© 1995 American Heart Association, Inc.
Articles |
Whole-Blood Platelet Aggregation Predicts In Vitro and In Vivo Primary Hemostatic Function in the Elderly
From the Institute of Pathology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio (J.D.E., D.W.L., G.L.M., P.S., J.B.L.), and the Oklahoma Medical Research Foundation, Oklahoma City (J.H.M.).
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Abstract |
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Abstract Increased platelet aggregation is associated with higher coronary artery disease mortality. Enhanced platelet aggregation in platelet-rich plasma has also been described in the elderly. To define age-related changes in primary hemostasis, we studied 37 elderly and 31 young blood donors. There were no significant age-related differences in whole-blood platelet aggregation, platelet adherence and thrombus formation on human umbilical artery segments, or bleeding time. Plasma fibrinogen was significantly higher in elderly men and women, whereas activated factor VII was elevated only in elderly women. Collagen-induced platelet aggregation was significantly correlated with platelet adherence to the subendothelium in elderly (r=.488, P=.002) but not in young donors. Accordingly, collagen-induced platelet aggregation showed a significant inverse correlation with bleeding time only in the elderly (r=-.401, P=.014). Arachidonic acid–induced platelet aggregation was significantly associated with platelet adherence to the subendothelium (r=.658, P=.003) and bleeding time (r=-.540, P=.021) only in elderly men. In young donors, ADP-induced platelet aggregation was significantly correlated with platelet adherence to the thrombogenic adventitial surface (r=.395, P=.031); in the elderly this association only approached significance (r=.315, P=.058). Whole-blood platelet aggregation in response to collagen and arachidonic acid may be more useful in predicting primary hemostatic function in the elderly than in the young. Furthermore, in the elderly, the correlation between platelet aggregation in whole blood and platelet–arterial wall interactions in vitro and in vivo may contribute to the ability of this test to predict coronary risk.
Key Words: platelet adherence • platelet aggregation • aging • fibrinogen • factor VII
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Introduction |
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Arterial atherosclerotic disease is the most common cause of death in Western societies. The incidence of myocardial infarction, stroke, and peripheral vascular disease increases with advancing age. Several studies have demonstrated that enhanced platelet reactivity is also associated with increasing age. Thus, platelet aggregation in platelet-rich plasma (PRP) is increased in the elderly, relative to young individuals, in response to the agonists ADP, epinephrine, collagen, and arachidonic acid.1 2 3 Accordingly, bleeding time has been reported to be shortened in the elderly.4 Epidemiological studies have described an increased risk of myocardial infarction and higher mortality from coronary artery disease in men with increased ADP-induced platelet aggregation in PRP and whole blood and enhanced PRP aggregation in response to thrombin.5 6
Platelet-mediated thrombosis on the surface of the atherosclerotic plaque is recognized to be the most important event in the initiation of ischemic tissue injury in patients with atherosclerotic disease. Vasilieva and colleagues7 have reported that platelets from elderly subjects show enhanced adhesive responses to thrombogenic surfaces such as glass when compared with platelets from young donors. To define the effect of aging on platelet adherence to human arterial subendothelium in flowing blood, we perfused citrated whole blood from healthy elderly and young individuals over umbilical artery segments. We compared the resulting platelet adherence and thrombus formation on the arterial surface in both age groups. We also evaluated platelet aggregation in citrated whole blood with the agonists collagen, arachidonic acid, and ADP and measured plasma fibrinogen and activated factor VII (factor VIIa) levels and bleeding time in the elderly and young subjects. Because much remains to be learned about the relationship between platelet aggregation and in vitro and in vivo primary hemostasis, we compared the interrelationships among the hematologic variables, platelet aggregation, platelet-subendothelium interaction, and in vivo primary hemostasis, as measured by skin bleeding time, in elderly and young populations.
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Methods |
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Subjects
Thirty-seven healthy elderly volunteers, 18 men (age range, 65 to 79 years; mean age, 71.78) and 19 women (age range, 65 to 89 years; mean age, 73.37) were included in the study, as were 31 healthy young donors, 15 men (age range, 23 to 30 years; mean age, 25.40) and 16 women (age range, 21 to 30 years; mean age, 25.50). All subjects were free of any history of atherosclerotic disease, abnormal bleeding, and arterial or venous thrombotic disorders, as determined by an extensive questionnaire. For at least 1 week prior to phlebotomy, the subjects refrained from ingesting ethanol, aspirin, or other medications known to alter platelet function. The study was approved by the local Institutional Review Board, and informed consent was obtained from each donor.
Perfusion Studies and Morphometric Analysis
Human umbilical artery segments were obtained, deendothelialized
by a brief exposure to air, and mounted in annular perfusion chambers
as previously described.8 Citrated whole blood from each
donor was perfused for 2 minutes at 37°C over everted arterial
segments (to measure platelet adherence and thrombus formation on the
subendothelial surface) and over noneverted arterial segments (to
measure platelet interaction with the more thrombogenic adventitial
surface, which simulates the physiological response to deep arterial
injury). All perfusions were performed at a flow rate of 300 mL/min,
which resulted in a wall shear rate (2600 s-1) that
closely simulates physiological conditions in the microvasculature and
pathological conditions in stenosed arteries.9
After each perfusion experiment, the arterial segment was washed, fixed, and embedded in glycol methacrylate. Sections (1 µm thick) of each perfused arterial segment were prepared, stained with aniline blue and basic fuchsin, and morphometrically analyzed over their entire surfaces by light microscopy as previously described.8 Platelets adherent to the arterial surface were designated as either contact platelets (C), ie, discoid platelets attached to but not spread along the surface, or spread platelets (S). A subset of spread platelets was classified as platelet thrombi (T), defined as platelet aggregates extending 5 nm or more above the arterial surface. Platelet aggregation was defined as the platelet thrombus formation normalized for surface coverage with spread platelets (ie, 100T/S). Total platelet adherence was defined as C+S, and each parameter is expressed as a percentage of the total number of points counted (approximately 1500) per vessel segment.
Platelet Aggregation Studies
Citrated whole blood was obtained from each volunteer whose
blood was used in perfusion experiments, and this was diluted with an
equal volume of isotonic saline. Platelet aggregation was performed as
described10 11 12 using a Whole Blood Lumi-Aggregometer
(Chrono-Log Corp). Platelet aggregation was measured as the change in
impedance produced 6 minutes after the addition of agonist. The
following agonists were used: 2 ng/mL collagen, 0.3 mmol/L
arachidonic acid, and 5 nmol/L ADP (all obtained from
Chrono-Log Corp). Agonist-induced platelet release of ATP was measured
by luminescence with the luciferin-luciferase reaction (Chrono-Log
Corp).
Measurement of Hematologic Variables and Bleeding Times
For all subjects, complete blood counts were performed on a
Sysmex NE-8000 automated hematology analyzer (Toa Medical Electronics).
Plasma fibrinogen levels were measured by a Clauss clotting time assay
(Dade Thrombin Reagent, Baxter-Dade). Clot formation was monitored by
changes in optical density with an automated coagulation analyzer
(MLA-900C; Medical Laboratory Automation). Factor VIIa levels were
measured by a recently described, highly sensitive, clot-based
assay that is free from interference by zymogen factor
VII.13 Measurement of the skin bleeding time was performed
with a spring-loaded device (Simplate, Organon Teknika Corp) while
blood pressure was maintained at 40 mm Hg in the tested
arm.14
Statistical Analysis
All values are expressed as the mean±SEM, and Student's
t test was employed to evaluate the significance of
differences between groups. Linear regression analysis was employed
to evaluate the significance of relationships between variables using a
statistical software package (SPSS for
WINDOWS, version 6.0, SPSS).
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Results |
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Hematologic Variables
There were no significant differences between the elderly and young donors in platelet or leukocyte count. The hematocrit was slightly but significantly greater in elderly women than in young women, but hematocrit did not vary with age in men (Table 1
). The elderly had significantly higher mean platelet
and mean corpuscular volume values than did the young. Elderly subjects
also had significant elevations in plasma fibrinogen and factor VIIa
relative to the young subjects (Table 1). The age-related increase in
fibrinogen was significant in both men and women, whereas factor VIIa
levels were significantly greater only in elderly women compared with
young women (Table 1).
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Among the elderly, women had significantly higher platelet counts than
did men (Table 1
, P=.002), whereas men had a higher mean
hematocrit than did women (Table 1, P<.001). Elderly women
had significantly higher plasma fibrinogen and factor VIIa levels than
did elderly men (Table 1, P=.014 and P=.013,
respectively). The only significant sex-related difference in
hematologic variables in the young population was the higher hematocrit
observed in men (Table 1, P<.001).
Platelet-Vasculature Interactions In Vitro and In Vivo
There was significantly greater surface coverage on the
subendothelium with unspread C platelets in the elderly than the young
subjects (Table 2). Subendothelial coverage with S
platelets, total platelet (C+S) adherence to the subendothelium, and
subendothelial coverage with platelet T were slightly but
insignificantly increased in the elderly population. The proportion of
S platelets that formed platelet T (defined as platelet aggregation, or
100T/S) was comparable in the elderly (5.45±1.20%) and the young
(4.66±1.16%; P=.668). C, S, C+S, T, and 100T/S on the
arterial adventitial surface also failed to show significant
age-related differences (Table 2).
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No significant age-related differences were noted among either men or
women in the platelet-subendothelium or platelet-adventitia interaction
(Table 2). However, there was a trend toward higher C+S values for the
subendothelium in elderly women (26.87±2.94%) than in young women
(23.04±2.18%, P=.336).
Skin bleeding times in the elderly were 4.96±0.49 minutes compared with 5.55±0.48 minutes in the young subjects. This difference did not reach statistical significance (P=.249).
Platelet Aggregation Studies
There were no significant age-related differences in
platelet aggregation in citrated whole blood in response to the
agonists collagen, arachidonic acid, and ADP (Fig 1). Similarly, platelet secretion in response to these
agonists did not differ between the elderly and young donors (eg,
collagen-induced ATP secretion was 1.95±0.14 nmol/108
platelets in the elderly versus 2.04±0.15 nmol/108
platelets in the young).
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, n=37) and young donors
(hatched bars; n=31). None of the differences was statistically
significant.
Relationships Among Hematologic Variables, Platelet Aggregation,
and Platelet–Arterial Wall Interaction
Marked age-related disparities were observed in the correlation
between platelet aggregation responses and in vitro and in vivo primary
hemostasis. By univariate linear regression analysis,
collagen-induced platelet aggregation was significantly correlated with
S and C+S on the subendothelium in the elderly but not young donors
(Table 3). Similarly, platelet aggregation in response
to collagen showed a significant inverse correlation with skin bleeding
time only in the elderly (Table 3). The relationships among
collagen-induced platelet aggregation, platelet-subendothelium
interactions, and bleeding time were similar in elderly men and
women.
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Arachidonic acid–induced platelet aggregation showed similar
relationships with platelet adherence and bleeding time, with
significant correlations observed in the elderly but not in the young
(Table 3). However, when the data for elderly men and women were
analyzed separately, only men showed significant correlations between
arachidonic acid–induced platelet aggregation and in
vitro and in vivo primary hemostasis (Table 3 and Fig 2). Furthermore, arachidonic
acid–induced platelet aggregation showed a significant correlation
with T on the subendothelium only in elderly men (r=.604,
P=.008). When multivariate linear regression analysis
was used with the independent variables arachidonic
acid– and collagen-induced platelet aggregations and plasma fibrinogen
level, only arachidonic acid–induced whole-blood
platelet aggregation was a significant independent predictor of C+S on
the subendothelium in elderly men.
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There was no correlation between ADP-induced platelet aggregation and
platelet adherence to the subendothelium or to bleeding time (Table 3).
However, in young donors, platelet spreading (S) and adherence (C+S) to
the adventitial surface were significantly associated with platelet
aggregation in response to ADP (r=.395, P=.031
for both correlations); this association approached significance in the
elderly subjects (r=.312, P=.060 and
r=.315, P=.058, respectively).
Interestingly, plasma fibrinogen was significantly associated with S and C+S on the subendothelium in elderly men (r=.614, P=.011 and r=.615, P=.011, respectively) and in young women (r=.678, P=.015 and r=.677, P=.016, respectively). T on the subendothelium was strongly associated with plasma fibrinogen in young women (r=.656, P=.021), as was the bleeding time in this population (r=.553, P=.050). There was no relationship between plasma fibrinogen and any of these variables in elderly women or young men.
By univariate analysis, platelet aggregation in response to
collagen and ADP was significantly correlated with plasma fibrinogen in
young but not elderly donors, although in the latter group, the
relationship between fibrinogen and ADP-induced platelet aggregation
approached significance (Table 4). In both groups of
subjects, the relationship between plasma fibrinogen and
arachidonic acid–induced platelet aggregation
approached statistical significance (Table 4). In the young donors,
platelet aggregation responses to collagen and
arachidonic acid were significantly correlated
with leukocyte count, whereas no correlation among these variables was
observed in the elderly (Table 5). There was a
significant inverse correlation between ADP-induced platelet
aggregation and hematocrit in the young (r=-.530,
P=.003) but not the elderly (r=-.052,
P=.761).
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Multivariate linear regression analysis of collagen- and arachidonic acid–induced platelet aggregation in the elderly failed to reveal any significant correlations with hematologic variables. By contrast, in the young, leukocyte count was an independent predictor of platelet aggregation in response to these agonists when analyzed together with hematocrit, platelet count, and plasma fibrinogen. In multivariate analysis, platelet count was a significant independent predictor of platelet aggregation in the young in response to arachidonic acid but not to collagen. Multivariate analysis showed that platelet count was the only statistically significant independent predictor of ADP-induced platelet aggregation in the elderly, whereas platelet count and hematocrit were each independently correlated with ADP-induced platelet aggregation in the young donors. Plasma factor VIIa activity was unrelated to any of the measured platelet function variables.
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Discussion |
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Platelet reactivity has been reported to increase with advancing age. Platelet aggregation in PRP,1 2 3 platelet adherence to thrombogenic surfaces,7 and plasma levels of the secreted platelet
-granule protein thromboglobulin15 are
increased in the elderly. Bastyr et al16 have reported
that platelet basal and thrombin-stimulated phosphoinositide turnover
rates increase with advancing age and that this increase is correlated
with both plasma thromboglobulin levels and ADP-induced platelet
aggregation. Platelet cyclooxygenase and lipoxygenase activity levels
increase with increasing age in healthy subjects, reflective of a
higher "peroxide tone",17 and urinary excretion of
metabolites of thromboxane A2 has been reported to be
elevated in the elderly.18 19
As previously reported by others,13 20 21 we found plasma
fibrinogen and factor VIIa to be elevated in the elderly population,
although only elderly women showed a significant increase in the latter
(Table 1). Total platelet adherence (C+S) to the subendothelium in the
elderly was not significantly different from the values obtained with
young donors, except for a slight but significant increase in surface
coverage with unspread C platelets in the elderly (Table 2).
Platelet-surface interactions on the more thrombogenic adventitial
surface also failed to show significant age-related differences (Table 2), and fluid-phase platelet aggregation responses in whole blood also
were not different in the two age groups (Table 3). The
aging-associated decrease we observed in skin bleeding time failed to
achieve statistical significance.
However, the relationship between whole-blood platelet aggregation and
platelet–arterial wall interaction (measured by both our in vitro
perfusion system and the in vivo skin bleeding time assay) differed
significantly according to age (Table 3). Collagen-induced platelet
aggregation was significantly correlated with S and C+S on the
subendothelium in elderly men and women, whereas there was no
association between these variables in the young (Table 3). Consistent
with this observation was the significant inverse correlation we
observed between collagen-induced platelet aggregation and skin
bleeding time (Table 3). Platelet aggregation in response to
arachidonic acid was similarly associated with in vitro
and in vivo primary hemostasis only in elderly men (Table 3). By
multivariate analysis, only arachidonic
acid–induced platelet aggregation was a significant independent
predictor of platelet adherence to the subendothelium in this
population. This suggests that arachidonic
acid/cyclooxygenase/thromboxane A2 metabolism may be more
important for platelet-subendothelium interactions in elderly men than
in the other three age/sex groups studied. This is of interest, because
several clinical trials have found that aspirin exhibits greater
efficacy for the primary and secondary prevention of coronary artery
disease, stroke, and thromboembolism in men than
women.22 23 The available meta-analysis data
concerning the beneficial effects of aspirin are restricted to patients
with atherosclerotic diseases, whereas the present study was
performed with healthy subjects. However, in healthy individuals, it
has been reported that aspirin causes a greater prolongation of
bleeding time in men than women.24 The latter study, in
conjunction with our data, suggests that the differential activity of
platelet cyclooxygenase according to gender likely occurs in subjects
without atherosclerotic diseases as well.
ADP-induced platelet aggregation in whole blood was not correlated with either platelet adherence to the subendothelium or skin bleeding time. However, ADP-induced platelet aggregation was significantly associated with platelet attachment to the more thrombogenic adventitial surface in young subjects; this relationship approached significance in the elderly. This implies that platelet aggregation in response to ADP may more closely reflect the in vivo response to deep vascular injury than does collagen- or arachidonic acid–induced platelet aggregation. Our in vivo and in vitro data suggest that ADP-induced platelet aggregation may be better correlated with thrombotic risk than with primary hemostatic function. This is consistent with epidemiological reports showing that enhanced ADP-induced platelet aggregation in healthy men is associated with both an increased incidence of myocardial infarction and higher coronary heart disease mortality.5 6
Our data suggest that the mechanisms that govern primary hemostasis in
healthy elderly persons may differ in some important respects from
those operative in healthy young individuals. Plasma fibrinogen was
significantly correlated with platelet aggregation responses to
collagen and ADP in young but not elderly donors (Table 4). However,
fibrinogen was strongly associated with platelet-subendothelium
interactions in elderly men and young women. The inverse correlation
between hematocrit and ADP-induced platelet aggregation in whole blood
that we observed in young donors has been previously described in
PRP.25 This effect has been attributed to a higher plasma
citrate concentration and the correspondingly reduced ionized calcium
levels, which result from a higher hematocrit.25 However,
we found no such correlation between hematocrit and ADP-induced
platelet aggregation in elderly subjects. Thus, it appears that
cyclooxygenase metabolism, platelet-fibrinogen interactions, and the
influence of hematocrit and ionized calcium assume differing importance
for platelet reactivity according to age and gender.
Furthermore, leukocyte count was a significant independent predictor of collagen- and arachidonic acid–induced platelet aggregation in young but not elderly subjects. The importance of platelet-leukocyte interaction has been increasingly recognized in recent years.26 Both inhibitory and stimulatory effects of leukocytes on platelet reactivity have been described. Our data suggest that there may be important age-related differences that influence the modulatory effect that leukocytes exert on platelet function.
Our study suggests that whole-blood platelet aggregation may be more useful in predicting primary hemostatic function in healthy elderly than healthy young subjects. Collagen appears to be an effective agonist for this purpose in both elderly men and women, although in men arachidonic acid–induced platelet aggregation may be more predictive of platelet-subendothelium interactions. Moreover, we found a direct correlation between ADP-induced platelet aggregation in whole blood and platelet spreading and adherence on the thrombogenic adventitial surface that is exposed during deep vascular injury, such as during rupture of an atherosclerotic plaque. This suggests that ADP-induced platelet aggregation may prove useful as part of the assessment of an individual's risk for thrombotic events.5 6
Although antiplatelet therapy has proven efficacious when given to
large populations for the primary or secondary prevention of coronary
heart disease, this regimen is associated with an increased risk of
gastrointestinal bleeding and, in some studies, hemorrhagic stroke. In
the present and previous studies, we have observed significant
variability in platelet adherence and aggregation on human arterial
subendothelium among different healthy donors (Fig 2), although the
values for a single subject are generally reproducible when studied on
multiple occasions. This suggests that platelet adhesiveness may differ
substantially in healthy subjects. It is probable that subjects with
greater basal platelet reactivity would derive maximal antithrombotic
benefit and the least risk of hemorrhage from antiplatelet agents such
as aspirin, whereas individuals with low platelet adhesiveness would
show comparatively less benefit and greater hemorrhagic risk. Because
the present study demonstrates a correlation between whole-blood
platelet aggregation and in vitro platelet adherence and in vivo
primary hemostasis, our data suggest that use of this assay might prove
beneficial by targeting antiplatelet coronary preventive therapy toward
a more appropriate population.
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Footnotes |
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Reprint requests to Jeffry B. Lawrence, MD, Clinical Laboratory Medicine, Lilly Research Laboratories, Lilly Corporate Center, Drop Code 2133, Indianapolis, IN 46285. E-mail lawrence_jeffry_b@lilly.com.
Received November 21, 1994; accepted April 4, 1995.
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