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2 AUTHORS:
David M Wootton
David N Ku
SEE PROFILE
SEE PROFILE
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Biological Responses to Hemodynamics ............................................... 305
Hemodynamics of Stenoses ................................................................ 308
1
Department of Biomedical Engineering, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205
15239829/99/08200299$08.00
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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 flow 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 flow and pressure conditions by growing
or shrinking to meet changing hemodynamic demands.
It is important to study blood flows 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 flow in arteries. This review focuses on some selected
areas of importance to cardiology.
PHYSIOLOGIC ENVIRONMENT
The fluid 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 field of biorheology and has
been reviewed by others (e.g. 21, 89).
Blood flow 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 flow 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 flows dominate many of the problems in the cardiovascular system.
The existence of unsteady flow forces the inclusion of a local acceleration term
in most analyses. In contrast to unsteadiness, several features of biological flows
may often be neglected as being of secondary importance for particular situations.
These include vessel wall elasticity, non-Newtonian viscosity, slurry particles in
the fluid, body forces, and temperature. Although each of these factors is present
in physiology, the analysis is greatly simplified if they can be justifiably neglected,
which is the case in most arterial flows.
Biologists are often concerned with the local hemodynamic conditions in a
particular artery or branch. The important fluid mechanic parameter is often a detailed local description of the fluid-wall shear stress in a blood vessel for a given
pulsatile flow situation. The three-dimensional nature of many of these unsteady
flows 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 flow must decelerate,
and an adverse pressure gradient can exist. In this situation, flow separation is
possible and typically occurs along the walls of the sinus.
As blood flows across the endothelium, a shear stress is generated to retard
the flow. The wall shear stress is proportional to the shear rate c (velocity gradient)
at the wall, and the fluid dynamic viscosity l: s 4 lc. Shear stress for laminar
steady flow in a straight tube is
s 4 32lqp11D13,
where q is volume flow 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 flow 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 flows. The
velocity and velocity gradient must be measured very close to a wall, which is
technically difficult. The gradient will depend highly on the shape of the velocity
profile and the accurate measurement of distance from the wall. For blood flow,
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 flow rates directly. Determination
of the flow 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 flow 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 4 0.5PDt11,
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).
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FIGURE 1 Hydrogen bubble visualization of flow through a model carotid bifurcation illustrating the laminar flow at the
flow divider and separation of flow 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 coefficients
greater than 0.9, p , 0.001. Comparison of the unsteady, three-dimensional in
vitro results against in vivo measurements with Doppler ultrasound confirms that
the assumptions of the modeling are valid (66). Several groups have recently used
computational fluid dynamics to study the effects of wall elasticity and nonNewtonian viscosity (4, 86). These effects are small in comparison with the anatomic and flow 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 flow 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 outflow 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
profiles in the sinus region of a
three-dimensional model of the
carotid bifurcation, using laser
Doppler anemometry (LDA) and
computational fluid dynamics
(CFD). b. Flow in the carotid
sinus is unsteady with a transient
reverse flow 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.)
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ies, having more flow during diastole. Flow can be reversed during systole. The
high pressure in the myocardium during systolic contraction causes the blood
flow 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 flows during part of the cardiac cycle. The actual fluid
dynamics have been characterized with large-scale experimental models (103)
and spectral-element computational modeling (50, 51). Comparison of the flow
field 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 flow
field regimes in a dramatic way (50). However, changes in the coronary flow
waveform affect the magnitudes of oscillation significantly (50).
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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 defined as percent occlusion
by diameter, as follows:
% stenosis 4 (D11D2)/D1 2 100%,
where D1 is upstream diameter and D2 is the minimum diameter in the stenosis.
As disease advances, the percent stenosis increases.
Stenotic flows have been well characterized by a number of investigators.
Some important summary features are that flow 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%, flow 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 flow 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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Two important clinical consequences arise from the collapse of stenoses. One
is that the flow rate can be limited by choking, beyond that of purely turbulent
losses. This flow limitation or critical flow rate has long been observed by physiologists and described as the coronary flow reserve that is limited even with
decreases in distal resistance. Estimates of coronary flow reserve should include
this choking flow 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 flow 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 fluid-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 significant 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 flow waveform in the leg
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Shear-Dependent Thrombosis
Stenotic flows 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 fills 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 fibrin.
Arterial thrombosis is an extremely significant 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 fibrin emboli
are frequently found in the myocardium (heart muscle) of victims of heart disease
(28, 37). Clinical studies confirm the link between thrombosis and atherosclerosisantithrombotic drugs significantly reduce the risk of clinical ischemia (40,
81, 108).
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Vessel (reference)
Femoral artery (44)
Common carotid (65)
Internal carotid (65)
Left main coronary (51)
Right coronary (50)
a
Diameter
(mm)
Average flow
rate (ml/s)
Mean
Reynolds
number
5.0
5.9
6.1
4.0
3.4
3.7
5.1
5.0
2.9
1.7
280
330
220
240
150
Mean wall shear rate and shear stress are estimated from the Poiseuille profile.
Mean wall
Mean wall
shear
shear stressa
ratea (s!1)
(dyne/cm2)
300
250
220
460
440
11
8.9
8
16
15
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collagen increases for shear rates from 100 to at least 10,000 s11 (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 s11 (11), whereas another
experiment shows an increase in deposition rate between 4,300 and 20,000 s11
(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 s11 (72). On smooth
artificial 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 s11 (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 (2) (72),
and in U-channels (n) (8). Platelet accumulation rate on collagen III over 5 min (m,n)
(11, 92), estimated from thrombus volume by a linear correlation of data published for the
same system (93), platelets/thrombus volume 4 9 2 1010 platelets/ml.
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(1)
(2)
with c 4 0.15 5 0.03 and m 4 0.8 5 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 s11. The model is consistent with transport rates for a
variety of solutes in whole blood and was later confirmed 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 s11 to 1200 s11 (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 s11 (52) and
fit to a platelet stimulation function, PSF (16), such that PSF 4 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 flowing 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 flow that has a gradually changing shear rate,
stenotic flow with a rapid increase in shear stress may significantly 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 fluid mechanical stress. A theoretical model has
been developed for embolization in steady and pulsatile flows (14), based on
models of drag on a protrusion into steady (12) and pulsatile (13) flow. The stress
on the thrombus depends on the particle Reynolds number, Rep 4 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 fivefold the wall shear stress
of the approaching flow. 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 flow. But separated flow
occurs at bifurcations, and downstream of stenoses that occur in atherosclerosis.
In regions of complex flow, the relationships between flow and thrombosis are
not very clear.
Convection patterns and high residence times may modulate thrombosis in
separated flows. 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 fibrin polymerization in shear flow (36, 82).
Based on steady-flow experiments, residence time on the order of at least 10
s is required for significant shear-induced aggregation (56) or fibrin polymer
accumulation (82). In physiologic pulsatile flow, 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
flow separator, which could be created by a tear or flap following plaque rupture,
or by a poorly designed prosthetic valve. A sudden expansion, which has a geometric flow separator, creates an environment favoring a fibrin-rich red thrombus
(18). High residence time could also occur distal to a flow-limiting acute platelet
plug, in which case occlusion becomes the primary cause of high residence time
and fibrin coagulation.
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statistics. However, using only stenosis severity misses patients with moderate or
mild stenoses (,50% diameter reduction), who have a significant 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 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 flow rate, occlusion occurs for smaller lumen sizes (,2.7 to 3 mm) and for higher shear rates
(.600 s11) (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 flow 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 flow and platelet accumulation, but in other experiments, the rate
of accumulation is limited by a drop in the aggregation rate. To first order, the
final size of a thrombus is proportional to the acute rate of platelet accumulation
and the duration of the acute phase of platelet deposition.
The first 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-fluid interactions and thrombus shape or are explor-
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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 modified 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 first-order reaction
step that includes both aggregation and activation. Flow and transport equations
can be solved analytically in tubular flow. For a stenosis, a commercial computational fluid dynamics package is used to compute the flow field 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 flow, 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 flow.
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 difficult 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 4
DlumenCth
` td ,
2fjlumen
(3)
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WOOTTON n KU
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 f 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 benefit of surgery with percent stenosis. Platelet count is a hematologic parameter that should also have a strong influence 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 flow 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 field that allows one to characterize the
biological responses to mechanical forces. Specific arteries exhibit flow characteristics that are three-dimensional and developing. Diseased arteries can create
high levels of turbulence, head loss, and a choked flow condition in tubes that
can collapse. The pulsatile nature of the flow creates a dynamic environment with
many interesting fundamental fluid mechanics questions. The fundamental knowledge can be used to predict and change blood flow 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 fluid 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.
Visit the Annual Reviews home page at http://www.AnnualReviews.org.
LITERATURE CITED
1. Aarts PAMM, Steendijk P, Sixma JJ,
Heethaar RM. 1986. Fluid shear as a
possible mechanism for platelet diffusivity in flowing 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 flowing 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 flowing 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
8.
9.
10.
11.
12.
13.
324
14.
15.
16.
17.
18.
19.
20.
21.
22.
WOOTTON n KU
thrombiII. The effect of pulsatile
blood flow. 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.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
325
326
WOOTTON n KU
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
327
328
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
WOOTTON n KU
1994. Platelet adhesion to collagen types
I through VIII under conditions of stasis
and flow 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
fibrin. Arteriosclerosis 10(2):27684
Sakariassen KS, Kuhn H, Muggli R,
Baumgartner HR. 1988. Growth and stability of thrombi in flowing 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 flow distal to a stenosis.
Int. J. Cardiol. 2:2327
Savage B, Saldivar E, Ruggeri ZM.
1996. Initiation of platelet adhesion by
arrest onto fibrinogen 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 fluid
dynamics on regional platelet deposition
on artificial 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.
329