in the pulsatile pressure lead to changes in organization of the elastin and collagen structure within the media (41, 88). The effects of ow, shear stress, and stretch on arteries in vivo have been studied by several groups. Flow can be augmented through an artery by the creation of an arteriovenous stula. Such increased ow causes a dilation of the artery until the wall shear stress reaches the baseline level of the artery (60, 116). This baseline appears to be 1520 dyn/cm2 for most arteries in a wide range of species (41). Conversely, restricted ow through an artery produces a smallerdiameter vessel (68). Several pathological states may arise from an excessive or uncontrolled response to a hemodynamic stimulus. Long-term hypertension produces a generalized medial thickening of blood vessels. Studies of intimal hyperplasia in a canine model clearly indicate that low shear stresses can accelerate intimal thickening. Shear stress can also be varied in a single artery by using tapered vascular grafts with differing diameters. In this case, intimal thickening follows from low shear stresses even for a constant ow rate as depicted in Figure 3a (94). Atherosclerotic disease forms over decades. Atherosclerosis is highly localized to only a few places in the systemic vasculature. The primary locations of atheroma are at the carotid artery sinus, the coronary arteries, the abdominal aorta, and the supercial femoral arteries. In each of these arteries, there are localized sites where the mean wall shear stress is very low and oscillates between positive and negative directions during the cardiac cycle. Comparisons of the sites of disease with the local hemodynamic conditions reveal a consistent curve where low wall shear stress is strongly correlated with atherosclerotic intimal thickening (Figure 3b) (51, 67, 77). Typically, most intimal thickening is found where the average wall shear stress is 10 dyn/cm2 and follows the curve shape shown for intimal hyperplasia and arterial adaptation. Thus the biological pattern of arterial response to shear stress appears to be consistent and preprogrammed. Currently, a eld of cellular and tissue engineering is developing that attempts to subject cultured cells and tissues to well-dened stresses in an in vitro envi-

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FIGURE 3 a. Neointimal hyperplasia thickening vs wall shear stress in a dog arterial graft. The inverse relationship indicates more thickening at low shear stresses. b. Atherosclerotic intimal thickening vs wall shear stress in human carotid arteries. The reciprocal relationship holds for mean and maximum wall shear stresses and correlates directly with oscillatory shear stress.

ronment. The creation of ow chambers that recreate physiologically realistic in vivo stresses is an important area of research (53, 75). The effects of hemodynamics on convective mass transfer should not be neglected. Most biologically active molecules are convected from one site to another. These molecules may be nutrients, wastes, growth factors, or vasoactive compounds. Systemic hormones reach an artery by convection and then may diffuse through the wall, with the intima as a major barrier. However, convective mass transport may be a limiting factor for small molecules such as nitrous oxide and oxygen, which diffuse rapidly through the wall. Such convection would be impaired in areas of ow separation or reversing wall shear at sites prone to atherosclerosis (70, 71). Alternatively, biologically active molecules released by endothelial cells may have an effect downstream if the molecules are trapped in a boundary layer near the wall.

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HEMODYNAMICS OF STENOSES
When arteries become severely diseased, the arterial lumen becomes restricted over a short distance of about 1 cm. This constriction is commonly referred to as a stenosis. An example of an atherosclerotic carotid artery stenosis is depicted in Figure 4. In clinical medicine, percent stenosis is commonly dened as percent occlusion by diameter, as follows: % stenosis (D1 D2)/D1 100%,

where D1 is upstream diameter and D2 is the minimum diameter in the stenosis. As disease advances, the percent stenosis increases. Stenotic ows have been well characterized by a number of investigators. Some important summary features are that ow separation (Figure 5b) occurs in the expansion region at Reynolds numbers of 10 for a 70% stenosis, a strong shear layer develops between the central jet and the recirculation region, the critical upstream Reynolds number for turbulence is 300 (114), turbulence intensity levels reach up to 100% of the upstream velocity values, and the turbulence is high for 1.56 diameters downstream (69). For stenoses 75%, ow is limited severely by two mechanisms. Intense turbulence downstream of the stenosis creates large pressure losses. In addition, low pressure at the stenosis throat, owing to a Bernoulli-type pressure drop, can cause local collapse in severe stenoses.
FIGURE 4 X-ray contrast angiogram of a diseased carotid bifurcation illustrating the focal nature of a stenosis. The stenosis (arrow) will reduce blood ow and pressure to the brain. (From Strandness DE and van Breda A, 1994. Vascular Diseases: Surgical and Interventional Therapy. Reprinted with permission of Churchill Livingstone Inc.)

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FIGURE 5 Steady ow through a moderate stenosis (50% diameter reduction, 1.2 cm long, 4-mm diameter, Re 160) (98). a. Stenosis conguration. b. Streamlines show separation distal to the throat. c. Wall shear rate. Shear rate increases sharply in the converging stenosis, reaching a peak just upstream of the throat. Shear rate is negative and low in the post-stenotic recirculation region.

Two important clinical consequences arise from the collapse of stenoses. One is that the ow rate can be limited by choking, beyond that of purely turbulent losses. This ow limitation or critical ow rate has long been observed by physiologists and described as the coronary ow reserve that is limited even with decreases in distal resistance. Estimates of coronary ow reserve should include this choking ow limitation as well as other forms of viscous losses (46, 95). A second consequence is that of the imposed loading conditions on an atherosclerotic plaque. Stenotic ow collapse creates a compressive stress that may buckle the structure. The oscillations in compressive loading may induce a fracture fatigue in the surface of the atheroma, causing a rupture of the plaque cap. Because plaque cap rupture is the precipitating event in most heart attacks and strokes, the uid-solid mechanical interactions present in high-grade stenosis may contribute to the catastrophic material failure (74).

Diagnosis of Disease
There are a wide variety of clinical applications for hemodynamic studies of stenoses. One area of investigation revolves around the diagnosis of severe stenosis. The most accepted clinical predictors of impending heart attack, stroke, and lower-limb ischemia are based on the presence of hemodynamically signicant stenoses. Currently, the best indicator for surgical treatment of arteriosclerosis is the degree of stenosis. Although X-ray angiography is currently the standard, cost and morbidity are distinct disadvantages. Doppler ultrasound can be used to measure the increased velocities in the stenotic jet and back out a percent stenosis. This technique is widely used to determine levels of stenosis in carotid artery disease, with an accuracy of 90%. Doppler ultrasound can also be used to measure the ow waveform in the leg

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arteries. Normal arteries have a characteristic triphasic pattern, whereas diseased arteries with a stenosis exhibit a blunted monophasic pattern. Recently, magnetic resonance imaging (MRI) has been proposed as a less expensive, less morbid alternative to X-ray angiography (115). In contrast to Doppler techniques, which require an acoustic or optical window, MRI uses an electromagnetic window that does not contact the ow. Thus, much more of the body can be studied.

Shear-Dependent Thrombosis
Stenotic ows become critical to clinical medicine in the acute symptoms of atherosclerosis. After the plaque cap ruptures, the revealed contents of the atheroma stimulate a blood-clotting reaction called thrombosis. For the arterial system, thrombosis is initiated by the adherence of platelets at the surface with rapid accumulation of additional platelets. Although a number of confusing in vitro experiments are described in the literature, studies with nonanticoagulated blood through stenoses indicate that platelets stick at the throat of the stenosis. The adherence and accumulation of these platelets are shear dependentwith more accumulation at higher shear rates. The time scale of adhesion is on the order of milliseconds. Likewise, the adhesion strength must be enormous because the shear stresses on the platelet are large and increasing as the throat lls with clot. The following sections explore some of the relationships between thrombosis and hemodynamics and how these relationships may be used to understand the risk of clinical thrombosis.

ARTERIAL THROMBOSIS
Thrombosis is the formation of a blood clot, called a thrombus, inside a living blood vessel. The mechanisms of thrombosis are identical to the mechanisms of hemostasis, the clotting system that protects the body from excessive blood loss. A thrombus is composed primarily of two blood cell types, platelets and RBCs. The cells are bound together by molecules in the cell membrane of the platelets, called membrane glycoproteins (GPs), by a variety of plasma proteins, and by a network of polymerized plasma protein called brin. Arterial thrombosis is an extremely signicant health problem because it is linked to the onset of acute clinical symptoms in atherosclerosis. Thrombus superimposed on ruptured atherosclerotic plaque is commonly found in autopsy studies of heart disease (2427). Thrombosis is also associated with carotid artery plaque rupture in stroke and transient ischemic attack (24, 85). Platelets and brin emboli are frequently found in the myocardium (heart muscle) of victims of heart disease (28, 37). Clinical studies conrm the link between thrombosis and atherosclerosisantithrombotic drugs signicantly reduce the risk of clinical ischemia (40, 81, 108).

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Cellular and Molecular Mechanisms of Thrombosis

Thrombosis is a complicated interaction of platelets and plasma proteins. At a functional level acute thrombosis is described by three platelet functions (adhesion, activation, and aggregation) and the coagulation cascade (Figure 6). These mechanisms can occur simultaneously and have multiple interactions, with the enzyme thrombin playing a central role. Adhesion Thrombosis is triggered when a thrombogenic surface is exposed to blood (Figure 6a). Thrombogenic surfaces include most articial surfaces, the subendothelial and medial layers of blood vessels, and subendothelial components of atherosclerotic lesion such as brous plaque cap and atheromatous core (30). Platelets adhere to proteins in the surface via platelet membrane GPs (62). Subendothelial tissue and atheroma contain collagen, to which platelets bind via glycoprotein GPIa/IIa (91), and von Willebrand factor (vWF), to which platelets bind via two GPs. GPIb mediates a rapid but transient binding to vWF, whereas GPIIb/IIIa mediates more permanent binding (96). GPIIb/IIIa can bind to many other plasma and vessel wall proteins, including brinogen, brin, bronectin, thrombospondin, and vitronectin (62). Activation Activation refers to platelet functions triggered by chemical or physical agonists (stimuli). Chemical agonists include ADP, thrombin, thromboxane A2 (TxA2), brillar collagen, platelet-activating factor, and serotonin (23). Shear stress (in the presence of vWF, ADP, and Ca2 ) can activate platelets (52). Platelets may also be activated by biomaterials via the complement system (39, 59). Perhaps the most important activation function is a conformational change in GPIIb/IIIa that allows it to bind to plasma proteins. GPIIb/IIIa activation has been estimated to occur within 0.1 s (84) and is required for aggregation and permanent adhesion to vWF (96).
FIGURE 6 Thrombosis in late-stage atherosclerosis. a. Plaque rupture exposes subendothelium to the blood, causing platelet adhesion. b. Platelet aggregation forms a platelet plug. c. Coagulation and platelet aggregation may cause occlusion.

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Activation causes shape change with pseudopod extension, which increases the strength of adhesion and may decrease the resistance of platelets to aggregation. Activation triggers upregulation and local clustering of GPIIb/IIIa, which may also strengthen adhesion. Activated platelets contract, consolidating loose cells and brin into compacted thrombus, and release granular contents (23). Several activation functions are positive feedback mechanisms for activation of other platelets (23). Activated platelets synthesize platelet agonist TxA2 and release ADP from dense granules; inhibition of either the ADP (87) or TxA2 (64) activation pathway signicantly reduces thrombus growth. Activated platelets also catalyze thrombin production (23). Aggregation Aggregation is essential to formation of a platelet plug (Figure 6b). Aggregation can proceed via several mechanisms. At low to moderate shear rates, activated platelets can bind to other activated platelets via brinogen or brin and GPIIb/IIIa. At higher shear rates, platelets aggregate primarily via vWF (3, 58, 73). It is not clear whether activation occurs before or after initial vWF binding. Incoming platelets may be activated by passing through an agonist cloud of thrombin, TxA2, or ADP before interacting with an adherent thrombus (57, 84). Alternatively, vWF on the surface of aggregated and activated platelets could support binding of unactivated platelets via GPIb, followed by activation and permanent binding via GPIIb/IIIa. Coagulation Exposure of a thrombogenic surface is also likely to trigger the coagulation cascade, leading to brin coagulation (Figure 6c). In normal hemostasis, injury exposes tissue factor, which rapidly leads to thrombin generation. Tissue factor is found at high concentrations in the necrotic core of the atheroma (110) and may be exposed by plaque rupture. Coagulation may also be triggered by exposure of collagen or an articial surface (23). The ultimate reaction in the coagulation cascade converts prothrombin to thrombin. Thrombin cleaves brinogen so that it can polymerize to form brin, which traps red cells in the clot and supports platelet adhesion. Thrombin is also one of the most potent platelet agonists, causing activation, release of granular contents, and irreversible aggregation (23). This interaction between platelets and thrombin is important in thrombosis lasting longer than 10 or 15 min (48, 49, 61).

HEMODYNAMICS AND THROMBOSIS

Thrombosis is fundamentally linked to hemodynamics because blood transports cells and proteins to the thrombus and applies stresses that may disrupt the thrombus. In this section, we review how blood ow conditions affect the rate and localization of platelet accumulation, platelet activation, and brin coagulation.

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Hemodynamics in Advanced Atherosclerosis

Most thrombosis experiments with controlled ow report the wall shear rate, c s/l. In major arteries subject to occlusive clinical thrombosis (Table 1), mean shear rate normally ranges from 200 to 500 s 1 and mean ow Reynolds numbers range from 100 to 400. Where atherosclerosis creates a stenosis, shear rate increases to a peak just upstream of the stenosis throat (Figure 5c). The wall shear rate may be estimated by using scaling based on the Reynolds number and geometry (99). Peak shear rate increases with Reynolds number and stenosis severity, to 10,000 s 1 for moderate stenoses and 100,000 s 1 for severe stenoses. Distal to the stenosis, a recirculation region may develop, with unusually high residence time and low shear rate.

Hemodynamics and Thrombus Composition

The composition of a thrombus depends on local ow conditions. In static and low-shear recirculating ow, the bulk of a thrombus consists of RBCs trapped in brin. But in unidirectional ow at shear rates of 100 s 1 and higher, the bulk of an acute thrombus consists of platelets (18, 92, 101). At arterial and stenotic shear rates, mechanisms of platelet adhesion, activation, and aggregation dominate, and the thrombus size can be estimated by counting the number of platelets that accumulate.

Shear and Platelet Accumulation

Platelet Accumulation Rate Increases with Shear Rate An increase in platelet accumulation is directly related to the shear rate. This has been observed in vitro for platelet deposition on subendothelium (106) and collagen-coated surfaces (3, 8, 93, 100). The effect of shear rate has also been demonstrated in human (11, 92), baboon (72), and porcine (8) ex vivo experiments, which are dominated by the aggregation phase of thrombosis. The rate of platelet accumulation on brillar
TABLE 1 Mean blood ow parameters for human arteries commonly subject to occlusive thrombosis in atherosclerosis Diameter (mm) 5.0 5.9 6.1 4.0 3.4 Average ow rate (ml/s) 3.7 5.1 5.0 2.9 1.7 Mean Reynolds number 280 330 220 240 150 Mean wall Mean wall shear shear stressa ratea (s 1) (dyne/cm2) 300 250 220 460 440 11 8.9 8 16 15

Vessel (reference) Femoral artery (44) Common carotid (65) Internal carotid (65) Left main coronary (51) Right coronary (50)
a

Mean wall shear rate and shear stress are estimated from the Poiseuille prole.

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collagen increases for shear rates from 100 to at least 10,000 s 1 (Figure 7). At low shear rates, accumulation is roughly proportional to shear rate. At higher shear rates, there may be a divergence from this trend. One experiment shows a decrease in deposition rate between 10,000 and 32,000 s 1 (11), whereas another experiment shows an increase in deposition rate between 4,300 and 20,000 s 1 (72). Platelets Adhere Preferentially in High-Shear Regions Shear also appears to affect where platelets are deposited. Platelet accumulation on collagen-containing stenotic surfaces is highest at the stenosis throat, where shear rate is highest (8, 72), for peak shear rates ranging from 1,300 to 20,000 s 1 (72). On smooth articial surfaces by contrast, platelet accumulation may be depressed in high shear regions (15, 97).

Shear-Linked Mechanisms
The correlations between shear and platelet accumulation may be explained in terms of several shear-linked mechanisms: platelet transport, platelet activation, and embolization. Transport Platelet transport is important in acute thrombosis because platelet accumulation on highly thrombogenic surfaces in vivo may be transport limited or transport modulated for shear rates up to at least 20,000 s 1 (111). Transport

FIGURE 7 Average platelet accumulation rate in ex vivo baboon (72), pig (8), and human (11, 92) experiments, as a function of peak wall shear rate. Platelet accumulation rate on collagen I is averaged over 15 min, measured on tubes () and stenoses ( ) (72), and in U-channels ( ) (8). Platelet accumulation rate on collagen III over 5 min ( , ) (11, 92), estimated from thrombus volume by a linear correlation of data published for the same system (93), platelets/thrombus volume 9 1010 platelets/ml.

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in blood is still not completely understood, partly because there is no fundamental theory to predict dispersion in a concentrated suspension like blood. But experimental studies have identied two mechanisms that inuence the rate of platelet interaction with a thrombogenic surface: (a) RBC motion, the dominant mechanism, increases small-scale transport by several orders of magnitude (44); (b) nonuniform platelet concentration may increase platelet transport by a factor of 110. Both of these mechanisms increase platelet transport as shear rate increases. RBC motion RBCs exhibit randomlike transverse motion and rotation in shear ow (43), which displaces plasma and platelets and increases lateral transport. The rate of platelet transport has often been quantied by an effective diffusivity, derived by tting experimental data to a species transport model of platelet adheD1 (c/c1)n, where c is sion (e.g. 106). Power law correlations in the form De 1 the shear rate and c 1 s ) give power n and coefcient D1 that are functions of hematocrit and the stiffness and size of the RBCs. For platelets or chemical solutes in anticoagulated human blood at 40% hematocrit, n ranges from 0.49 to 10 8 cm2/s (1, 5, 107, 109). From these 0.89, and D1 ranges from 10 9 to 3 8 10 to 3 10 7 cm2s 1 at shear rate 100 correlations, De ranges from 2 1 7 5 2 1 s and from 5 10 to 1 10 cm s at shear rate 10,000 s 1, 1 to 4 orders of magnitude above the thermal diffusivity for platelets in plasma (1.6 10 9 cm2s 1). Estimates of De vary by up to an order of magnitude between experiments. One source of variation may be the variability of platelet adhesion rates with differences in anticoagulation and platelet handling; the adhesion rate begins to affect the deposition rate in vitro for shear rates 300 s 1 (107). This difculty can be avoided by using a global model of enhanced diffusivity in sheared concentrated suspensions (117). Assuming that RBC rotation is relatively unimportant, the effective diffusivity De is the sum of the RBC dispersion and the thermal diffusivity: De DR Ds (1)

where DR is the RBC dispersion coefcient and Ds is the thermal diffusivity of the solute or platelets in the stationary blood. The dispersion coefcient for RBCs is correlated to experiments by DR a2cc
p(1 m p)

(2)

with c 0.15 0.03 and m 0.8 0.3, where a is the RBC major radius, c is the shear rate, and up is the hematocrit. For platelets, De is essentially proportional to c for c 10 s 1. The model is consistent with transport rates for a variety of solutes in whole blood and was later conrmed for macromolecule transport (63). Nonuniform Concentration RBCs are concentrated in the center of a blood vessel, and appear to force increased platelet concentration toward the vessel wall.

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This effect has been studied most heavily in narrow vessels (e.g. 43, 104) but has also been observed in 3-mm-diameter tubes at arterial and higher shear rates (2). Platelet concentration at the wall increases with increasing hematocrit, shear rate, and platelet concentration. For example, in a 3-mm tube with a 40% hematocrit and a 0.25 billion/ml average platelet count, near-wall concentration is a factor of 2 to 4 higher than the average platelet count as the shear rate increases from 240 s 1 to 1200 s 1 (2). Both RBC motion and enhanced platelet concentration link high shear to increased platelet deposition. As long as molecular mechanisms of adhesion and aggregation are rapid enough to permit platelet incorporation into a thrombus, increasing shear will drive more platelets into the thrombus, resulting in more rapid thrombus growth. Activation The role of shear stress activation in clinical thrombosis is not clear. The threshold shear exposure required for platelet activation in vitro has been measured for shear rate (in whole blood) ranging from 103 to 107 s 1 (52) and t to a platelet stimulation function, PSF (16), such that PSF s t 0.452, where s is shear stress in dynes per square centimeter and t is exposure time in seconds. The threshold for shear-induced activation is PSF 1000 (16). High shear stress activates platelets with short exposure, whereas lower shear stress activates platelets over longer durations. A platelet owing through a stenosis in vivo is exposed to high shear stress, but the exposure time is at least one order of magnitude lower than the threshold for shear-induced platelet activation (16). Shear stress exposure may not be directly responsible for platelet activation in most cases of relatively severe atherosclerosis, if activation is required for the initial interaction between a circulating platelet and growing thrombus. Shear stress exposure time will exceed the activation threshold only if a platelet adheres to a stenosis. Even if shear stress is not the sole activating agonist in vivo, the history of shear stress exposure may change the threshold of platelet activation by chemical agonists (42, 45). Compared with ow that has a gradually changing shear rate, stenotic ow with a rapid increase in shear stress may signicantly increase platelet activation and platelet deposition (54, 111, 112). Embolization Another feature of thrombosis is embolization, the removal of parts of the thrombus owing to uid mechanical stress. A theoretical model has been developed for embolization in steady and pulsatile ows (14), based on models of drag on a protrusion into steady (12) and pulsatile (13) ow. The stress on the thrombus depends on the particle Reynolds number, Rep cHp2/t, where Hp is the thrombus height and t is the kinematic viscosity. For small thrombi (Rep 1), stress on an isolated thrombus is four- to vefold the wall shear stress of the approaching ow. For larger thrombi, stress becomes a function of thrombus height, and stress increases rapidly as the thrombus grows.

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The missing part of the model is quantitative data on the stress required for platelet removal from a surface. Mechanical properties of platelets are the subject of ongoing study (47), so the critical stress for embolization may soon be within reach, using a combination of modeling and experiments. Differences in platelet embolization stress may explain the difference between platelet accumulation patterns on collagen (72) or damaged artery (7) and accumulation on Lexan (97). Platelets probably adhere more strongly to collagen in the natural surfaces than to the smooth Lexan surface and can support larger thrombi without embolization. Ultrasound measurements of embolization from knitted Dacron or collagen surfaces in ex vivo experiments show low embolization rates (111). Recirculation and Residence Time The effect of hemodynamics on thrombosis is well documented in uniform or unidirectional shear ow. But separated ow occurs at bifurcations, and downstream of stenoses that occur in atherosclerosis. In regions of complex ow, the relationships between ow and thrombosis are not very clear. Convection patterns and high residence times may modulate thrombosis in separated ows. In vitro experiments show increased platelet accumulation near the reattachment point in Lexan stenoses, presumably caused by increased convection (15). Platelets may recirculate in the separated region long enough to become activated and form small aggregates. Residence time and convection patterns have also been related to brin polymerization in shear ow (36, 82). Based on steady-ow experiments, residence time on the order of at least 10 s is required for signicant shear-induced aggregation (56) or brin polymer accumulation (82). In physiologic pulsatile ow, 10-s residence is quite long; for example, 99% of particles are washed out of the recirculation zone of a 75% or 95% area reduction stenosis within 10 s (19). One potential location for physiologic high residence time would be along the trailing edge of a sharp geometric ow separator, which could be created by a tear or ap following plaque rupture, or by a poorly designed prosthetic valve. A sudden expansion, which has a geometric ow separator, creates an environment favoring a brin-rich red thrombus (18). High residence time could also occur distal to a ow-limiting acute platelet plug, in which case occlusion becomes the primary cause of high residence time and brin coagulation.

MODELING CLINICAL THROMBOSIS

Despite the well-documented role of thrombosis in clinical ischemia, thrombosis risk is not used as a surgical indicator in atherosclerosis. Stenosis severity is used to identify patients who are good candidates for surgical treatment because it correlates with risk of ischemia (6, 20, 78). The relationships between shear rate, stenotic ow, and thrombus growth rate are probably reected in the clinical

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statistics. However, using only stenosis severity misses patients with moderate or mild stenoses ( 50% diameter reduction), who have a signicant risk of ischemic attack and death (17, 25, 105). Clinically it is important to know the likelihood that thrombosis will lead to occlusion following plaque rupture or ulceration. A model of occlusion risk could be combined with a model of plaque rupture risk to decide which patients are good candidates for surgical treatment and which patients can be managed medically. A clinical thrombosis model has not been developed yet, owing to the complexity of thrombosis and the wide range of data produced by different thrombosis experiments. But there is enough experimental data available to begin building a model, based on a theoretical mechanistic thrombosis model. The model can estimate the time required for a thrombus to occlude a vessel, based on hemodynamics and geometry, and the occlusion time can be used as a measure of risk of occlusion in the event of plaque rupture.

Model Based on Ex Vivo Experiments

Only a few experiments are representative of clinical occlusive thrombosis. In vivo and ex vivo experiments, which use nonanticoagulated blood or mildly heparinized blood, include all of the major mechanisms of thrombosis and can occur over time periods long enough for occlusion of a major artery. In contrast, in vitro experiments require anticoagulation and often involve extensive blood sample manipulation, and platelet deposition rates are much lower in in vitro than in ex vivo experiments (9, 30, 92). For model development, ex vivo experiments have an advantage over in vivo experiments; precise control of ow rate and thrombogenic surface geometry allows the shear rate to be calculated. Relevant thrombosis experiments need to match the hemodynamic environment of stenotic arteries subject to clinical occlusive thrombosis. The controlling hemodynamic variable is the shear rate on the thrombogenic surface, inuenced by the shear rate history of platelets owing over the thrombogenic surface in stenotic ow. The Reynolds number does not appear to be signicant for forward ow, apart from its direct effect on the shear rate. Several experiments approximate the hemodynamic and hematologic environment expected in atherosclerosis in vivo. Baboon (72) and porcine (7, 8, 30) ex vivo experiments span physiologic shear rates and approach a physiologic Reynolds number, using little or no anticoagulation; the baboon experiments also have well-characterized stenotic ow (72). Human ex vivo experiments (11, 92) match physiologic shear rates without anticoagulation, although the duration of the experiments is limited. These experiments can be used to guide and test a model of occlusive thrombosis. Well-characterized in vivo canine experiments can also be used to test an occlusion model (101).

Model Development
Several experiments provide insight into occlusion when platelets may adhere to the entire lumen surface, a relatively severe injury. In stenotic geometry, the

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stenosis throat is the location of most rapid platelet accumulation and of occlusion (72, 101). For 4-mminside-diameter stenoses at a 100-ml/min ow rate, occlusion occurs for smaller lumen sizes ( 2.7 to 3 mm) and for higher shear rates ( 600 s 1) (72). Occlusion occurs consistently and rapidly for narrower lumens and higher shear rates (33, 101). A theoretical model can help scale experimental data to other ow conditions. Occlusion can be estimated by predicting the size of the thrombus, which is proportional to the number of accumulated platelets, because platelets comprise the bulk of the thrombus. The time course of platelet accumulation in ex vivo experiments (72) is dominated by an acute phase, which eventually decelerates to a slow phase (Figure 8). In some experiments, a platelet plug occludes the lumen, slowing ow and platelet accumulation, but in other experiments, the rate of accumulation is limited by a drop in the aggregation rate. To rst order, the nal size of a thrombus is proportional to the acute rate of platelet accumulation and the duration of the acute phase of platelet deposition. The rst objective of the model is to estimate the acute rate of platelet accumulation, as a function of hematologic and hemodynamic variables. Several good theoretical thrombosis models have been developed to understand thrombosis experiments. Some models treat platelets as discrete particles (31, 55, 84, 90, 102); this approach has the potential to be more accurate as molecular models of adhesion are developed, but can become complicated. Current particle models idealize or ignore the particle-uid interactions and thrombus shape or are explor-

FIGURE 8 The characteristic time course of platelet accumulation on collagen-coated tubes, in ex vivo baboon experiments ( ) (72). The experiment can be divided into three phases: (I) an accelerating phase, lasting for about 5 min, (II) an acute phase, lasting 50 min, and (III) a slow phase, which extends to the end of the experiment, characterized by a lower accumulation rate than the acute phase. The total platelet accumulation can be approximated by a 5-min delay, constant accumulation at the acute rate, and no accumulation during the slow phase (solid line).

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atory tools. Other models treat platelets as a continuous chemical species (29, 32, 34, 106, 112) reacting with a reactive surface. Species transport models are quantitative and relatively simple but have not been applied to clinical thrombosis and occlusion. A modied species transport model has been developed to compute platelet accumulation rates based on hemodynamics, geometry, platelet count, and aggregation rate (111, 112). Unactivated platelets in the blood are treated as a chemical species, which is transported by convection and shear-enhanced diffusion (117). Near-wall platelet concentration is enhanced by a factor of two above average platelet concentration, consistent with experiments in similar-sized tubes (2). Platelets at the surface are incorporated into the thrombus by a rst-order reaction step that includes both aggregation and activation. Flow and transport equations can be solved analytically in tubular ow. For a stenosis, a commercial computational uid dynamics package is used to compute the ow eld and platelet accumulation rate. This approach predicts the acute platelet accumulation rate on collagen-coated tubes and in the upstream, converging, and throat sections of collagen-coated stenoses (111, 112) of differing stenosis severity (Figure 9c). The platelet accumulation rate is highest at the stenosis throat and increases with increasing percent stenosis (Figure 9b). The model is less successful in recirculating post-stenotic ow, but in experiments the maximum platelet deposition rate is located in the throat section (7, 72), where occlusion occurs (101), so the model is applicable to predicting occlusion in stenotic ow.

A Model of Occlusion
A model of acute platelet accumulation rate can be used to estimate thrombus size and occlusion risk if the duration of the acute phase can be predicted. Unfortunately, the mechanisms that are responsible for reducing the accumulation rate are not well studied. Embolization has been assumed an important limiting mechanism, but embolization loss is difcult to measure, and large emboli appear to be infrequent in ex vivo experiments (111). A model of embolization has been derived (14), but the embolization stress is unknown. In addition, systemic changes may reduce the rate of platelet activation, or the concentration of platelet activation agonists may decrease locally as the thrombus size increases. Absent a clear mechanism to limit thrombus growth, the occlusion time can be estimated from the acute accumulation rate and lumen diameter, assuming that the acute phase does not end. This extrapolated occlusion time can be used as a risk indicator; a short occlusion time indicates a higher risk of occlusion when there is plaque rupture. For a fully reactive surface, occlusion occurs when the thrombus height reaches the lumen radius. The occlusion time is Tocclusion DlumenCth 2 jlumen td , (3)

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FIGURE 9 Model of platelet accumulation on 4-mm-inner-diameter collagen-coated stenoses (111). a. Collagen-coated surface consists of straight segment from x 1.2 cm to 0.6 cm, a cosine-shaped stenosis from 0.6 cm to 0.6 cm, and a straight segment from 0.6 cm to 1.2 cm. b. Acute platelet accumulation rate (j*) vs axial location (x) in 50%, 75%, and 90% area reduction stenoses. j* peaks just upstream of the throat. Peak accumulation rate increases with increasing stenosis severity. c. Average platelet accumulation in the stenosis throat section (x 0.48 cm to x 0.48 cm), for 50% ( ), 75% ( ), and 90% ( ) area reduction (72), compared with model (lines).

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where Dlumen is the diameter of the vessel lumen (throat diameter in a stenosis), Cth is the concentration of platelets in arterial thrombus [estimated to be 75 billion/ ml from ex vivo experiments (111)], and is the ratio of thrombus height to thrombus cross-section area, which accounts for the roughness of the thrombus (estimated to be 2 based on experimental occlusion times in stenoses). A 5-min delay (td) is used to model the effect of the accelerating phase of thrombosis. The acute rate of platelet accumulation jlumen is computed by using the species transport model. Equation 3 estimates occlusion times of 16, 28, and 66 min for 90%, 75%, and 50% area reduction stenoses, respectively. In experiments, occlusion times were 1825 min for the 90% stenosis and 2535 min for the 75% stenoses (72), relatively close to the model. The 50% stenosis does not occlude, so an occlusion time somewhere between 30 and 60 min indicates a low risk of occlusive thrombosis. The model predicts increased risk of occlusion (decreasing occlusion time) with increasing shear rate, decreasing lumen diameter, and increasing platelet count. Because shear rate increases and lumen diameter decreases with increasing percent stenosis, the correlation is consistent with clinical studies linking risk of ischemia and benet of surgery with percent stenosis. Platelet count is a hematologic parameter that should also have a strong inuence on risk of occlusion, based on this model.

Future Directions
The knowledge that shear affects platelets is already being applied to the design of cardiovascular devices, to minimize shear stress and residence time in blood pumps, cardiopulmonary bypass devices, and prosthetic valves. Clinical application of an occlusive thrombosis model depends on a better understanding of mechanisms that limit thrombus growth after the acute aggregation phase that is typically observed. Embolization and systemic negative feedback may contribute to subocclusive thrombus under some ow conditions. A second requirement for an occlusive thrombosis model is a risk model for plaque rupture. Combined understanding of plaque rupture and thrombosis, along with measurements of degree of stenosis, could increase the accuracy of screening patients for surgical treatment of atherosclerosis.

CONCLUSIONS
The study of hemodynamics is a rich eld that allows one to characterize the biological responses to mechanical forces. Specic arteries exhibit ow characteristics that are three-dimensional and developing. Diseased arteries can create high levels of turbulence, head loss, and a choked ow condition in tubes that can collapse. The pulsatile nature of the ow creates a dynamic environment with many interesting fundamental uid mechanics questions. The fundamental knowledge can be used to predict and change blood ow to alter the course of disease.

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Shear stress and shear rate have emerged as important parameters that modulate both chronic and acute biological responses. The relationships between thrombosis and uid mechanics are complicated. A species transport model can be used to estimate clinical thrombosis risk based on the hemodynamic environment. Future studies will be driven by the need to understand the complex effect of hemodynamics on cells and the design of new devices to modulate this effect.
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LITERATURE CITED
1. Aarts PAMM, Steendijk P, Sixma JJ, Heethaar RM. 1986. Fluid shear as a possible mechanism for platelet diffusivity in owing blood. J. Biomech. 19(10):799805 2. Aarts PAMM, van den Broek SA, Prins GW, Kuiken GDC, Sixma JJ, Heethaar RM. 1988. Blood platelets are concentrated near the wall and red blood cells, in the center in owing blood. Arteriosclerosis 8(6):81924 3. Alevriadou BR, Moake JL, Turner NA, Ruggeri ZM, Folie BJ, et al. 1993. Realtime analysis of shear-dependent thrombus formation and its blockade by inhibitors of von Willebrand factor binding to platelets. Blood 81(5):126376 4. Anayiotos AS, Jones SA, Giddens DP, Glagov S, Zarins CK. 1994. Shear stress at a compliant model of the human carotid bifurcation. J. Biomech. Eng. 116:98106 5. Antonini G, Guiffant G, Quemada D, Dosne AM. 1978. Estimation of platelet diffusivity in owing blood. Biorheology 15:11117 6. Asymptomatic Carotid Atherosclerosis Study (ACAS). 1995. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 273(18):142128 7. Badimon L, Badimon JJ. 1989. Mechanisms of arterial thrombosis in nonparallel streamlines: Platelet thrombi grow on the apex of stenotic severely injured vessel wall. Experimental study in the pig model. J. Clin. Invest. 84(4):1134 44 Badimon L, Badimon JJ, Galvez A, Chesebro JH, Fuster V. 1986. Inuence of arterial damage and wall shear rate on platelet deposition. Ex vivo study in a swine model. Arteriosclerosis 6:31220 Badimon L, Badimon JJ, Lassila R, Heras M, Chesebro JH, et al. 1991. Thrombin regulation of platelet interaction with damaged vessel wall and isolated collagen type I at arterial ow conditions in a porcine model: effects of hirudins, heparin, and calcium chelation. Blood 78(2):42334 Bargeron CB, Deters OJ, Mark FF, Friedman MH. 1988. Effect of ow partition on wall shear in a cast of a human coronary artery. Cardiovasc. Res. 22(5):34044 Barstad RM, Kierulf P, Sakariassen KS. 1996. Collagen induced thrombus formation at the apex of eccentric stenosesa time course study with non-anticoagulated human blood. Thromb. Haemost. 75(4):68592 Basmadjian D. 1984. The hemodynamic and embolizing forces acting on thrombi, from incipient attachment of single cells to maturity and embolization. J. Biomech. 17(4):28798 Basmadjian D. 1986. The hemodynamic and embolizing forces acting on

8.

9.

10.

11.

12.

13.

324

WOOTTON

KU lamellar unit revisited. Arteriosclerosis 5:1924 Colman RW. 1993. Mechanisms of thrombus formation and dissolution. Cardiovasc. Pathol. 2(3):S2332 Constantinides P. 1990. Cause of thrombosis in human atherosclerotic arteries. Am. J. Cardiol. 66(16):G37G40 Davies MJ. 1990. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 82(Suppl. 3):II3846 Davies MJ, Thomas A. 1984. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N. Engl. J. Med. 310(18):113740 Davies MJ, Thomas AC. 1985. Plaque ssuringthe cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br. Heart J. 53(4):36373 Davies MJ, Thomas AC, Knapman PA, Hangartner JR. 1986. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 73(3): 41827 Eckstein EC, Belgacem F. 1991. Model of platelet transport in owing blood with drift and diffusion terms. Biophys. J. 60(1):5369 Fernandez-Ortiz A, Badimon JJ, Falk E, Fuster V, Meyer B, et al. 1994. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J. Am. Coll. Cardiol. 23(7):156269 Fiechter J, Ku DN. 1998. Numerical study of platelet transport in owing blood. Proc. ASME Biomed. Eng. Div., NYC. Adv. Bioeng. 39:1112, Anaheim, Ca Fogelson AL. 1992. Continuum models of platelet aggregation: formulation and mechanical properties. SIAM J. Appl. Math. 52(4):1089110 Folts JD, Crowell EB Jr, Rowe GG.

14.

15.

16.

17.

18.

19.

20.

21.

22.

thrombiII. The effect of pulsatile blood ow. J. Biomech. 19(10):83745 Basmadjian D. 1989. Embolization: critical thrombus height, shear rates, and pulsatility. Patency of blood vessels. J. Biomed. Mater. Res. 23(11):131526 Bluestein D, Niu L, Schoephoerster RT, Dewanjee MK. 1997. Fluid mechanics of arterial stenosis: relationship to the development of mural thrombus. Ann. Biomed. Eng. 25:34456 Boreda R, Fatemi RS, Rittgers SE. 1995. Potential for platelet stimulation in critically stenosed carotid and coronary arteries. J. Vasc. Invest. 1(1):2637 Brown BG, Gallery CA, Badger RS, Kennedy JW, Mathey D, et al. 1986. Incomplete lysis of thrombus in the moderate underlying atherosclerotic lesion during intracoronary infusion of streptokinase for acute myocardial infarction: quantitative angiographic observations. Circulation 73(4):65361 Cadroy Y, Horbett TA, Hanson SR. 1989. Discrimination between plateletmediated and coagulation-mediated mechanisms in a model of complex thrombus formation in vivo. J. Lab. Clin. Med. 113(4):43648 Cao J, Rittgers SE. 1998. Particle motion within in vitro models of stenosed internal carotid and left anterior descending coronary arteries. Ann. Biomed. Eng. 26(2):19099 Chaitman BR, Fisher LD, Bourassa MG, Davis K, Rogers WJ, et al. 1981. Effect of coronary bypass surgery on survival patterns in subsets of patients with left main coronary artery disease. Report of Collaborative Study in Coronary Artery Surgery (CASS). Am. J. Cardiol. 48(4):76577 Chien S. 1970. Shear dependence of effective cell volume as a determinant of blood viscosity. Science 168:977 Clark JM, Glagov S. 1985. Transmural organization of the arterial wall: the

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

FLUID MECHANICS AND THROMBOSIS 1976. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 54(3):36570 Friedman LI, Liem H, Grabowski EF, Leonard EF, McCord CW. 1970. Inconsequentiality of surface properties for initial platelet adhesion. Trans. Am. Soc. Artif. Intern. Organs 16:6373 Friedman MH, Bargeron CB, Hutchinson GM, Mark FF, Deters OJ. 1980. Hemodynamic measurements in human arterial casts and their correlation with histology and luminal area. J. Biomech. Eng. 102:247 Friedrich P, Reininger AJ. 1995. Occlusive thrombus formation on indwelling catheters: in vitro investigation and computational analysis. Thromb. Haemost. 73(1):6672 Frink RJ, Rooney PA Jr, Trowbridge JO, Rose JP. 1988. Coronary thrombosis and platelet/brin microemboli in death associated with acute myocardial infarction. Br. Heart J. 59(2):196200 Fung YC. 1984. Biodynamics: Circulation. New York: Springer-Verlag. 404 pp. Gemmell CH, Black JP, Yeo EL, Sefton MV. 1996. Material-induced up-regulation of leukocyte CD11b during whole blood contact: material differences and a role for complement. J. Biomed. Mater. Res. 32(1):2935 Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, et al. 1989. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1(8649):121520 Glagov S, Zarins C, Giddens DP, Ku DN. 1988. Hemodynamics and atherosclerosis: insights and perspectives gained from studies of human arteries. Arch. Pathol. Lab. Med. 112:101831 Goldsmith HL, Frojmovic MM, Braovac S, McIntosh F, Wong T. 1994. Adenosine diphosphate-induced aggregation of human platelets in ow through tubes. III. Shear and extrinsic brinogen-

325

43.

34.

44.

35.

36.

45.

46.

37.

47.

38.

48.

39.

49.

40.

50.

41.

51.

42.

52.

dependent effects. Thromb. Haemost. 71(1):7890 Goldsmith HL, Marlow JC. 1979. Flow behavior of erythrocytes. II. Particle motions in concentrated suspensions of ghost cells. J. Colloid Interface Sci. 71(2):383407 Goldsmith HL, Turitto VT. 1986. Rheological aspects of thrombosis and haemostasis: basic principles and applications. ICTH-ReportSubcommittee on Rheology of the International Committee on Thrombosis and Haemostasis. Thromb. Haemost. 55(3):41535 Goldsmith HL, Yu SS, Marlow J. 1975. Fluid mechanical stress and the platelet. Thromb. Diath. Haemorrh. 34(1):3241 Gould KL. 1978. Pressure-ow characteristics of coronary stenoses in unsedated dogs at rest and during coronary vasodilation, Circ. Res. 43(2):24253 Haga JH, Beaudoin AJ, White JG, Strony J. 1998. Quantication of the passive mechanical properties of the resting platelet. Ann. Biomed. Eng. 26(2):268 77 Hanson SR, Harker LA. 1988. Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone. Proc. Natl. Acad. Sci. USA 85(9):318488 Hanson SR, Markou C, Lindahl AK, Ku DN, Scarborough RM, et al. 1993. Inhibition of in vivo thrombus formation in an arterial stenosis model. Thromb. Haemost. 69:540 (Abstr.) He X. 1993. Numerical simulations of blood ow in human coronary arteries. PhD thesis. Georgia Inst. Technol., Atlanta. 249 pp. He X, Ku DN. 1996. Pulsatile ow in the human left coronary artery bifurcation: average conditions. J. Biomech. Eng. 118:7482 Hellums JD. 1994. 1993 Whitaker lecture: biorheology in thrombosis research. Ann. Biomed. Eng. 22:44555

326

WOOTTON

KU cellular interactions. Annu. Rev. Cell Biol. 6:32957 Kim D, Beissinger RL. 1993. Augmented mass transport of macromolecules in sheared suspensions to surfaces. J. Colloid Interface Sci. 159:920 Kotze HF, Lamprecht S, van Badenhorst PN, vanWyk V, Roodt JP, Alexander K. 1993. In vivo inhibition of acute plateletdependent thrombosis in a baboon model by Bay U3405, a thromboxane A2receptor antagonist. Thromb. Haemost. 70(4):67275 Ku DN, Giddens DP. 1987. Laser Doppler anemometer measurements of pulsatile ow in a model carotid bifurcation. J. Biomech. Eng. 20:407 Ku DN, Phillips DJ, Giddens DP, Strandness DE. 1985. Hemodynamics of the normal human carotid bifurcation: in vitro and in vivo studies. Ultrasound Med. Biol. 11:1326 Ku DN, Zarins CK, Giddens DP, Glagov S. 1985. Pulsatile ow and atherosclerosis in the human carotid bifurcation: positive correlation between plaque localization and low and oscillating shear stress. Arteriosclerosis 5:292302 Langille BL, ODonnell F. 1986. Reduction in arterial diameter produced by chronic decreases in blood ow are endothelium-dependent. Science 231:4057 Lieber BB, Giddens DP. 1990. Post-stenotic core ow and its effects on wall shear stress. J Biomech. 23(6):597605 Lutostansky EM. 1996. The role of convective mass transfer in atherosclerosis. PhD thesis. Georgia Inst. Technol. Atlanta. 195 pp. Ma P, Li X, Ku DN. 1994. Heat and mass transfer in a separated ow region for high Prandtl and Schmidt numbers under pulsatile conditions. Int. J. Heat Mass Transf. 37(17):272336 Markou CP, Hanson SR, Siegel JM, Ku DN. 1993. The role of high wall shear rate of thrombus formation in stenoses. Proc. ASME Biomed. Eng. Div., NYC.

53. Helmlinger G, Geiger RV, Schreck S, Nerem RM. 1991. Effects of pulsatile ow on cultured vascular endothelial cell morphology. J. Biomech. Eng. 113:123 31 54. Holme PA, Orvim U, Hamers MJ, Solum, NO, Brosstad FR, et al. 1997. Shear-induced platelet activation and platelet microparticle formation at blood ow conditions as in arteries with a severe stenosis. Arterioscler. Thromb. Vasc. Biol. 17(4):64653 55. Huang PY, Hellums JD. 1993. Aggregation and disaggregation kinetics of human blood platelets: Part I. Development and validation of a population balance model. Biophys. J. 65(1):33443 56. Huang PY, Hellums JD. 1993. Aggregation and disaggregation kinetics of human blood platelets: Part II. Shearinduced platelet aggregation. Biophys. J. 65(1):34453 57. Hubbell JA, McIntire LV. 1986. Platelet active concentration proles near growing thrombia mathematical consideration. Biophys. J. 50:93745 58. Ikeda T, Handa M, Kawano K, Kamata T, Murata M, et al. 1991. The role of von Willebrand factor and brinogen in platelet aggregation under varying shear stress. J. Clin. Invest. 87:123440 59. Kalman PG, McCullough DA, Ward CA. 1990. Evacuation of microscopic air bubbles from Dacron reduces complement activation and platelet aggregation. J. Vasc. Surg. 11(4):59198 60. Kamiya A, Togawa T. 1980. Adaptive regulation of wall shear stress to ow change in the canine carotid artery. Am. J. Physiol. 239:H1421 61. Kelly AB, Marzec UM, Krupski W, Bass A, Cadroy Y, et al. 1991. Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. Blood 77(5):100612 62. Kieffer N, Phillips DR. 1990. Platelet membrane glycoproteins: functions in

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

FLUID MECHANICS AND THROMBOSIS Adv. Bioeng. 26:55558, New Orleans, La Markou CP, Lindahl AK, Siegel JM, Ku DN, Hanson SR. 1993. Effect of blocking the platelet GPIb interaction with von Willebrand factor under a range of shearing forces. Ann. Biomed. Eng. 21:220 (Abstr.) McKinsey J, McCord BN, Aoki T, Ku DN. 1991. Can mechanical stress cause fatigue of the atherosclerotic plaque? Surg. Forum 42:319 Moore JE Jr, Burki E, Suciu A, Zhao SM, Burnier M, et al. 1994. Device for subjecting vascular endothelial cells to both uid shear stress and circumferential cyclic stretch. Ann. Biomed. Eng. 22:41622 Moore JE Jr, Maier SE, Ku DN, Boesiger P. 1994. Hemodynamics in the abdominal aorta: a comparison of in vitro and in vivo measurements. J. Appl. Physiol. 76:152027 Moore JE Jr, Xu C, Glagov S, Zarins CK, Ku DN. 1994. Fluid wall shear stress measurements in a model of the human abdominal aorta: oscillatory behavior and relationship to atherosclerosis. Atherosclerosis 110(2):22540 North American Symptomatic Carotid Endarterectomy Trial Collaborators (NASCET). 1991. Benecial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N. Engl. J. Med. 325:44553 Perktold K Rappitch G. 1995. Computer simulation of local blood ow and vessel mechanics in a compliant carotid artery bifurcation model. J. Biomech. 28:845 56 Peskin CS McQueen DM. 1989. A threedimensional computational method for blood ow in the heart. I. Immersed elastic bers in a viscous incompressible uid. J. Comput. Phys. 81:372405 Physicians Health Study Research Group (PHSRG). 1989. Final report on the aspirin component of the ongoing

327

73.

82.

74.

83.

75.

84.

76.

85.

86.

77.

87.

78.

79.

88.

89.

80.

90.

81.

91.

Physicians Health Study. Steering Committee of the Physicians Health Study Research Group. N. Engl. J. Med. 321(3):12935 Reininger AJ, Reininger CB, Heinzmann U, Wurzinger LJ. 1995. Residence time in niches of stagnant ow determines brin clot formation in an arterial branching modeldetailed ow analysis and experimental results. Thromb. Haemost. 74(3):91622 Reuderink PJ. 1991. Analysis of the ow in a 3D distensible model of the carotid artery bifurcation. PhD thesis. Technische Univ. Eindhoven, Netherlands Richardson PD. 1973. Effect of blood ow velocity on growth rate of platelet thrombi. Nature 245(5420):1034 Ricotta JJ, Schenk EA, Ekholm SE, DeWeese JA. 1986. Angiographic and pathologic correlates in carotid artery disease. Surgery 99(3):28492 Rindt CC, van Steenhoven AA, Janssen JD, Reneman RS, Segal A. 1990. A numerical analysis of steady ow in a three-dimensional model of the carotid artery bifurcation. J. Biomech. 23(5):46173 Roald HE, Barstad RM, Kierulf P, Skjorten F, Dickinson JP, et al. 1994. Clopidogrela platelet inhibitor which inhibits thrombogenesis in non-anticoagulated human blood independently of the blood ow conditions. Thromb. Haemost. 71(5):65562 Rodbard S. 1970. Negative feedback mechanisms in the architecture and function of the connective and cardiovascular tissues. Perspect. Biol. Med. 13:50727 Rodkiewicz CM, Sinha P, Kennedy JS. 1990. On the application of a constitutive equation for whole blood. J. Biomech. Eng. 112:198206 Ruckenstein E, Marmur A, Gill WN. 1977. Growth kinetics of platelet thrombi. J. Theor. Biol. 66(1):14768 Saelman EU, Nieuwenhuis HK, Hese KM, de Groot PG, Heijnen HFG, et al.

328

WOOTTON

KU man B. 1993. Analysis of shear stress and hemodynamic factors in a model of coronary artery stenosis and thrombosis. Am. J. Physiol. 265(5):H178796 Tandon P, Diamond SL. 1997. Hydrodynamic effects and receptor interactions of platelets and their aggregates in linear shear ow. Biophys. J. 73(5):281935 Tang TD. 1990. Periodic ow in a bifurcating tube at moderate Reynolds number. PhD thesis. Georgia Inst. Technol., Atlanta. 211 pp. Tilles AW, Eckstein EC. 1987. The nearwall excess of platelet-sized particles in blood ow: its dependence on hematocrit and wall shear rate. Microvasc. Res. 33(2):21123 Torvik A, Svindland A, Lindboe CF. 1989. Pathogenesis of carotid thrombosis. Stroke 20(11):147783 Turitto VT, Baumgartner HR. 1975. Platelet deposition on subendothelium exposed to owing blood: mathematical analysis of physical parameters. Trans. Am. Soc. Artif. Intern. Organs 21:593 601 Turitto VT, Weiss HJ, Baumgartner HR. 1980. The effect of shear rate on platelet interaction with subendothelium exposed to citrated human blood. Microvasc. Res. 19(3):35265 United Kingdom Transient Ischaemic Attack Study Group (UK-TIA). 1988. United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. UK-TIA Study Group. Br. Med. J. Clin. Res. Ed. 296(6618):31620 Wang NHL, Keller KH. 1985. Augmented transport of extracellular solutes in concentrated erythrocyte suspensions in Couette ow. J. Colloid Interface Sci. 103(1):21025 Wilcox JN, Smith KM, Schwartz SM, Gordon D. 1989. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc. Natl. Acad. Sci. USA 86(8):283943 Wootton DM. 1998. Mechanistic mod-

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

1994. Platelet adhesion to collagen types I through VIII under conditions of stasis and ow is mediated by GPIa/IIa (alpha 2 beta 1-integrin). Blood 83(5):124450 Sakariassen KS, Joss R, Muggli R, Kuhn H, Tschopp TB, Sage H, Baumgartner HR. 1990. Collagen type III induced ex vivo thrombogenesis in humans: role of platelets and leukocytes in deposition of brin. Arteriosclerosis 10(2):27684 Sakariassen KS, Kuhn H, Muggli R, Baumgartner HR. 1988. Growth and stability of thrombi in owing citrated blood: assessment of platelet-surface interactions with computer-assisted morphometry. Thromb. Haemost. 60(3):392 98 Salam TA, Lumsden AB, Suggs WD, Ku DN. 1996. Low shear stress promotes intimal hyperplasia thickening. J. Vasc. Invest. 2:1222 Santamore WP, Bove AA, Carey RA. 1982. Tachycardia induced reduction in coronary blood ow distal to a stenosis. Int. J. Cardiol. 2:2327 Savage B, Saldivar E, Ruggeri ZM. 1996. Initiation of platelet adhesion by arrest onto brinogen or translocation on von Willebrand factor. Cell 84(2):289 97 Schoephoerster RT, Oynes F, Nunez G, Kapadvanjwala M, Dewanjee MK. 1993. Effects of local geometry and uid dynamics on regional platelet deposition on articial surfaces. Arterioscler. Thromb. 13(12):180613 Siegel JM. 1992. Wall shear stress through an arterial stenosis and its implications to thrombosis. MS thesis. Georgia Inst. Technol., Atlanta. 88 pp. Siegel JM, Markou CP, Ku DN, Hanson SR. 1994. A scaling law for wall shear stress through an arterial stenosis. J. Biomech. Eng. 116:44651 Sixma JJ, de Groot PG. 1994. Regulation of platelet adhesion to the vessel wall. Ann. NY Acad. Sci. 714:19099 Strony J, Beaudoin A, Brands D, Adel-

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

FLUID MECHANICS AND THROMBOSIS eling of occlusive arterial thrombosis. PhD thesis. Georgia Inst. Technol., Atlantic. 421 pp. 112. Wootton DM, Markou CP, Hanson SR, Ku DN. 1998. Mechanistic model of arterial thrombosis in collagen-coated stenoses. Proc. ASME Biomed. Eng. Div., NYC. Adv. Bioeng. 39:11314, Anaheim, Ca 113. Yoganathan AP, Lemmon JD Jr, Kim YH, Walker PG, Levine RA, Vesier CC. 1994. A computational study of a thinwalled three-dimensional left ventricle during early systole. J. Biomech. Eng. 116:30717 114. Young DF. 1979. Fluid mechanics of

329

arterial stenoses. J. Biomech. Eng. 101: 15775 115. Yucel EK. 1994. Magnetic Resonance Angiography in Vascular Diseases: Surgical and Interventional Therapy, ed DE Strandness Jr, pp. 289302. New York: Churchill Livingstone 116. Zarins CK, Zatina MA, Giddens DP, Ku DN, Glagov S. 1987. Shear stress regulation of artery lumen diameter in experimental atherogenesis. J. Vasc. Surg. 5:41320 117. Zydney AL, Colton CK. 1988. Augmented solute transport in the shear ow of a concentrated suspension. PhysicoChem. Hydrodyn. 10:7796