| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 1996 American Heart Association, Inc.
Articles |
Inhibition of Thrombin Generation by Aspirin Is Blunted in Hypercholesterolemia
Departments of Medicine, Cardiology (W.P.), and Physics (P.F.G.), Jagellonian University, Cracow, Poland.
Correspondence to Prof Andrew Szczeklik, Jagellonian University, Department of Medicine, 8, Skawinska St, 31-066 Cracow, Poland.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Recent evidence indicates that aspirin inhibits thrombin generation in clotting blood. We noticed that this effect was less pronounced in patients with hypercholesterolemia. The aim of the study was to prove this observation. The effects of aspirin on thrombin generation were evaluated in (1) 46 healthy volunteers, 2 hours after ingestion of a single, 500-mg dose and (2) 28 survivors of myocardial infarction who took 300 mg aspirin/d for 2 weeks. In both populations, two well-matched subgroups were distinguished, using a serum cholesterol level of 6.2 mmol/L (240 mg/dL) and an LDL cholesterol level of 4.0 mmol/L (155 mg/dL) as borderline. Thrombin generation was monitored ex vivo in blood emerging from a skin microvasculature injury and additionally, in a single-dose study in vitro in recalcified plasma. Aspirin depressed thrombin generation in the group of subjects with serum cholesterol <6.2 mmol/L and LDL cholesterol <4.0 mmol/L but not in the group with high blood cholesterol levels. Inhibitory effects of aspirin were more pronounced after the 2-week treatment than after a single dose. There was a significant correlation between total serum cholesterol or LDL cholesterol and total amount of thrombin generated after aspirin treatment. In subjects with high blood cholesterol levels, thrombin generation was not affected by aspirin. Blunting of aspirin action in hypercholesterolemia might be explained by (1) alterations in platelet lipid-protein matrix that render their membrane proteins less accessible for acetylation by aspirin and (2) changes in composition and structure of plasma lipoproteins that diminish the chance of aspirin to interact with prothrombin.
Key Words: thrombin generation • hypercholesterolemia • myocardial infarction
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Thrombin is formed from a precursor prothrombin in the reaction involving several well-defined plasma proteins, which are assembled as prothrombinase complex on the activated platelet membrane.1 Generated thrombin clots the blood. It also exerts a variety of cellular effects that might mediate inflammatory and reparative responses to vascular injury.2 Generation of thrombin has attracted considerable interest that led to development of the methods for its assessment, mainly in vitro,3 4 seldom ex vivo.5 Such methods are useful not only for evaluation of factors controlling the reaction but also for study of the action of drugs. Recent evidence indicates that aspirin, following a single-dose administration5 or 1 week low-dose treatment,6 depresses generation of thrombin in the blood of healthy subjects.
It appears that the unequivocal antithrombotic effect of aspirin, demonstrated in patients with ischemic heart disease and cerebrovascular disease,7 might be explicable by more than one mechanism.8 The most popular and well-founded concept is that aspirin acts through inhibition of platelet cyclooxygenase and, in consequence, reduces thromboxane A2 formation.9 This anti-platelet effect of aspirin is shared by other cyclooxygenase inhibitors. On the contrary, depression of thrombin generation by aspirin is not paralleled by some antiplatelet agents.5 It has been suggested5 that aspirin modifies thrombin generation rather by acetylating macromolecules of platelet membrane and/or prothrombin than by blocking cyclooxygenase.
While studying the effects of aspirin on thrombin generation, we noticed that some subjects with high serum cholesterol were less responsive to aspirin than those who had normal cholesterol levels. This prompted us to perform the present study.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Design
The study consisted of two parts. The first evaluated the hemostatic effects of a single dose of 500 mg aspirin 2 hours after its ingestion by healthy volunteers. In the second part, aspirin at a daily dose of 300 mg was administered to survivors of myocardial infarction for 2 weeks, and the influence of this treatment on thrombin generation and other hemostatic parameters was assessed. In both parts of the study, special attention was paid to the possible relationship between blood cholesterol and thrombin generation.
The study was approved by the University Ethical Committee, and the subjects gave informed consent to participate.
Subjects
Part One: Single-Dose Study
Healthy volunteers (46; 11 women and 35 men), 25 to 69 years old (mean, 48 years) were studied. They were recruited from hospital personnel and from those who had been referred for evaluation to the outpatient clinic because of elevated serum cholesterol and in whom subsequent checkup revealed no signs of pathology. The subjects abstained from aspirin and any other drugs for at least 2 weeks preceding the study.
All subjects were divided into two groups on the basis of cholesterol level. The serum cholesterol concentration of 6.2 mmol/L (240 mg/dL) was arbitrarily chosen as the cutoff value discriminating the two groups (Table 1
).
|
Part Two: 2-Week Treatment With Aspirin
This part included 28 men, 42 to 65 years old (mean, 52 years), who had suffered a myocardial infarction 0.5 to 10 years (average, 2.5 years) before the study. At the time of the study they were either asymptomatic or had stable angina pectoris. Sixteen patients were on chronic treatment, which consisted of isosorbide dinitrate 60 mg/d (n=16); molsidomine, 4 mg/d (n=6); nifedipine, 30 mg/d (n=4); metoprolol, 50 mg/d (n=3); and captopril, 25 mg/d (n=1). These patients were equally distributed in the two subgroups studied. They continued the above treatment throughout the study but stopped the drugs at least 10 hours before having blood drawn. Aspirin and other antiplatelet drugs were stopped at least 14 days before initiation of the study.
After completion of measurements, for the purpose of statistical analysis, the subjects participating in both parts one and two were divided into two groups. The criterion was a cholesterol level of 6.2 mmol/L. This cutoff point was chosen arbitrarily on the basis of the recent report of the Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults.10
Methods
Blood samples were drawn by venipuncture between 8:30 and 10 AM after an overnight fast.
Total serum cholesterol, triglycerides, lipoprotein(a) (Lp[a]), and immunoglobulin E (IgE) levels as well as prothrombin time were determined by standard methods. Plasma prothrombin concentration and plasma fibrinogen were determined by nephelometry (Behring).
Platelet aggregation by ADP, collagen, and arachidonic acid (AA) were measured in platelet-rich plasma of all subjects. The threshold concentration for each agent was determined, as described previously.11 If platelets did not respond to 1200 µmol AA, the subjects were considered to be under the probable influence of platelet-inhibiting drugs and they did not enter the study.
Two thrombin generation markers, the thrombin-antithrombin III complexes (TAT) and the prothrombin fragment 1+2 (F1+2), were measured in plasma by the ELISA technique (Behring Diagnostica).
Malondialdehyde concentration in plasma was measured as thiobarbituric acid–reacting substances according to Satoh.12
Thrombin generation was determined both in vitro and ex vivo.
Generation of thrombin in vitro, in recalcified plasma, was assessed in part one of the study by the method of Pitney and Dacie3 with a modification previously described.13 In essence, at intervals of 1 minute following recalcification, equal samples were withdrawn from the incubation mixture, consisting of platelet-rich plasma containing 200 000 to 300 000 platelets/mm3 and diluted 1:1 with saline. The samples were assayed for fibrinogen clotting time, and their activity was expressed in terms of thrombin NIH units. Effect of aspirin was assessed by comparing times (t) at which thrombin reached its peak activity.
The thrombin generation ex vivo assay5 consisted of monitoring the rate of increase of fibrinopeptide A (FPA) concentration (Byk Gulden), a specific thrombin marker, in blood emerging from standardized skin incisions of a forearm. The thrombin concentration, c(t), varies in time as
 | (E1) |
determines the rate of increase of the curve. As it is impossible to measure c0 and directly, we calculated the pretreatment and after-treatment values of these parameters for each individual subject via the following procedure: The blood samples were collected at 30-second intervals. The average FPA concentration in the nth sample, cn, is proportional to the integral of c(t) over time in which the sample was taken:
 | (E2) |
were fitted by means of a nonlinear least-squares method to match the experimental values of cn for each subject before and after administration of aspirin. An example of the experimental values of cn for a single subject after aspirin, as well as cns corresponding to the fitted values of c0 and for this specific subject after aspirin, is given in Fig 1. In some subjects, FPA concentration eventually saturated, and the experimental cns reached a plateau; these plateau values were not taken into account while we fit the parameters c0 and .
|
), with their experimental error bounds, and cns calculated from Equation 2 (
) in an individual subject. The c0 and
Neither changes in c0 nor in alone can fully reflect the influence of various parameters, and aspirin in particular, on thrombin generation ex vivo. Therefore, we used the mean integral concentration of thrombin, S, as a quantitative measure of differences between the individual subjects. S is defined as
 | (E3) |
fitted to match the experimentally obtained concentrations cns. Parameters of the model are graphically explained in Fig 2.
|
0) are auxiliary quantities needed to explain the precise meaning of
The exponential mode of growth of thrombin concentration (see Equations) is valid only in a certain time interval: It breaks for long times, when the measured FPA concentrations saturate (Fig 1), but as a large difference between the measured FPA concentration in blood prior to the incision (Table 1) and the estimated c0 values (Table 2) indicate, it is also probably not valid for very short times, just after the incision. In this short time interval, thrombin appears to be generated faster than Equation 1 suggests. Character and duration of this rapid initial process cannot be assessed with the present experimental technique. However, the exponential mode of growth appears to be already well established in all subjects at the time of the first measurement. Therefore, while c0 is merely a parameter characterizing our model curves and does not directly correspond to the initial FPA concentration, the mean integral concentration, S, is little affected by the initial deviation from the exponential growth.
|
Note that while our experimental concentrations are in fact FPA concentrations, they are directly proportional to corresponding concentrations of thrombin. Furthermore, since we are mostly interested in the rate at which these concentrations change, and in ratios of these concentrations in different subjects (or groups of subjects), rather than in their absolute values, in the following we shall refer to them as if they were thrombin concentrations. S and c0 are measured in the units of FPA concentration, while , being the rate of increase of thrombin concentration, is measured in the inverse units of time, seconds-1.
Statistical Analysis
Mean values of c0, , and S before and after administration of aspirin were calculated for the two groups (parts one and two of the study) of subjects, as well as for the two subgroups (high and low cholesterol) within each group. These mean values for each group and subgroup before and after aspirin administration were compared by the paired Student's t test. Furthermore, Pearson's correlation coefficients between the parameters c0, , and S and serum cholesterol and LDL cholesterol levels for each group and subgroup were calculated. Other parameters characterizing the groups and subgroups of subjects were compared by using nonparametric tests for paired (signed-rank test) and unpaired (Wilcoxon two-sample test) values.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Part One
The concentrations of fibrinogen, Lp(a), IgE, and thrombin markers (TAT, F1+2) did not differ between the two groups and showed no changes after aspirin administration (Table 1
). In all individuals studied, blood platelet count was in the normal range and did not differ between subjects with total serum cholesterol below and above 6.2 mmol/L. Plasma triglycerides were significantly higher in the group with high serum cholesterol. No sex-dependent differences were found.
Before aspirin, plasma malondialdehyde levels were similar in both groups. Administration of 500 mg aspirin led to a relatively greater fall in malondialdehyde concentration in the group with serum cholesterol 
6.2 mmol/L. As the result of aspirin ingestion, malondialdehyde concentration became significantly lower in this group compared with the high blood cholesterol group (0.84 nmol/mL versus 1.32 nmol/mL, P=.03).
Bleeding time was similar in the two populations studied; 2 hours after aspirin administration, bleeding time increased in both groups (P<.005).
Platelets of subjects with high blood cholesterol were more prone to aggregate than those with blood cholesterol 6.2 mmol/L. The mean threshold aggregation concentrations of AA and ADP, but not of collagen, were moderately lower in the former group compared with the latter (Table 1).
At baseline, thrombin generation measured by the in vitro method was not related to serum cholesterol level (Table 2). In the group of subjects with serum cholesterol 6.2 mmol/L, aspirin markedly prolonged the time at which thrombin reached its peak clotting activity (7.63 minutes versus 8.16 minutes, P=.02) (Table 2). However, the drug did not cause any change in subjects with high blood cholesterol levels.
In blood collected from skin incisions, mean FPA levels rose exponentially in each group both before and after aspirin. No differences were found between groups before drug intake. After aspirin ingestion, the rate of thrombin generation, , became significantly depressed in subjects with a serum cholesterol level 6.2 mmol/L (Table 2). Aspirin, however, did not influence the formation of thrombin in the group of subjects with high blood cholesterol levels. When the two groups were combined, there was a significant correlation between thrombin generation rate, , and total serum cholesterol level after aspirin (r=.431, P=.001) but not before its administration (r=-.185, P=.181).
Part Two
Comparison of the two groups studied revealed that the subjects with a serum cholesterol level >6.2 mmol/L had not only significantly higher mean serum cholesterol but also higher LDL cholesterol and plasma prothrombin concentrations. Other parameters evaluated were similar (Table 1). In all individuals studied, blood platelet count was in the normal range (from 185 000 to 330 000 per microliter) and did not change between subjects with total serum cholesterol below or above 6.2 mmol/L.
After 2 weeks of aspirin treatment, bleeding time became prolonged in both groups, and plasma FPA levels diminished only in the group with serum cholesterol 6.2 mmol/L (P<.05, signed-rank test). Other hemostatic variables showed no statistically significant changes.
At baseline, thrombin generation was very similar in the two groups. Specifically, no differences could be detected in the main parameters describing the reaction, ie, the reaction rate, , initial thrombin concentration, c0, and total thrombin generated, S. In the group formed by subjects with total serum cholesterol 6.2 mmol/L, aspirin markedly depressed thrombin generation. At the time intervals 0 to 180 seconds, mean FPA values were significantly higher before than after the treatment (Table 3). Aspirin also depressed significantly c0 and S while remained unchanged. However, in the group of subjects with high blood cholesterol, all the above three parameters were not affected by aspirin treatment (Table 2).
|
In the whole population studied, there was no correlation between either c0 or S versus serum cholesterol. Following aspirin treatment, a weak but statistically significant correlation between S and serum total cholesterol level became evident (r=.414, P=.03), while c0 showed a similar tendency (r=.373, P=.02). It is interesting to note that S subsequent to aspirin ingestion was higher in all individuals with serum cholesterol >7.7 mmol/L, while it was uniformly lower in all those with a cholesterol level below 6.2 mmol/L (Fig 3). A similar distinct tendency was also observed between serum LDL cholesterol levels and S after (r=.397, P=.049) but not before (r=.113, P=.590) aspirin treatment. Serum HDL cholesterol was not correlated with any indices of thrombin generation, either before or after aspirin treatment (data not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The results obtained indicate that aspirin impairs thrombin generation in subjects with a serum cholesterol level
6.2 mmol/L (240 mg/dL). This action of aspirin was observed 2 hours after ingestion of a 500-mg dose, and following 2-weeks of treatment at a daily dose of 300 mg. The response to chronic aspirin treatment was more pronounced than that to a single dose. Chronic administration led to a distinct suppression of both S and c0. The latter finding was paralleled by a significant fall in FPA level, measured in plasma obtained from peripheral venous blood. A single dose of aspirin depressed but caused a modest, though significant, rise in c0, which resulted in a lack of any significant changes in S, as this last quantity depends on both and c0. This depressed , observed ex vivo, was confirmed by in vitro studies, which showed a significant delay in the peak thrombin clotting activity 2 hours after administration of a 500-mg dose, as previously described.5 Little data have been available on the effects of chronic aspirin treatment on thrombin generation. Kyrle et al6 reported that administration of 300 mg aspirin/d for a week was associated with depression of thrombin generation, studied by an ex vivo method, in four of seven volunteers. Ratnatunga et al8 found that a 1-month administration of aspirin at a daily dose of 300 mg inhibited the effect of shear stress on platelets and thrombin generation, measured by an in vitro method. Our data suggest that aspirin influences thrombin generation both after a single dose and after a chronic (2-week) administration. However, there appears to be a significant and qualitative difference in those effects: While a single dose of aspirin depresses the rate of thrombin generation, chronic treatment reduces the total amount of thrombin generated. The precise mechanism of these phenomena is at present unknown. The relationship of aspirin dose to efficacy is still controversial.7 14 Aspirin at a daily dose of 300 mg markedly inhibited thrombin generation in survivors of myocardial infarction studied by us. Clearly, it will be important to establish whether low-dose aspirin treatment impairs thrombin generation as well. It is possible that different actions of aspirin (for instance, the effect on cyclooxygenase versus the inhibition of thrombin generation) may require different doses.
Our observations indicate that the effects of aspirin on thrombin generation depend on serum cholesterol level. Thus, in subjects with high blood cholesterol, thrombin generation remained unaffected following either single dosing or 2-week treatment with aspirin. We have arbitrarily divided the population studied into two groups, using a total serum cholesterol level of 6.2 mmol/L (240 mg/dL) as a cutpoint. Thus, according to the recent report of the Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults,10 our subjects with cholesterol levels below these cutpoints would fit into the category of "desirable" and "borderline-high cholesterol," while subjects above those levels would be classified as "high blood cholesterol group." Results obtained by comparison of these two groups get strong support from analysis of correlation between total serum cholesterol (or LDL cholesterol) and the inhibitory effect of aspirin on total thrombin generated: The higher the serum cholesterol level, the less likely was the depressive action of aspirin on thrombin generation to occur. Distribution of some other factors that might affect thrombin generation, eg, plasma concentrations of fibrinogen, Lp(a), and IgE,15 16 was similar in both groups studied.
Since the precise mechanism of the inhibitory action of aspirin on thrombin generation is not known, the explanation of the phenomenon described here must remain hypothetical. For reasons presented elsewhere,5 we are inclined to think that suppression of thrombin generation by aspirin results rather from acetylation of macromolecules of platelet membranes and/or of prothrombin than from the inhibition of platelet cyclooxygenase. If that indeed is the case, then several explanations could be envisaged. First, in hypercholesterolemia, alterations in the lipid-protein matrix and rearrangement in the lipid bilayer of the platelet17 could render the membrane proteins less accessible for acetylation by aspirin.18 Second, prothrombin circulates partly associated with plasma lipoproteins19 ; changes in their composition and structure, occurring in hypercholesterolemia, might diminish the chance of aspirin to interact with prothrombin.5 Third, in our group with high blood cholesterol, contrary to the group with serum cholesterol 6.2 mmol/L, aspirin did not diminish the level of plasma lipid peroxides; previous studies20 have shown that lipid peroxides promote thrombin generation in plasma. However, we did not measure plasma lipid peroxides in part two of the study, during chronic aspirin treatment.
The dampening of thrombin formation by aspirin might be one of the mechanisms responsible for its prophylactic and therapeutic efficacy. This could be of special interest in hypercholesterolemia, which is associated with a prothrombotic state. Thus, in hypercholesterolemia, platelet membrane fatty acid composition is altered,17 thromboxane A2 production increased,21 and sensitivity to agonists such as ADP, collagen, or epinephrine was enhanced.22 23 Furthermore, in hypercholesterolemia there is an increased generation of reactive oxygen species by endothelium, leukocytes, macrophages, and possibly platelets.24 25 26 27 This often, though not invariably,24 28 results in clinically detectable enhanced peroxidation of plasma lipoproteins; oxidized LDL may inactivate nitric oxide26 and contribute to injury of endothelial cells.29
Aspirin is widely used in the prevention and treatment of cardiovascular diseases. Its use is not devoid of side effects and its efficacy might differ depending on many factors, still rather poorly defined. Aspirin nonresponders were reported in a subgroup of patients who suffered from stroke30 and in heart transplant recipients31 ; increased platelet aggregability and enhanced lipid peroxidation were speculated to be the reason for this resistance to the antithrombotic action of aspirin. Our results suggest that in patients with high blood cholesterol in contrast to patients with desirable or borderline blood cholesterol, aspirin does not depress thrombin generation.
|
Acknowledgments |
|---|
This work was supported by a grant from The State Research Council of Poland, No. 4P05B 026 08.
Received December 6, 1995;
revision received April 30, 1996;
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Swords NA, Mann KG. The assembly of the prothrombinase complex on adherent platelets. Arterioscler Thromb.. 1993;13:1602-1612.
2. Stubbs MT, Bode W. A player of many parts: the spotlight falls on thrombin's structure. Thromb Res.. 1993;69:1-58.[Medline] [Order article via Infotrieve]
3. Pitney WR, Dacie JV. A simple method of studying the generation of thrombin in recalcified plasma. J Clin Pathol.. 1953;6:9-13.
4. Hemker HC, Wielders S, Kessels H, Beguin S. Continuous registration of thrombin generation in plasma: its use for the determination of the thrombin potential. Thromb Haemost.. 1993;70:617-624.[Medline] [Order article via Infotrieve]
5.
Szczeklik A, Krzanowski M, Gora P, Radwan J. Antiplatelet drugs and generation of thrombin in clotting blood. Blood.. 1992;80:2006-2011.
6. Kyrle PA, Westwick J, Scully MF, Kakkar VV, Levis GP. Investigation of the interaction of blood platelets with the coagulation system at the site of plug formation ex vivo in man: effect of low-dose aspirin. Thromb Haemost.. 1987;57:62-69.[Medline] [Order article via Infotrieve]
7.
Fuster V, Dyken ML, Vokonas PS, Hennekens C. Aspirin as a therapeutic agent in cardiovascular disease. Circulation.. 1993;87:659-675.
8.
Ratnatunga CP, Edmondson SF, Rees GM, Kovacs IB. High-dose aspirin inhibits shear-induced platelet reaction involving thrombin generation. Circulation.. 1992;85:1077-1082.
9. Vane JR, Flower RJ, Botting RM. The mechanism of action of aspirin. In: Vane RJ, Botting RM, eds. Aspirin and Other Salicylates London, England: Chapman and Hall; 1992:35-62.
10. Grundy SM. National Cholesterol Education Program: second report of the Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Circulation.. 1994;89:1336-1343.
11. Szczeklik A, Gryglewski RJ, Musial J, Grodzinska L, Serwonska M, Marcinkiewicz E. Thromboxane generation and platelet aggregation in survivals of myocardial infarction. Thromb Haemost.. 1978;40:66-74.[Medline] [Order article via Infotrieve]
12. Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta.. 1978;90:37-43.[Medline] [Order article via Infotrieve]
13. Szczeklik A. Generation of the proteolytic activity bound with alpha 2-macroglobulin during plasma clotting. Clin Chim Acta.. 1970;27:339-344.[Medline] [Order article via Infotrieve]
14.
Dyken ML, Barnet HJM, Easton JD, Fields WS, Fuster V, Hachinski V, Norris JW, Sherman DG. Low-dose aspirin and stroke. Stroke.. 1992;23:1395-1399.
15. Hamsten A. The hemostatic system and coronary heart disease. Thromb Res.. 1993;70:1-38.[Medline] [Order article via Infotrieve]
16. Szczeklik A, Schmitz-Schumann M, Krzanowski M, Virchow C. Delayed generation of thrombin in clotting blood of atopic patients with hay fever and asthma. Clin Exp Allergy.. 1991;21:411-415.[Medline] [Order article via Infotrieve]
17. Chetty N, Naran NH. Platelet hyperreactivity in hyperlipidaemia with specific reference to platelet lipids and fatty acid composition. Clin Chim Acta.. 1992;213:1-13.[Medline] [Order article via Infotrieve]
18. Watala C, Gwozdzinski K. Effect of aspirin on conformation and dynamics of membrane proteins in platelets and erythrocytes. Biochem Pharmacol. 1993;45:1343-1349.[Medline] [Order article via Infotrieve]
19. Bradley WA, Song J-N, Gianturco SH. Thrombin-prothrombin interactions with very low density lipoprotein. Ann N Y Acad Sci.. 1986;485:159-169.[Medline] [Order article via Infotrieve]
20. Barrowcliffe TW, Gray E, Kerry PJ, Gutteridge JMC. Triglyceride-rich lipoproteins are responsible for thrombin generation induced by lipid peroxides. Thromb Haemost.. 1984;52:7-10.[Medline] [Order article via Infotrieve]
21.
Davi G, Averna M, Catalano I, Barbagallo C, Ganci A, Notarbartolo A, Ciabattoni G, Patrono C. Increased thromboxane biosynthesis in type IIa hypercholesterolemia. Circulation.. 1992;85:1792-1798.
22. Croft KD, Beilin LJ, Vandongen R, Rouse I, Masarei J. Leukocyte and platelet function and eicosanoid production in subjects with hypercholesterolemia. Atherosclerosis.. 1990;83:101-109.[Medline] [Order article via Infotrieve]
23. Surya II, Gorter G, Mommersteeg M, Akkerman JWN. Enhancement of platelet functions by low density lipoproteins. Biochim Biophys Acta.. 1992;1165:19-26.[Medline] [Order article via Infotrieve]
24. Szczeklik A, Gryglewski RJ, Domagala B, Dworski R, Basista M. Dietary supplementation with vitamin E in hyperlipoproteinemias: effects on plasma lipid peroxides, antioxidant activity, prostacyclin generation and platelet aggregability. Thromb Haemost.. 1985;54:425-430.[Medline] [Order article via Infotrieve]
25. Krause S, Pohl A, Pohl C, Liebrenz A, Ruhling K, Losche W. Increased generation of reactive oxygen species in mononuclear blood cells from hypercholesterolemic patients. Thromb Res.. 1993;71:237-240.[Medline] [Order article via Infotrieve]
26. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest.. 1993;91:2546-2551.
27.
Kaul S, Waack BJ, Padgett RC, Brooks RM, Heistad DD. Altered vascular responses to platelets from hypercholesterolemic humans. Circ Res.. 1993;72:737-743.
28. Kameda-Takemura K, Corder CN, Lee DM. Lipid peroxide levels in type II hyperlipoproteinemic subjects. Artery.. 1993;20:189-200.[Medline] [Order article via Infotrieve]
29. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature.. 1993;362:801-809.[Medline] [Order article via Infotrieve]
30. Grotemeyer KH, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non-responder: a pilot-study including 180 post-stroke patients. Thromb Res.. 1993;71:397-403.[Medline] [Order article via Infotrieve]
31. de Lorgeril M, Dureau G, Boissonnat P, Ovize M, Monnez C, Monjaud I, Salen P, Renaud S. Increased platelet aggregation after heart transplantation: influence of aspirin. J Heart Lung Transplant.. 1991;10:600-603.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  C. Patrono, C. Baigent, J. Hirsh, and G. Roth Antiplatelet Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 199S - 233S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Faraday, L. R. Yanek, R. Mathias, J. E. Herrera-Galeano, D. Vaidya, T. F. Moy, M. D. Fallin, A. F. Wilson, P. F. Bray, L. C. Becker, et al. Heritability of Platelet Responsiveness to Aspirin in Activation Pathways Directly and Indirectly Related to Cyclooxygenase-1 Circulation, May 15, 2007; 115(19): 2490 - 2496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Undas, K. E. Brummel-Ziedins, and K. G. Mann Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions Blood, March 15, 2007; 109(6): 2285 - 2292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. H. Wang, D. L. Bhatt, and E. J. Topol Aspirin and clopidogrel resistance: an emerging clinical entity Eur. Heart J., March 2, 2006; 27(6): 647 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Patrono, B. Coller, G. A. FitzGerald, J. Hirsh, and G. Roth Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 234S - 264S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Undas, K. Brummel, J. Musial, K. G. Mann, and A. Szczeklik PlA2 Polymorphism of {beta}3 Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury Circulation, November 27, 2001; 104(22): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Undas, K. Brummel, J. Musial, K. G. Mann, and A. Szczeklik Blood coagulation at the site of microvascular injury: effects of low-dose aspirin Blood, October 15, 2001; 98(8): 2423 - 2431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Patrono, B. Coller, J. E. Dalen, G. A. FitzGerald, V. Fuster, M. Gent, J. Hirsh, and G. Roth Platelet-Active Drugs : The Relationships Among Dose, Effectiveness, and Side Effects Chest, January 1, 2001; 119 (2009): 39S - 63S. [Full Text] [PDF]
|
|
|
|
 |
|
 R J Gryglewski, W Uracz, and J Swies Unusual effects of aspirin on ticlopidine induced thrombolysis Thorax, October 1, 2000; 55(90002): 17S - 19. [Full Text]
|
|
|
|
 |
|
 R. Altman, A. Scazziota, J. Rouvier, and C. Gonzalez Effects of Ticlopidine or Ticlopidine Plus Aspirin on Platelet Aggregation and ATP Release in Normal Volunteers: Why Aspirin Improves Ticlopidine Antiplatelet Activity Clinical and Applied Thrombosis/Hemostasis, October 1, 1999; 5(4): 243 - 246. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Szczeklik, J. Musial, A. Undas, P. Gajewski, P. Gora, J. Swadzba, and M. Jankowski Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1286 - 1293. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||