© 1995 American Heart Association, Inc.
Articles |
Gemfibrozil Enhances Platelet Activity in Patients With Combined Hyperlipoproteinemia
From the Departments of Clinical Pharmacology (A.B., P.H.) and Physiology and Pharmacology (A.B.), Karolinska Institute, and the Metabolism Unit, Department of Medicine, Karolinska Institute at Huddinge University Hospital (M.E., B.A.), Stockholm, Sweden.
Correspondence to Paul Hjemdahl, MD, PhD, Department of Clinical Pharmacology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
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Abstract |
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Abstract A placebo-controlled crossover study was conducted to evaluate whether lipid-lowering with gemfibrozil (10 to 12 weeks) affects platelet function in vivo at rest and during mental stress in 21 men with combined hyperlipoproteinemia. Gemfibrozil lowered plasma triglycerides and total and VLDL cholesterol (P<.001 for all), whereas HDL cholesterol increased (P<.001). Gemfibrozil increased platelet counts by 18% (P<.001) and, according to filtragometry measurements, enhanced overall (means of rest and stress values) platelet aggregability in vivo (P=.014); this effect was more evident during mental stress (P=.027) than at rest (P=.18). Moreover, the urinary excretion of 11-dehydro-thromboxane-B2 was 54% higher during treatment with gemfibrozil (P<.001), whereas the excretion of ß-thromboglobulin in urine was unaltered. Plasma ß-thromboglobulin tended to be slightly elevated during active treatment (P=.15). Mental stress increased heart rate and catecholamine levels and elevated all cholesterol fractions (P<.01) and plasma ß-thromboglobulin (during placebo, P=.02), but platelet aggregability did not increase significantly. A positive correlation was found between 11-dehydro-thromboxane-B2 excretion and LDL cholesterol levels during placebo (r=.62, P=.0057). In conclusion, gemfibrozil has beneficial effects on plasma lipoprotein levels but enhances several aspects of platelet activity in vivo and increases platelet counts. These changes might be prothrombotic and thus adverse for the hyperlipidemic patient. Primary preventive effects of gemfibrozil might be enhanced if a platelet inhibitor such as aspirin is administered with gemfibrozil.
Key Words: hyperlipoproteinemia • lipoproteins • gemfibrozil • ß-thromboglobulin • platelet function • filtragometry • thromboxane
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Introduction |
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Blood platelets and plasma lipoproteins are vital components in the pathogenesis of coronary artery disease (CAD).1 2 Elevated plasma cholesterol levels lead to atherosclerosis. A possible influence of plasma cholesterol levels on thrombus formation through promotion of endothelial dysfunction and/or direct stimulation of platelets has also been suggested.
Platelets from patients with hypercholesterolemia aggregate in vitro at lower concentrations of aggregating substances than do platelets from normocholesterolemic volunteers.3 Hypercholesterolemic patients also exhibit increased formation of thromboxane,4 a marker for platelet activation and a proaggregatory substance. Shortened bleeding time5 and elevated plasma levels of platelet-specific products6 are other in vivo indexes of enhanced platelet activation in these patients. Furthermore, incubation of whole blood with autologous LDL enhances platelet aggregability in vitro dose dependently.7 Thus, the increased risk of CAD complications in patients with hypercholesterolemia may be related to both progressive atherosclerosis and platelet activation.
Sympathoadrenal activation evoked by mental stress8 or physical exercise9 10 is considered to be a trigger of sudden cardiac death and myocardial infarction. The mechanisms involved are poorly understood, but adverse effects on platelet function may be of pathological importance.11 Indeed, both mental stress12 13 and physical exercise14 have been shown to enhance platelet aggregability, as assessed by filtragometry ex vivo.
Pharmacological lipid-lowering intervention might influence both plasma lipids and platelet function and thus be beneficial from antithrombotic and antiatherosclerotic points of view. Fibric acid derivatives reduce plasma lipoprotein levels and have been claimed to possess antiplatelet properties in vitro at rest15 16 and after physical exercise.17 The effect of these agents on platelet function in vivo, however, has been investigated less frequently.
The Helsinki Heart Study showed that treatment with the fibric acid derivative gemfibrozil reduces the incidence of cardiovascular disease.18 Theoretically, this result could partly have been mediated through beneficial alterations in platelet function. The present randomized, placebo-controlled study of gemfibrozil was therefore carried out to investigate whether this drug alters platelet function in vivo at rest and during mental stress in men with combined hyperlipoproteinemia.
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Methods |
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Patients and Study Design
Twenty-one men, 21 to 70 years of age (mean, 47 years), with combined hyperlipoproteinemia (cholesterol
6.4 mmol/L and
triglycerides 2.3 mmol/L) were enrolled from the Metabolism Unit at
Huddinge University Hospital. Inclusion was based on plasma lipid
values obtained less than 2 weeks before randomization. Fifteen
patients were previously untreated for their lipid disorder. Patients
who had experienced myocardial infarction or unstable angina pectoris
during the preceding 12 months were not included; neither were those
with hyperlipoproteinemia secondary to, for example, hypothyroidism,
diabetes mellitus, and nephrosis. Six patients received concomitant
medication. Of these, two had anti-ischemic treatment with
ß–adrenergic receptor antagonists and a calcium antagonist, whereas
another three were treated for hypertension with diuretics,
ß–adrenergic receptor antagonists and angiotensin-converting enzyme
inhibitors. One of the hypertensive patients also had gout, for which
he received allopurinol. One patient received clomipramine. This
concomitant medication was kept constant during the trial. Six patients
were current smokers.
The patients entered the trial after receiving 4 to 6 weeks of the
American Heart Association step 1 diet as the only lipid-lowering
intervention (Fig 1
). Previous lipid-lowering therapy (6
patients) was discontinued at the onset of diet. The randomization
allocated patients to receive either gemfibrozil (Lopid 600 mg twice
daily, Parke-Davis) or placebo in a double-blind fashion. After 10 to
12 weeks on the first treatment, the patients crossed over to the
alternate treatment. The manufacturer randomized the treatment order
(11 started on placebo). Compliance was monitored by tablet count.
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Platelet function testing was performed at the end of each treatment
period (Fig 1
). Measurements and blood collection were conducted with
the patient in the semirecumbent position after 60 minutes of rest, and
after 15 minutes of mental stress (a modified Stroop Color Word
Conflict Test).19 The stress procedure was continued
throughout the measurements. The experiments were always conducted
between 8:30 and 11:30 AM after an overnight fast, and the
subjects were instructed to abstain from smoking and
caffeine-containing beverages on these days. Drugs containing
acetylsalicylic acid were discontinued at least 2 weeks before the
experiments.
The Ethics Committee of the Karolinska Institute approved the study. All patients gave informed consent to participate.
Filtragometry Ex Vivo
Filtragometry ex vivo, originally described by Hornstra and ten
Hoor,20 measures the existence of platelet aggregates in
blood drawn continuously from a forearm vein. In brief, each
measurement requires a venipuncture without stasis, using a 19-gauge
butterfly needle. We pretreat the skin above an antecubital vein with
an anesthetic gel (EMLA, ASTRA) to minimize the stress of venipuncture.
The needle is connected to a siliconized plastic tubing system,
allowing blood to flow at a constant speed (2 mL/min) through a
siliconized nickel filter (pore size, 20 µm; filter diameter, 2.0
mm). Solitary platelets traverse the filter, whereas platelet
aggregates are retained. The time to occlude 25% of the filter pore
area (defined as a 5–mm Hg pressure differential across the filter)
(tA) is inversely related to platelet aggregability in
vivo. Thus, a short reading implies high aggregability. Heparin (final
concentration, 5 IU/mL) is infused into the filtragometer to prevent
clotting. This concentration does not influence filtragometry
readings.20 Validation with scanning electron microscopy
has revealed that retained platelet aggregates cause filter
occlusion.20 The intraindividual between-day
reproducibility (CV) of the technique in our laboratory is 10% for log
tA values, as determined in 20 healthy middle-aged and
older men (H. Wallén, unpublished data, 1994).
ß-Thromboglobulin and 11-Dehydro-Thromboxane-B2
Venous blood for plasma ß-thromboglobulin (ßTG) measurements
was sampled without stasis in the arm not used for filtragometry
measurements by use of an 18-gauge Wassermann needle. The first portion
of blood (2 mL) was discarded; the following 8 mL was allowed to flow
into prechilled sampling tubes filled with an anticoagulating and
platelet-stabilizing solution consisting of EDTA, theophylline, and
prostaglandin E1. The samples were centrifuged immediately
(15 000g, 30 minutes, 4°C) and the midportion of plasma
was aliquoted and kept frozen at -80°C until analysis. This
procedure results in few sampling artifacts.21
The urinary excretions of high-molecular-weight (HMW) ßTG and 11-dehydro-thromboxane-B2 (11-dehydro-TxB2) were determined in urine voided after the night preceding the experiment (night) and immediately after the experiment (day). The levels of plasma ßTG and urinary HMW ßTG were assessed with a commercially available radioimmunoassay kit (IM-88, Amersham, UK) with the modifications recently described.22 Urinary 11-dehydro-TxB2 was determined by use of a commercially available enzyme immunoassay kit (Cayman Chemical) after purification by solid-phase extraction (Bond-Elut Certify, Analytichem International). Urinary creatinine was measured by the Jaffé reaction with a Monarch 2000 automated analyzer (Instrumentation Laboratories, IL Test 181615-60).
Lipoproteins and Lipids
Lipoproteins were quantified by a combination of
ultracentrifugation and precipitation.23 24 The
cholesterol and triglyceride contents of the various lipoprotein
fractions were assessed by standard enzymatic techniques
(Boehringer-Mannheim). For analyses of apoA-I and apoB,
immunoturbidometric methods were used (Orion Diagnostica). Lp(a) levels
were determined by radioimmunoassay (Pharmacia Diagnostics).
Other Measurements
The hematologic parameters were always assessed 2 hours after
blood collection (EDTA final concentration, 10 mmol/L) in a cell
analyzer (Medonic, CA 460). Blood pressures and heart rates were
monitored with an Ohmeda 2300 Finapress blood pressure monitor (Ohmeda
Monitoring Systems). The catecholamine concentrations in venous plasma
were determined by cation-exchange high-performance liquid
chromatography with amperometric detection.25 Urinary
catecholamines were analyzed with a previously described and validated
modification of the plasma method,26 and their excretions
were related to that of creatinine.
Statistics
Data are presented as mean±SEM (n=19 unless otherwise
stated). From power calculations (using pooled data from repeated
filtragometry measurements in 28 male healthy volunteers at rest), it
was found that a sample size of 15 individuals was required to detect a
20% difference in resting filtragometry measurements at the 5%
significance level (
=.05, ß=.20). All platelet function variables
were considered to be approximately log normally distributed. Three-way
ANOVA according to the standard 2x2 crossover model was applied to
evaluate differences between treatments, controlling for subject and
period effects.27 Stress-induced changes for each variable
were analyzed by Student's paired t test, and treatment
effects for stress-induced changes were analyzed with 
values (ie,
rest minus stress). Tests for carryover effects were applied according
to standard procedures.27 Mean and 95% confidence
intervals were calculated for the ratios of plasma and urinary
ßTG.28 Correlations were tested with Pearson's
correlation coefficient. Statistical evaluation was performed on a
Macintosh computer using SUPERANOVA version 1.02 and
STATVIEW 4.0 (Abacus Concepts Inc).
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Results |
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Treatment duration was 10.6 weeks for placebo and 11.0 weeks for gemfibrozil. Of the 21 randomized patients, 19 completed the study. The two dropouts were from noncompliance and acute myocardial infarction. According to tablet counts, the proportion of prescribed tablets taken were 94±1% (placebo) and 93±2% (gemfibrozil). No carryover effects were noted for lipids (total cholesterol and triglycerides) or for platelet function (filtragometry and 11-dehydro-TxB2).
Lipoproteins and Lipids
Table 1 shows the lipoprotein and lipid changes. At
rest, large reductions of total triglycerides (-57±4% compared with
placebo), and VLDL cholesterol (-64±3%) were noted after gemfibrozil
administration. In addition, mean total cholesterol was lowered by
16±3%, whereas the plasma levels of LDL and HDL cholesterol were 8%
(-11 to +39; median with 25th and 75th percentiles) and 22±5% higher
after gemfibrozil, respectively. The resting levels of apoB, apoA-I,
and Lp(a) were not significantly altered. Mental stress increased the
cholesterol contents of all lipoprotein fractions during placebo
treatment, whereas VLDL cholesterol was not altered during gemfibrozil
treatment.
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Platelet Function In Vivo
Filtragometry data are based on 17 patients (2 patients could not
be venipunctured adequately). Plasma ßTG results are calculated with
n=12 because blood could not be obtained from 4 subjects, and 3
patients were excluded before breaking of the treatment code because of
extremely high ßTG values in combination with poor blood flow at
venipuncture.
According to filtragometry readings, gemfibrozil enhanced the overall
(means of rest and stress values) platelet aggregability (Fig 2); ie, tA was shorter during gemfibrozil
than placebo treatment (antilog of mean, 138 versus 193 seconds).
Separate analyses at the different time points revealed that the
proaggregatory effect of gemfibrozil was most pronounced during mental
stress (antilog of mean, 126 versus 182 seconds for placebo).
Corresponding antilog values at rest were 150 and 205 seconds
(P=.18). Mental stress as such did not significantly affect
platelet aggregability during either therapy, and there was no
difference in stress-induced changes between the treatments (three-way
ANOVA based on values, ie, rest minus stress).
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) and
gemfibrozil (
) on ex vivo filtragometry measurements (n=17; a low
tA value indicates high aggregability) and plasma
ß-thromboglobulin (ßTG) (n=12) at rest and after 15 minutes of
mental stress. Values are mean±SEM (based on antilog transformation).
*P<.014 for the overall difference (means of rest and
stress values); 
P=.027 for the difference between the
treatments during mental stress. tA indicates the time to
occlude 25% of filter pore area.
No difference between the treatments was observed for the overall
plasma ßTG values (P=.15) or at the different time points
(rest, P=.12; stress, P=.32; Fig 2). The mean
ratio between gemfibrozil and placebo values was 1.25 (95% CI, 0.98 to
1.52). Mental stress elevated plasma ßTG during placebo (n=15;
P=.02; Student's t test) but not during
gemfibrozil therapy (n=15; P=.13). The stress-induced
changes, however, did not differ between the treatments.
The average of individual night and day urinary excretions of
11-dehydro-TxB2 was 54% (28% to 87%; median with 25th
and 75th percentiles) higher during gemfibrozil treatment (n=18, Fig 3). During placebo treatment, the median night excretion
was 399 (313 to 471) ng/mmol creatinine whereas the daytime excretion
was 362 (278 to 418) ng/mmol. Corresponding values during gemfibrozil
treatment were 670 (533 to 976) and 505 (343 to 592) ng/mmol
creatinine, respectively.
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The average urinary excretion of HMW ßTG was not affected by the treatments (n=16, P=.68). The mean (95% CI) for the ratio between treatments was 1.14 (0.87 to 1.41). Night and day excretions during placebo were 2.4 (2.1 to 3.5) and 2.5 (1.7 to 4.6) ng/mmol creatinine, respectively. During active treatment, these excretions were 3.8 (2.5 to 5.0) and 2.7 (2.0 to 4.6) ng/mmol creatinine, respectively.
Hematologic Variables
Platelet counts were 18±4% higher at rest after gemfibrozil
therapy (Table 2). Leukocyte counts tended to be reduced
(P=.051), whereas median platelet volume remained unaltered.
Mental stress caused an increase in leukocyte counts during both
treatments.
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Catecholamines and Cardiovascular Variables
Venous plasma norepinephrine and epinephrine levels were not
affected by gemfibrozil treatment (Table 3). Mental
stress elevated the plasma epinephrine levels during both treatments,
whereas norepinephrine increased only during gemfibrozil treatment. The
stress-induced changes did not differ between the treatments. The night
urinary excretion of epinephrine was higher during placebo than
gemfibrozil treatment.
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Diastolic blood pressure at rest was slightly lower during gemfibrozil
treatment (Table 3), but cardiovascular responses to mental stress were
not affected by gemfibrozil (peak values and values at the end of the
test). Heart rate and blood pressures increased similarly during mental
stress with both treatments.
Correlations
During placebo treatment, the excretion of
11-dehydro-TxB2 in urine correlated positively to LDL
cholesterol and inversely to VLDL cholesterol and total
triglycerides (Fig 4). These associations were not
present during gemfibrozil therapy. Changes in LDL and VLDL
cholesterol between the treatments were not correlated to the changes
in 11-dehydro-TxB2 excretion. Platelet counts were
inversely correlated to filtragometry measurements at rest during
placebo (r=-.66, P=.0017) but not during
gemfibrozil treatment (r=-.30, P=.23). The
gemfibrozil-induced changes in platelet counts were not correlated to
changes in filtragometry readings.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study was designed to examine the effects of gemfibrozil on platelet activity in vivo at rest and during mental stress in men with combined hyperlipoproteinemia. Interestingly, our results show that several aspects of platelet function in vivo—ie, platelet aggregability, thromboxane production, and release of platelet specific products—were adversely affected by the therapy.
Fibric acid derivatives have previously been shown either to reduce15 16 29 30 or not to influence17 31 32 33 platelet aggregation in vitro during resting conditions. The present data show that platelet aggregation in vivo, as measured by filtragometry, is enhanced by gemfibrozil and that this effect is more consistent during mental stress than at rest. A more pronounced effect of gemfibrozil during stress might suggest that it enhances the effect of weak platelet agonists, such as catecholamines, released during stress. However, this hypothesis is contradicted by earlier findings that gemfibrozil attenuates epinephrine-induced aggregation in vitro after physical exercise.17 Platelet counts increased during gemfibrozil treatment, which might facilitate formation of circulating platelet aggregates by increased platelet-to-platelet contact. However, the correlation between platelet counts and filtragometry readings during placebo was lost during gemfibrozil treatment, and changes in these parameters were not correlated. Thus, platelet counts are not related to aggregation in a simple fashion.
It is noteworthy that we recently observed that the cholesterol synthesis inhibitor pravastatin also enhances platelet aggregability in vivo as assessed by filtragometry.34 Direct proaggregatory effects of these drugs cannot be excluded.
The urinary excretion of 11-dehydro-TxB2 may serve as an index for the in vivo production of TxA2, which has been implicated in the pathogenesis of ischemic heart disease.35 Patients with isolated hypercholesterolemia (type IIa) excrete more 11-dehydro-TxB2 than do normolipidemic subjects, and the excretion is positively correlated to plasma cholesterol levels.36 Moreover, treatment with the cholesterol synthesis inhibitor simvastatin reduces the excretion rate of this metabolite.4 We found a clear-cut increase in the urinary excretion of 11-dehydro-TxB2 during gemfibrozil treatment, despite a significant reduction of plasma cholesterol levels.
We also found a positive correlation between the excretion of 11-dehydro-TxB2 and LDL cholesterol levels but inverse correlations to VLDL cholesterol and triglycerides during placebo treatment. LDL cholesterol increased during gemfibrozil therapy, but scrutiny of individual data revealed that the excretion of 11-dehydro-TxB2 increased similarly whether LDL cholesterol levels increased or decreased during gemfibrozil treatment in individual patients. In addition, changes in lipoprotein cholesterol fractions and 11-dehydro-TxB2 excretion during treatment were not correlated. Thus, the increased excretion seems to be related to factors other than changes in plasma cholesterol levels. Interestingly, clofibrate was recently shown to enhance the conversion of linoleic acid to the thromboxane precursor arachidonic acid in rat liver.37 A similar effect of gemfibrozil might contribute to our findings of enhanced thromboxane excretion. Because platelets are the major source for TxA2 production, the higher platelet count during gemfibrozil treatment may also have contributed, even though platelet counts and 11-dehydro-TxB2 excretion were not correlated.
The levels of ßTG in plasma and urine reflect platelet secretion in vivo. The literature offers contrasting data regarding the effect of lipid-lowering interventions on plasma ßTG levels. Simvastatin has been shown to lower plasma ßTG,38 whereas bezafibrate may30 or may not38 have a similar effect. Treatment with gemfibrozil,17 pravastatin,34 and probucol39 40 has failed to substantially alter plasma ßTG levels in smaller trials. In the present study, gemfibrozil elevated plasma ßTG slightly, whereas the urinary excretion of ßTG was unaltered. The effect on plasma ßTG was not significant, but the power to detect a difference was low because only 12 of the patients were successfully investigated. The present results are thus not conclusive with regard to platelet secretion.
The dynamic regulation of platelet activity may link stress and sympathoadrenal activation to cardiovascular disease. Mental stress enhances platelet aggregability in vivo in healthy young volunteers11 12 13 but not in the present hyperlipoproteinemic population, despite similar neurohormonal responses. We have no explanation for this difference, which may be related to the hyperlipidemia and/or age differences in the studies. Platelet release may increase during stress,41 and we found that stress raised ßTG levels during placebo treatment. Thus, moderately intense mental stress seems to enhance the platelet release reaction, whereas the platelet aggregability response is more variable in patients with combined hyperlipoproteinemia.
Total platelet counts are positively related to the risk of cardiovascular death in healthy men.42 Therefore, the gemfibrozil-induced increase in platelet counts reported here and by others43 44 45 may be unfavorable. Recently, Wilkes et al45 suggested that the increase could reflect a reduced platelet consumption, but our findings of platelet-activating effects of gemfibrozil treatment do not support this hypothesis. The decrease in leukocyte counts, however, may be beneficial because white blood cell counts are also associated with the risk of coronary heart disease.46
Different kinds of physiological stress elevate plasma cholesterol levels.47 We found an elevation of less than 3% for total cholesterol during stress, but correction for hemoconcentration normalized the cholesterol levels. These changes are too small to be of clinical relevance. However, long-term stress and stress that is more relevant for the individual than a laboratory stress test may have larger influences on plasma cholesterol levels47 and thereby be relevant to the atherosclerotic process. Plasma Lp(a) levels, which also are related to ischemic heart disease,48 are reduced by nicotinic acid therapy49 but, according to our data, not by gemfibrozil treatment.
It may be argued that concomitant medication in some patients and the inclusion of patients with and without cardiovascular disease might limit the interpretation of our results. However, concomitant medication was kept constant throughout the trial, and the patients served as their own controls. Furthermore, we believe that the study population is representative of patients receiving gemfibrozil therapy.
We conclude that gemfibrozil treatment increases platelet counts and enhances platelet activity in vivo. These changes in indexes of platelet function may be considered prothrombotic and thus adverse for the hyperlipidemic patient, who is already at high risk of developing atherothrombotic disease. It is tempting to speculate that the favorable effect on cardiovascular mortality observed in the Helsinki Heart Study might have been even more pronounced if a platelet inhibitor such as aspirin had been administered with gemfibrozil. Our results further underline that the connection between plasma lipids and platelet function in vivo is not straightforward. The theory of adverse effects of LDL cholesterol per se on platelet function is not supported by the present study. However, direct effects of gemfibrozil or its metabolites may have obscured the relations.
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Acknowledgments |
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We are indebted to Maud Daleskog, Maj-Christina Johansson, Lilian Larsson, and Christina Perneby for excellent technical assistance. We also wish to thank Pia Gustavsson for taking care of the patients and Martin Åhlenius for expert assistance with the statistical analysis. This study was supported by grants from Parke-Davis, the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (5930 and 7137), the Thuring Foundation, the Swedish Society of Medicine, and the Karolinska Institute.
Received May 25, 1994; accepted October 28, 1994.
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