BRIEF REVIEWS
Flow-Induced Trauma to Blood Cells
SALVATORE P. SUTERA
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THE TECHNOLOGY of implantable vascular prostheses
and extracorporeal circulation is now commonplace in
modern medicine. The essential function of this technology is the passage and/or processing of blood in some
manner, and this inevitably requires intimate and prolonged contact between the blood and various manmade
devices, e.g., pumps, valves, tubing, membranes, etc.
Some systems, such as the extracorporeal heart-lung bypass, may be used acutely for periods of only a few hours
but others are implanted for indefinite terms. In either
case the associated blood trauma must be kept within
tolerable limits. In surgical practice blood trauma is often
a limiting factor in the duration of an acute procedure. It
can also cause significantly abnormal physiological states
during chronic exposures such as hemodialysis. To cope
with these problems will require a thorough understanding
of how blood is traumatized during circulation through
artificial organs. It is only through such understanding that
rational criteria for the design of these systems can evolve.
Reports of blood degradation associated with artificial
organs have been appearing in the literature for at least 20
years. The majority of the very early papers dealt with the
hemolytic anemia generally found following the installation of valvular protheses. It was not until the mid-1960's
that the attack on the problem began to take a more
scientific turn by focusing on the mechanisms responsible
for blood trauma rather than the mere reporting of the
amount of trauma produced by particular devices or procedures. Attracted by the challenging fluid-mechanical
and transport aspects of the problem, many engineers
with experience in these disciplines joined medical colleagues in formulating theoretical and experimental studies of flow-induced blood trauma. As a result, most of the
research groups which have contributed consistently in
this area tend to be highly interdisciplinary. Indeed, like
the entire field of artificial organs, the blood degradation
problem has provided a fruitful meeting ground for the life
scientist and the engineer.
Classification of Trauma Mechanisms
It has been the common approach to classify the various
processes suspected of being traumatic as basically me-
From the Department of Mechanical Engineering, Washington University, St. Louis, Missouri.
Original work reported in this review was supported by Grant HL
12839 from the National Heart, Lung and Blood Institute.
Address for reprints: S.P. Sutera, Ph.D., Washington University. Box
1185, St. Louis, Missouri 63130.
chanical or basically chemical, but there is a good reason
to suspect that certain of the processes in each class act in a
coupled fashion in any real flow situation. For example,
collisions between blood cells and a nonbiological surface
(a mechanical process), in addition to carrying the prospect of immediate physical damage to the cell membrane,
make possible chemical reactions between membrane constituents and the surface. Moreover, this cell-wall interaction might facilitate other chemical reactions between
plasma solutes and the surface, including adsorption and
denaturation of plasma proteins. These reactions may, in
turn, trigger release reactions among the cells, the platelets in particular, leading to thrombosis. Thrombosis, it
can certainly be said, is a complex type of blood degradation the course of which is known to be influenced by flow,
although the nature of the influence is far from being well
understood.
The likelihood of coupled mechanical and chemical effects notwithstanding, it has been the philosophy of most
of the investigations in this area to isolate, insofar as
possible, the various mechanisms and study them separately. For example, the majority of the work on the
tolerance of erythrocytes to fluid shear have been carried
out in vitro with the other cells and all plasma proteins
excluded from the suspending medium. Then, particular
plasma proteins have been added in a controlled manner
in order to expose their influence, if any, on the shear
effect. Other studies have concentrated on individual
plasma proteins in contact with particular surfaces of interest.
The majority of the research done on the subject of
blood trauma has concentrated on red cells. Platelets are
"runner-up" and presently seem to be attracting more
attention than red cells. White cells have received the least
attention to date in this field of research. The brief review
to follow is organized accordingly, beginning with the
erythrocyte and proceeding to the platelet and, finally, the
leukocyte. In the interest of brevity the survey has been
limited to a few specific papers published, for the most
part, over the last 6 years. The lists of references in these
papers should provide the interested reader with effective
keys to a wide selection of relevant background literature.
Apologies must be extended to the many investigators
whose work could not be cited here.
Before entering the subject proper it may be helpful to
readers who are not readily conversant with the discipline
of fluid mechanics to devote a few paragraphs of explanation to the principal terms and concepts to be used in the
discussion of "flow"-induced or "shear"-induced trauma.
BLOOD CELL TRAUMA/Sutera
TUBE FLOW
On the Nature of Shear Flow, Laminar and Turbulent
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Whenever a fluid moves in contact with a solid surface a
shearing action will occur in the fluid adjacent to the
surface. The nature of this shear flow can be qualitatively
described in terms of the two simple but highly ubiquitous
flows sketched in Figures 1 and 2: tube flow and jet flow.
In tube flow, the fluid in contact with the surface does not
slip past the surface, hence has zero velocity there. The
fluid velocity is maximum at the center line of the tube and
decreases gradually to zero at the wall. Laminar and turbulent flows present different velocity profiles, the latter
being generally flatter near the center line with steeper
gradients of velocity at the wall. Within these so-called
boundary layers shear stresses exist. Their effect is to
maintain the motion of the slow fluid adjacent to the wall
and, at the same time, to resist the motion of the faster
core flow past the wall. In laminar flow the intensity of the
shear stress locally is proportional to the velocity gradient
(slope of the velocity profile) and the fluid viscosity. In
turbulent flow, an additional mechanism associated with
chaotic eddy motion serves to increase the effective viscosity of the flow. This mechanism is described empirically in
terms of an "eddy viscosity."
A jet issuing from an orifice into a relatively quiescent
fluid (Fig. 2) will entrain some of the latter fluid and,
consequently, a gradually thickening shear layer develops
around the jet. In this situation the shear flow is not
intimately associated with a solid surface.
The basic characteristics of shear flows briefly described
above apply not only to pure fluids but also to complicated
suspensions like blood. Certainly the suspended cells will
affect such macroscopic features of the flow as the velocity
profile, but the shearing action will remain. A cell which is
entrained into a region of intense shearing will experience
a distribution of shear stress over its membrane. This
distributed stress is exerted by the surrounding fluid. In
response thereto, a blood cell will deform, and in the
process the cell membrane may be stretched substantially.
Short of cell lysis the membrane may suffer irreversible
changes detrimental to its essential function.
The details of the aforementioned distrubution of shear
stress over a cell surface will depend on the position and
orientation of the cell in the shear field, and the proximity
of other cells and containing surfaces. This last point is
important. If the cell is being transported through a
boundary layer, i.e., close to a surface, rather than a "free
jet", it faces the possibility of making contact with the
surface. Damage resulting from such a contact would not
be distinguishable from that occurring in the shear layer
itself unless one were able to follow individual cells and
see what happens to them, which is not usually practicable. This uncertainty, viz., whether cells are damaged by
shear forces in the bulk flow or by physical contact with
foreign surfaces, is highly pertinent to the succeeding discussion of shear-induced hymolysis.
Shear-Induced Hemolysis
Probably the most studied aspect of the blood degradation problem is shear-induced hemolysis, and the literature on this subject is now quite extensive. An excellent,
'/ / /
/\
LAMINAR
PROFILE
TURBULENT
PROFILE
BOUNDARY LAYER
FIGURE 1 Qualitative sketch of velocity distributions in laminar
and turbulent tube flow. The boundary layer adjacent to the wall is
the zone of most intense shearing action.
fairly recent review article by Blackshear1 will provide the
interested reader with valuable background and quick
access to pertinent references. The following summary will
concentrate mainly on work reported since Blackshear's
review appeared and discuss some important questions
remaining to be answered.
Controlled studies of shear-induced hemolysis have
been carried out almost exclusively in vitro. In attempting
to achieve simple, well defined flow fields, investigators
have resorted to a variety of flow systems. The concentric
cylinder viscometer or Couette cell has been preferred
because the shear stress is practically uniform through the
fluid or suspension being sheared and high rates of shear
are readily attainable.2"7 The uniformity of stress holds
true for both the laminar and turbulent flow regimes and
the latter is readily attainable in a Couette cell. The coneand-plate viscometer and the capillary tube have also been
used.8"10 In all of these systems the sheared suspensions
are confined by various nonbiological surfaces such as
steel, glass, plastic, and sometimes gas interfaces; and the
passages occupied by the suspensions are characteristically
narrow, ranging from less than 100 fj.m to a few millimeters. Because they are clearly accessible to the contained
ORIFICE FLOW
V/////////////////////A
FREE SHEAR LAYER
FIGURE 2 Shear flow generated by jet flow issuing from an
orifice.
CIRCULATION RESEARCH
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blood cells these surfaces could participate in the trauma
observed in a shearing experiment, and this possibility of a
simultaneous surface influence has complicated attempts
to interpret the effect of shear stress alone.
One experimental design used by the University of Minnesota group eliminated the presence of foreign surfaces in
the shear zone by using a liquid jet injected into a suspension of erythrocytes to create the shearing action."' 12 The
difficulty with this approach is that the jet flow field is
complex and the average time exposure of the cells to
shear is uncontrolled and very short (estimated at about
10"5 sec). Other noteworthy attempts to avoid or minimize the influence of foreign surfaces were reported by
Rooney,13 who used an ultrasonically pulsating gas bubble, and Williams et al.,l4 who generated a shear field with
an oscillating wire.
Examination reveals that the results of these experiments are not in complete agreement. A central issue in
the various interpretations is the extent to which containing surfaces are responsible for the hemolysis observed.
Some investigators2-4> 6 concluded that the hemolysis produced in their viscometric systems was predominantly surface-related and thus a characteristic of the particular
apparatus. Others claim to have measured true thresholds
for stress-induced, in-bulk hemolysis,3'5l9~12 but the
thresholds range widely, from less than 1,000 to over
40,000 dyn/sq cm.10"12
An appealing hypothesis which attempts to unify these
findings was advanced by Leverettef a/.5 According to this
hypothesis there are two primary determinants of in-bulk
hemolysis: shear stress and exposure time. Cells exposed
to stress for very short times, as in the jet test,"1 2 can
withstand very high stresses without lysing. On the other
hand, sustained exposure can cause lysis at much lower
stresses. Below a certain level of applied fluid stress normal erythrocytes will not rupture even if exposed idenfinitely. Independent studies at Rice University5 and at
Washington University7 indicate that this low stress
threshold is in the range 1,500-2,500 dyn/sq cm. This
stress-time relationship apparently reflects the true viscoplastic nature of the red cell membrane. The response of a
viscoplastic substance to an applied load which exceeds its
yield strength is naturally time-dependent and the resulting deformation or strain increases with the duration of the
load. If the load acts for a sufficiently short time the
material will not have time to deform to the point of
rupture.
It is also worthy of emphasis that the latter study7 was
done in turbulent shear flow, whereas the former was
done in laminar flow. It can thus be inferred that the
presence of turbulent fluctuations is not deleterious per se
provided the time-averaged shear stress does not exceed
the threshold. The relevance of turbulent flow to the
present discussion lies primarily in the possibility of its
employment to accelerate convective diffusuon on the
blood side of an oxygenator and/or heat exchanger. Because of the chaotic eddying motion characteristic of turbulent flow the transport of oxygen or heat away from a
boundary layer toward the central part of the flow should
be much more rapid than in a purely laminar flow wherein
VOL. 41, No.
1, JULY
1977
such transport is limited by molecular diffusion. Although
the use of turbulent blood flow to enhance transfer rates in
membrane oxygenators has been suggested and examined
theoretically,15 this idea has not yet been tested experimentally. Second, in an extracorporeal circuit which is
handling total cardiac output, say 5 liters/min, steadily,
the blood flow is very probably turbulent wherever the
conduit diameter is less than about 1 cm. In the natural
circulation of humans, fully developed turbulent flow does
not occur, although the flow in the thoracic aorta during
systolic ejection exhibits some of the randomness and
fluctuating characteristics of turbulent flow.
Further confirmation of in-bulk lysis of human red cells
at shear stresses slightly beyond the above-mentioned
threshold was obtained by fixation of cells while they were
suspended in shear flow.7 Figure 3 is a scanning electron
microphotograph of human red cells after 2 minutes of
exposure to 4,500 dyn/sq cm. Cell fragments are clearly
seen as well as one dumbbell-shaped cell whose rupture
into two fragments appears imminent. The remarkably
smooth ellipsoidal shapes were found to occur at stresses
above 2,000 dyn/sq cm in a saline suspension. Similar
shapes have been generated at lower stresses in high viscosity media.16 The velocity and stress distributions in the
membrane of such elongated cells, along with the role of
the external medium viscosity, are yet to be thoroughly
analyzed. These are fascinating problems, clearly relevant
to the subject of flow-induced trauma and certain to prove
challenging to rheologists inclined to tackle them.
The foregoing summary indicates that the shear stress
required to produce lysis of human erythrocytes in vitro is
quite high, on the order of 10 times the maximum shear
stress occurring in the normal human circulation, even
when the stress is sustained for long times. Hence, the
designer of components for extracorporeal circuits should
have no difficulty staying well below the lower stress
FIGURE 3 Human red cells fixed under stress at 4,500 dyn/sq cm
after 2-minute shearing at 37°C. Taken through scanning electron
microscope at 45° to plane of cell.
BLOOD CELL TRAUMA/Sutera
threshold of 1,500 dyn/sq cm. It would seem to follow
logically then that the widespread occurrence of intravascular hemolysis17"19 associated with valvular heart disease,
malfunctioning prosthetic valves, and severe stenosis is a
consequence primarily of cell-surface interactions promoted by markedly abnormal flow patterns. This was the
conclusion reached by Blackshear.1 Insofar as normally
functioning prosthetic valves are concerned, particularly
ball- and disk-type valves, a recent analysis by Roschke et
al.20 suggests that red cells passing through such valves
could be exposed to boundary layer stresses sufficiently
high for sufficiently long times to cause lysis.
Subhemolytic Trauma
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In spite of the seemingly high tolerance of erythrocytes
to fluid shear, it is well known that the cells can be altered
during prolonged in vitro exposure to shear stresses which
are well below any hemolytic threshold. This subhemolytic
or sublethal trauma can be very subtle and much more
difficult to detect and to characterize than outright lysis.
Significantly shortened cell life-spans following reinfusion
into the living circulation is possibly the most troublesome
consequence of this type of damage. In the clinical setting
its common manifestation is postperfusion anemia. The
related problem of hemolytic anemia associated with prosthetic heart valves was reviewed not long ago by Bernstein.21
Both autohemolysis and accelerated splenic sequestration of red cells have been observed to occur after blood
has been exposed to an extracorporeal system for even a
few hours.3'22 The experiments of Sandza et al.,22 in which
an isolated rabbit spleen was perfused by a mixture of
sheared and unsheared autologous erythrocytes, showed
that the spleen could "recognize" and selectively remove
cells that had been exposed to less than 100 dyn/sq cm for
2 hours. Although these cells appeared quite normal in
shape under the microscope, it is certainly conceivable
that the in vitro shearing had rendered them slightly less
deformable and/or slightly more adhesive and thus more
susceptible to being trapped in the spleen.
With regard to the detailed nature of subhemolytic
trauma, the extensive investigations of Indeglia et al.23
revealed increased hemoglobin and lactic dehydrogenase
release into plasma by damaged cells. This finding would
suggest cell fragmentation with partial loss of these large
intracellular constituents and subsequent resealing of the
fragments. The resulting fragments would be more spherical than the parent cell and thus more fragile to osmotic
stress. Also observed were decreased cellular sodium and
potassium concentrations and increases in serum fatty
acids, triglycerides, and total lipids that apparently occurred at the expense of the erthrocyte membranes. A
subsequent study24 of lipid loss from canine erythrocytes
simply pumped around a circuit of plastic tubing for 3
hours confirmed the release of several lipid and phospholipid components of the cell membrane. Free fatty acids
were also found to be eluted in relatively large quantities.
Increased membrane permeability to Na+ influx was
observed by Nanjappa et al.25 in erythrocytes exposed to
the relatively low stress of 100 dyn/sq cm in a cone-plate
device for periods ranging to 1 hour. In addition, a reduction in membrane-associated acetylcholinesterase activity
was measured. Since the enzyme acetylcholinesterase is a
membrane constituent this reduction may also indicate
loss of membrane due to shearing. It is also interesting to
note that similar reduction has been found to accompany
normal aging of red cells.
Lubowitz et al.26 forcused their attention on the permeability of human erythrocytes to sodium. Cells suspended
in phosphate-buffered saline in a Couette viscometer for
periods of 3-4 hours were sheared at stresses below 500
dyn/sq cm. In this particular case the shearing flows were
basically laminar but included the cellular vortical motion
known as Taylor vortices. Thus the flow regime may be
considered as intermediate to laminar and turbulent. Sodium permeability and, consequently, cell sodium content
were found to be permanently increased by shearing. The
increase in sodium permeability was attributed to shearinduced alterations in membrane structure. Since the red
cell membrane is freely permeable to water, cells with
increased sodium content would be more susceptible to
osmotic hemolysis. Although there is a theoretical possibility of osmotic hemolysis in vivo in areas of the kidney
(ascending loop of Henle) where erythrocytes are exposed
to a hypotonic milieu, this has not been proven as a
significant mechanism for hemolysis. Experimental evidence was also obtained indicating that the membrane
"sodium pump" was not damaged by the shearing and was
capable of compensating partially for the increased inward
diffusion of sodium by increasing active sodium efflux.
The stimulated activity of the sodium pump should also
increase the rate of glycolysis and work concomitantly to
maintain intracellular ATP levels adequate to support
transport.
If membrane permeability to Na ions is increased by
exposure to shear, it is to be expected that permeability to
K ions would also be affected, and this has been verified.27
The possibility that leakage of other molecules which may
be vital to membrane stability, e.g., ATP and 2-3 DPG,
may also be induced by subhemolytic levels of shear stress
has been advanced but not yet verified, to the reviewer's
knowledge.
A simple mechanism which has been hypothesized to
account for the effect of shear on membrane permeability
is the gradual opening of "pores" in the stretched membrane. Indeed, the prelytic escape of K ions has been
demonstrated to occur during gradual osmotic lysis28 and
filtration of red cells through micropores.29 Blackshear1
estimates that pores of order 10-20 A would allow the
cations Na+ and K+ as well as the larger ATP and 2-3 DPG
molecules to pass, but not the much larger Hb molecule
(—60 A). Chien et al.29 proposed that the openings may be
as large as 100 A but, being transitory, may not remain
open long enough for appreciable hemoglobin diffusion.
In this regard it should be noted that the findings of
Lubowitz et al.26 indicate that the increased permeability
to Na ions persists after the shearing is stopped and the
cells are allowed to relax to their normal biconcave form.
Thus, whatever the correct explanation of shear-induced
CIRCULATION RESEARCH
changes in membrane permeability, it appears that the
changes are not entirely transitory.
Whether or not transitory "pores" or "holes" can actually exist in the erythrocyte membrane is still a subject
for debate. The most widely accepted structural model of
the membrane presently is a composite one consisting of a
lipid bilayer in a liquid state superimposed on a solid-like
protein monolayer.30- 3I It is difficult to reconcile the appearance of holes, especially of well defined dimensions,
with the various modes of plastic failure that can occur in
the composite model.32'33 Instead, it seems plausible that
under appropriate distributions of tension there might be a
local, transient thinning of the membrane which would
permit accelerated diffusion of cation and hemoglobin
molecules inward or outward as the existing concentration
gradients would dictate.
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Platelets
Platelets are highly sensitive cells which, when exposed
to appropriate stimuli, may aggregate and release their
contents into the surrounding medium. They also adhere
readily to nonbiological surfaces. One example of the
response of platelets to "mechanical" or, more correctly,
"mechanochemical" stress is the disappearance of platelets from the circulation when blood is pumped by an
implanted mechanical heart. Ross et al.34 show platelet
counts in calves decreasing to values which are 10-20% of
the initial values after 2 days of pumping with the BaylorRice left ventricular bypass pump. Another example is
provided by the experience of Pierce et al.,35 who pumped
dog blood for 6 hours through a closed external circuit
equipped with either a disk or membrane oxygenator. The
decrease in the number of platelets ranged from essentially
zero (Teflon membrane) to 76% (disk at 100 rpm). In no
case, however, was there hemolysis of red cells. In contrast to these results, the less traumatic exposure of blood
to extracorporeal flow during hemodialysis seems to cause
little or no change in the platelet count, at least at some
hemodialysis centers. However, the situation here is more
complex since platelet function is known to be abnormal to
begin with in uremic patients.
A more recent study by McKenna et al.36 of patients
undergoing open heart surgery revealed a number of abnormal platelet functions caused by extracorporeal circulation. In addition to the usual precipitous drop in platelet
count during bypass, tests performed at the end of bypass
revealed significant abnormalities in (1) concentrations of
fibrinogen and circulating fibrin degradation products,
(2) platelet adhesiveness to glass beads (adhesiveness decreased), and (3) platelet aggregation induced by ADP
(aggregation response diminished). The authors concluded that two factors which contributed significantly to
the observed platelet dysfunction were (1) dilution of the
patient's blood supply with transfused blood containing
inactive platelets and (2) ADP released from hemolyzed
red cells. In apparent contrast, Manohitharajah et al.3?
found that platelet survival time was not influenced by the
presence or severity of hemolysis in 28 patients with homograft or prosthetic valves. Of course, the two situations,
extracorporeal circulation and implanted prosthetic
VOL. 41, No. 1, JULY
1977
valves, differ vastly in the extent of the nonbiological
surfaces accessible to the blood and in the exposure time
of individual cells to zones of high shearing stress.
In comparison to erythrocytes, platelets have only recently become the object of controlled in vitro studies
aimed at delineating their response to shear stress. The
Baylor-Rice group was apparently the first to study platelet response to shearing in a Couette viscometer designed
specifically for blood trauma work. Data reported in two
recent papers by Brown et al.38-39 indicate that human
platelets have a substantially lower tolerance to shear
stress than do erythrocytes when the exposure is on the
order of minutes. They found that platelet lysis, indicated
by release of acid phosphatase, occurred at stresses in the
range of 100-1 50 dyn/sq cm, i.e., nearly Vio the threshold
for human erythrocytes. This relatively low tolerance for
sustained shearing has been confirmed in independent
experiments by Hung et al.40 in which platelets were also
exposed to turbulent shear flow. The latter study, however, showed a clear influence of the surface to volume
ratio of the sheared samples and thus implicated the containing surfaces of the viscometer in the platelet destruction process. A predominant surface-mediated damage
mechanism was concluded also by Johnston et al.41 from
their observations of platelet suspensions "churned" in a
Fleisch hemoresistometer.
Like erythrocytes, platelets too have exhibited a higher
resistance to shear stress when the exposure time is very
short. This was indicated in jet-shearing tests reported by
Bernstein et al.42 Given the probable viscoplastic nature of
the platelet membrane and cytoplasm, this kind of inverse
relationship between shear-induced lysis and duration of
shear is to be expected.
At stresses as low as 50 dyn/sq cm platelets sheared in a
Couette viscometer gave up serotonin, ADP, and ATP,
possibly by stimulation of the release reaction.39 Whether,
in fact, the release reaction was actually triggered by
mechanical stress or the serotonin and nucleotides came
from a fragile fraction of the platelets which were lysed at
the low stress is still open to question. The measurements
of Hung et al.40 of acid phosphatase liberated by sheared
platelets suggest that it was lost by the lysosomes as a
consequence of lysis primarily, and impairment of the
release reaction was an observed result of platelet exposure to the Fleisch hemoresistometer.41
The shearing of platelet-rich plasma in Couette viscometers has been observed to induce immediate aggregation38"10 which is partially reversible.38-39 This effect could
be especially important if it were the first step in the formation of a thrombus. Whether this aggregation tendency
could be a response to ADP released by the stressed
platelets is unclear, as there is some evidence that shearing
can diminish the aggregation response to ADP.38'39-41
However, fairly long exposure times, on the order of 1
minute to several minutes, were required to produce that
effect. Such exposures are much longer than platelets
would encounter, for example, when circulating through a
prosthetic valve. Goldsmith43 offers the interesting suggestion that the diminshed aggregation response is actually
brought about by released ADP and could be a defense
BLOOD CELL TRAUMA/Sutera
mechanism within the blood to prevent thrombus formation from occurring at high shear stresses.
In summary, it is clear that platelets are highly susceptible to trauma under the action of shear stress in flowing
blood. They may suffer lysis or such functional impairment
that they can no longer fulfill their natural role in vivo, and
the possibility that flow-induced dysfunction can promote
thrombogenesis is a paramount concern. Many questions
remain to be answered about (1) the exact nature of the
trauma induced by shearing, (2) how the mechanical stress
on a platelet actually traumatizes it (is it simply a case of
excessive deformation?), and (3) the influence of the red
cells, if any, in the whole process.
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Leukocytes
To the author's knowledge Kusserow and his associates44-45 at the University of Vermont were the first to
publish evidence that pumping blood through extracorporeal circuits could result in significant deleterious alterations in leukocytes. From their studies of whole canine
blood pumped around a closed loop of sterile plastic tubing they detected decreases in phagocytic activity, oxygen
utilization, and total cell count, with a shift in the relative
proportions of granulocytes and nongranulocytes (lymphocytes, monocytes) in the cell population. There was a
greater disappearance of the nongranulocytic forms as
through they were more vulnerable to pumping trauma.
An attempt to subject pure white cell suspensions to
simple, well defined in vitro shearing was not made until
quite recently. At the 1976 annual meeting of the American Society for Artificial Internal Organs, Mclntire presented data46 from such a study showing significant decreases in the ability of sheared leukocytes to migrate
through a Millipore filter (3-/nm mean pore size) either
randomly or in response to an attractive antigen (casein).
Leukocyte adhesion to nylon filters was increased by
shearing and some morphological alterations were also
observed. These effects were produced by shearing leukocyte suspensions in a cone-plate device over the extremely
low range of 0.70-3 dyn/sq cm. However, there was no
provision in the experiments for separation of surface from
true bulk shearing effects and Mclntire stated afterward
his belief that interactions between the cells and the surfaces (stainless steel) of the viscometer were predominant.
In summary, the evidence gathered to date indicate
clearly that leukocytes too are susceptible to flow-induced
trauma. Although their precise fragility under shearing
stress remains to be determined, it appears that potentially
dangerous functional impairment can occur. Sequestration
of damaged, perhaps less deformable leukocytes in the
lung, leading to elevated pulmonary resistance and right
ventricular hypertension, and decreased protection from
infection are two possible consequences. Certainly the
subject of leukocyte trauma deserves more research and
there is every reason to expect that more experimental
data on these complicated and interesting cells are forthcoming.
Summary and Conclusions
A considerable amount of research has been done on
flow-induced trauma to blood cells. Much is now known
concerning the nature of the trauma and the minimum
levels of (sustained) shear stress required to lyse cells in
vitro. As these levels are generally higher than those which
blood cells encounter either in normal physiological circumstances or in a well functioning extracorporeal circuit,
it seems logical to conclude that cell-surface interactions,
probably influenced by shearing flow, are the primary
cause of blood damage when it occurs in such circumstances. If correct, this conclusion means that resolution of
the blood trauma problem is going to be very difficult
because, although the engineer can design a system so as
to keep the maximum shear stress within a prescribed
bound, he cannot eliminate manmade containing surfaces.
This fact, as alluded to many times in the preceding discussuon, has even posed a persistent obstacle in the way of
clear interpretation of the experimental data on shearinduced trauma.
It appears then that future research should focus more
and more on blood-surface interactions in the presence of
flow. A few of the basic points in need of study are: (1) the
physical and/or chemical nature of a collision between a
blood cell and a wall (does the cell make "dry" contact
with the wall or can the wall affect the cell at a distance?);
(2) the role of fluid dynamics (laminar and turbulent) in
the collisional process; (3) the role of the surface's chemical properties and texture in the interaction, whether it be
one of contact or "at a distance." The subject of bloodsurface interactions could easily be the subject of another
review and, indeed, an entire conference was devoted to
the subject in 1971. The proceedings of this were published in entirety in the Federation Proceedings.47 The
reader interested in delving more deeply into this challenging area should start with those proceedings. Another
conference, "On the Behavior of Blood and its Components at Interfaces," was organized by the New York
Academy of Sciences and took place March 24-26, 1976.
The papers presented there are scheduled to appear in
Volume 283 of the Annals of the New York Academy of
Science, 1977.
Acknowledgments
I express appreciation to my colleagues Dr. R.M. Hochmuth and Dr. H.
Lubowitz for many helpful discussions of the interpretations incorporated
in the review. Dr. M.H. Mehrjardi also deserves thanks for his assistance in
the preparation of the manuscript.
References
1. Blackshear PL: Mechanical hemolysis in flowing blood. In Biomechanics: Its Foundations and Objectives, edited by YC Fung et al.
Englewood Cliffs, N.J., Prentice-Hall, 1972, pp 501-528
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S P Sutera
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Circ Res. 1977;41:2-8
doi: 10.1161/01.RES.41.1.2
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