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PubMed2004

Effect of perindopril on platelet nitric oxide resistance in patients with chronic heart failure secondary to ischemic left ventricular dysfunction.

In 15 patients with chronic heart failure of ischemic origin who were not previously treated with angiotensin-converting enzyme inhibitors, platelets exhibited hyperaggregability and impaired responsiveness to the antiaggregatory and cyclic guanosine monophosphate-stimulatory effects of nitric oxide donor sodium nitroprusside compared with normal subjects; this was paralleled by increased blood levels of superoxide radicals. Treatment with perindopril for 4 days significantly improved platelet responses to sodium nitroprusside; there was also a trend toward a decrease in superoxide radical levels.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Relation of augmented platelet reactivity to the magnitude of distribution of atherosclerosis.

The extent of luminal involvement of atherosclerotic vascular disease and platelet reactivity portend subsequent cardiovascular events. This study was designed to determine whether platelet reactivity correlates with the extent of the territorial distribution of vascular disease. Blood was obtained from 130 patients who had known atherosclerotic vascular disease categorized as being in > or =1 of the following territories: coronary artery disease (CAD; n = 89), cerebrovascular disease (n = 36), and peripheral arterial disease (n = 61). Platelet reactivity, i.e., the activation of platelets in response to a low concentration of adenosine diphosphate (0.2 micromol/L), was measured using flow cytometry. Patients with vascular disease in >1 territory compared with those with disease in only 1 territory had greater platelet reactivity with respect to P-selectin expression (p = 0.01). The percentages of platelets expressing P-selectin (mean +/- SD) were 6.4 +/- 4.2 in patients who had involvement of 1 territory (n = 88), 10.0 +/- 6.8 in those who had involvement of 2 territories (n = 28), and 10.1 +/- 9.9 in those who had involvement of 3 territories (n = 14). Patients who had CAD and diabetes mellitus had greater P-selectin expression than did those who had CAD without diabetes (p <0.02 for interaction). Thus, platelet reactivity is greater in patients who have more extensive territorial distribution of atherosclerotic vascular disease and in those who have CAD and diabetes mellitus. Accordingly, patients who have more widely distributed vascular disease are likely to derive particular benefit from antiplatelet regimens that suppress platelet function to a greater extent.

Aged↗
PubMed2005

Plasma, serum, and platelet expression of CD40 ligand in adults with cardiovascular disease.

The application of soluble CD40 ligand (sCD40L) as a biomarker has garnered great scientific and clinical interest. However, there are many uncertainties with regard to the biology of sCD40L. Although presumed to be a marker of platelet activation, relative levels in plasma, serum, and platelet expression are unknown, as is the optimal method for its measurement. We measured CD40L from serum, platelet-poor plasma, and platelet surface in adults who had stable cardiovascular disease (CVD) and those who had unstable CVD (n = 40). Plasma sCD40L did not differ significantly between groups. Serum sCD40L was significantly lower (1.4 +/- 1.3 vs 5.2 +/- 3.7 ng/ml, p <0.001) and platelet membrane CD40L expression was higher (1.4 +/- 0.7% vs 0.9 +/- 0.6%, p = 0.03) in unstable compared with stable CVD. When the 2 groups were considered together, there was a significant correlation between plasma and serum sCD40L levels (rho = 0.4, p = 0.02) and negative correlations between plasma (rho = -0.3, p = 0.04) and serum (rho = -0.4, p = 0.01) sCD40L levels with platelet membrane CD40L expression. In unstable CVD, the correlation between sCD40L measurements was poor. Consistent with enhanced platelet activation, there was a positive correlation between platelet aggregation and surface CD40L expression (rho = 0.5, p = 0.02) and between platelet expression of CD40L and P-selectin (rho = 0.4, p = 0.05) in unstable CVD. There was no correlation between CD40L and platelet count or C-reactive protein. Only surface expression of CD40L compared with platelet-derived (plasma) or total (serum) CD40L level proved a reliable marker of platelet function in patients who had stable CVD and those who had unstable CVD. In conclusion, our data demonstrate the complex nature of CD40L and highlight the distinct processes of expression, shedding, and clearance of this ligand in patient populations.

Adult↗
PubMed2006

Relation between atherosclerosis risk factors and aspirin resistance in a primary prevention population.

Resistance to inhibition of platelet function by aspirin may contribute to future myocardial infarction and stroke. Adverse cardiovascular outcomes have been associated with aspirin resistance on several different platelet function assays, including the level of urinary 11-dehydro thromboxane B2 (Tx-M), platelet aggregation to arachidonic acid and adenosine diphosphate, and closure time on the platelet function analyzer-100. We examined the concordance of these aspirin-resistance assays and their relation to cardiovascular risk factors in a primary prevention population. Asymptomatic patients (n = 1,311) at increased risk for coronary heart disease were evaluated before and after 2 weeks of aspirin (81 mg/day). Aspirin resistance was defined according to published criteria for these 3 assays of platelet function. Subjects were characterized for the presence of atherosclerosis risk factors. Agreement among the 3 assays was poor. Only 5 patients met aggregation criteria for aspirin resistance. Attenuated suppression of urinary Tx-M by aspirin was associated with a greater atherosclerotic risk profile and Framingham risk score in multivariable regression analysis. Aspirin resistance by platelet function analyzer-100 was associated only with increased von Willebrand factor levels and not with atherosclerotic risk profile. In conclusion, in a primary prevention population, different published criteria for aspirin resistance classify distinct groups of patients as aspirin resistant with very little overlap. Higher Tx-M, which reflects decreased suppression of thromboxane production in vivo, is the only criterion associated with atherosclerosis risk factors, suggesting that this measurement may represent the most relevant approach for identifying asymptomatic subjects whose aspirin treatment will "fail."

Adenosine Diphosphate↗
PubMed2006

Clopidogrel response variability, resistance, or both?

Dual antiplatelet therapy represents an important advance for patients with established cardiovascular disease. Variable platelet response and potential resistance to therapy have emerged with aspirin and clopidogrel. There is no clear and accepted definition of clopidogrel resistance, but patients with lower responses to clopidogrel are at risk for ischemic events, particularly when they undergo percutaneous coronary intervention. Inconsistent nomenclature about this lower response has led to confusion about its potential clinical importance. The concern about nomenclature is less important than answers to key questions such as its mechanisms, how and in whom to measure platelet function, what levels of inhibition are associated with failure of therapy, what levels are adequate for improved clinical outcomes, and in what ways therapy could be altered in patients with lower responses to improve measures of platelet function and clinical outcomes. One option may be to target more aggressive intervention (higher loading and maintenance doses of clopidogrel or alternative agents) to specific patients who are at greater risk and/or least responsive to standard therapies. Clinically useful risk stratification requires an easily performed and reproducible measure of platelet aggregation, as well as standardized definitions of response that correlate with clinical outcomes. Point-of-care assays of platelet function may ultimately improve the ability of clinicians to modify therapy on the basis of response.

Aspirin↗
PubMed2004

Saratin (an inhibitor of platelet-collagen interaction) decreases platelet aggregation and homocysteine-mediated postcarotid endarterectomy intimal hyperplasia in a dose-dependent manner.

BACKGROUND: This study investigated Saratin's (Merck KGaA, Darmstadt, Germany) prevention of platelet adhesion and intimal hyperplasia at different doses and in the hyperhomocystinemia rat carotid endarterectomy (CEA) model. METHODS: Rats were divided into two groups: (1) platelet adhesion or (2) luminal stenosis because of intimal hyperplasia. At CEA, rats received 0, 0.5, 5.0, 10.0, or 20.0 microg Saratin on the artery. Post-CEA platelet aggregation was evaluated by standard error of the mean. Intimal hyperplasia group received either (1) control or (2) 4.5 g/kg DL-homocystine diets for two weeks followed by CEA and treated with diluent or 5.0 microg Saratin. Endpoints included platelet adhesion, intimal hyperplasia, plasma homocysteine (HCys), and its metabolic enzymes cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR). RESULTS: Platelet adhesion: post-CEA, platelet adhesion was reduced by 63%, 67%, and 67% in Saratin doses > or =5.0 microg. Intimal hyperplasia: 5.0 microg Saratin in the HCys group decreased intimal hyperplasia by 45% compared with the non-Saratin-treated HCys group. Plasma HCys levels were not altered with Saratin treatment in the HCys groups nor were CBS or MTHFR. CONCLUSIONS: Saratin significantly inhibited platelet adhesion at > or =5.0 microg, and Saratin at 5.0 microg attenuated luminal stenosis in a hyperhomocysteinemic rat CEA model.

Analysis of Variance↗
PubMed2006

Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease.

BACKGROUND AND OBJECTIVE: We performed a placebo-controlled, randomized study to address whether celecoxib or ibuprofen undermines the functional range of inhibition of platelet cyclooxygenase (COX)-1 activity by aspirin in patients with osteoarthritis and stable ischemic heart disease. METHODS: Twenty-four patients who were undergoing long-term treatment with aspirin (100 mg daily) for cardioprotection were coadministered celecoxib, 200 mg twice daily, ibuprofen, 600 mg 3 times daily, or placebo for 7 days. RESULTS: The coadministration of placebo or celecoxib did not undermine the aspirin-related inhibition of platelet COX-1 activity, as assessed by measurements of serum thromboxane B(2) (TXB(2)) levels, as well as platelet function. In contrast, a significant (P < .001) increase in serum TXB(2) level was detected on day 7 before drug administration (median, 19.13 ng/mL [range, 1-47.5 ng/mL]) and at 24 hours after the coadministration of aspirin and ibuprofen (median, 22.28 ng/mL [range, 4.9-44.4 ng/mL]) versus baseline (median, 1.65 ng/mL [range, 0.55-79.8 ng/mL]); this was associated with a significant increase in arachidonic acid-induced platelet aggregation (P < .01) and adenosine diphosphate-induced platelet aggregation (P < .05) and a decrease in the time to form an occlusive thrombus in the platelet function analyzer (P < .01). The urinary excretion of 11-dehydro-TXB(2), an index of systemic thromboxane biosynthesis, was not significantly affected by the coadministration of treatment drugs. At steady state, a comparable and persistent inhibition of lipopolysaccharide-stimulated prostaglandin E(2) generation, a marker of COX-2 activity ex vivo, was caused by ibuprofen (>or=80%) or celecoxib (>or=70%) but not placebo. CONCLUSIONS: Unlike ibuprofen, celecoxib did not interfere with the inhibition of platelet COX-1 activity and function by aspirin despite a comparable suppression of COX-2 ex vivo in patients with osteoarthritis and stable ischemic heart disease.

Adenosine Diphosphate↗
PubMed2006

Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment.

OBJECTIVES: This study sought to assess the influence of type 2 diabetes mellitus (T2DM) and the impact of hypoglycemic treatment (insulin vs. noninsulin) on platelet function profiles in patients treated with dual oral antiplatelet therapy. BACKGROUND: Insulin inhibits platelet aggregation by suppressing the P2Y12 pathway. However, T2DM patients have a loss of responsiveness to insulin that leads to upregulation of the P2Y12 pathway, increased platelet reactivity, and reduced responsiveness to antiplatelet agents. Patients with insulin-treated diabetes mellitus (ITDM) have a more advanced disease status and higher atherothrombotic risk compared with non-ITDM (NITDM). However, the impact of insulin therapy on platelet dysfunction in patients treated with P2Y12 antagonists is unknown. METHODS: A total of 201 T2DM and 65 nondiabetic patients with coronary artery disease in a steady phase of aspirin and clopidogrel treatment were studied. Platelet aggregation was assessed using agonists specific (6 and 20 microM adenosine diphosphate [ADP]) and nonspecific (6 microg/ml collagen and 20 microM epinephrine) for the P2Y12 pathway. High shear-induced platelet reactivity was assessed by means of the PFA-100 system (Dade-Behring International, Miami, Florida). RESULTS: The T2DM patients had platelet aggregation and shear-induced platelet function significantly increased compared with nondiabetic patients using all assays. Platelet aggregation was increased in ITDM (n = 68) compared with NITDM (n = 133) patients after P2Y12-specific stimuli. Insulin treatment was the strongest predictor of ADP-induced aggregation. Platelet function profiles were similar between ITDM and NITDM using assays nonspecific to the P2Y12 pathway. Platelet dysfunction was independent of glycemic control and inflammatory status. CONCLUSIONS: The P2Y12-dependent and -independent pathways of platelet reactivity are altered in T2DM compared with nondiabetic patients, and ITDM have greater ADP-induced platelet aggregation compared with NITDM.

Aged↗
PubMed2006

Duration of effects of aspirin on platelet function in healthy volunteers: an analysis using the PFA-100.

STUDY OBJECTIVE: The aim of the study was to determine the duration and effects of aspirin on platelet function. STUDY DESIGN: Prospective investigation. SETTING: Blood samples from volunteers. PATIENTS AND MONITORING: Ten healthy male volunteers took part in this investigation. After having measured baseline hemostatic parameters, 2000-mg aspirin was taken orally. Subsequently, the hemostatic profile had been compiled daily for a duration of 4 days after ingestion. MEASUREMENTS AND MAIN RESULTS: Platelet function was analyzed (1) after 3 hours and (2) daily for 4 days by the platelet function analyzer (PFA-100, Dade Co, Miami, Fla), which represents a sensitive investigation method for measuring platelet function and dysfunction. Routine hemostatic parameters were investigated. Three hours after ingestion of aspirin, abnormal PFA-100 values could be detected. Further detectable elevated values were found during the following 3 days. CONCLUSION: Effects of single-dose aspirin 2000 mg on platelet function were detected after 3 hours and had been lasting for the following 3 days. This result shows that PFA-100 may help by evaluating hemostasis during the preoperative period.

Adult↗
PubMed2003

Comparison of turbidimetric aggregation and in vitro bleeding time (PFA-100) for monitoring the platelet inhibitory profile of antiplatelet agents in patients undergoing stent implantation.

The present study compared classical ADP-induced platelet aggregation vs. PFA-100 closure times using collagen/ADP membrane cartridges to monitor the degree of platelet-inhibiting effect of three drug regimens: ticlopidin, abciximab/ticlopidin and loading dose clopidogrel, each on top of aspirin (acetylsalicylic acid, ASA) during and after elective stent placement (intervention) in a total of 31 patients with acute coronary syndrome. Ticlopidin was started directly after stent implantation, abciximab was started before coronary intervention and given intravenously for 12 h, and a clopidogrel loading dose was given before intervention. The 10 patients treated with ticlopidin (500 mg daily) showed no significant prolongation of PFA closure times and a slight increase of ADP-induced platelet aggregation shortly after intervention. In 11 patients treated with abciximab/ticlopidin, the PFA closure times were significantly prolonged, and ADP-induced platelet aggregation was reduced by more than 80% during the 12-h abciximab infusion after intervention. The 10 patients pretreated with loading dose clopidogrel (450 mg followed by 75 mg daily) showed an intermediate but significant prolongation of PFA closure times and reduction of ADP-induced platelet aggregation at levels between the ticlopidin/aspirin- and the abciximab/ticlopidin/aspirin-treated groups. At 20 h after intervention, a similar degree of PFA closure time prolongation and inhibition of ADP-induced aggregation was observed in the abciximab/ticlopidin/aspirin- and the clopidogrel/aspirin-treated patient groups. Both measurement of PFA-100 closure times and inhibition of ADP-induced platelet aggregation showed a similar degree of platelet inhibition, but had rather broad SD ranges, which limit their precision for the follow-up of individual patients. In conclusion, abciximab on top of ticlopidin/aspirin showed a stronger antiplatelet effect for only less than 20 h, as compared to loading dose clopidogrel/aspirin in acute coronary syndrome patients undergoing stent implantation. Whether such a short-term superiority of abciximab, as compared to loading dose clopidogrel, translates into an overall clinical benefit of thombotic and bleeding complications remains to be established in a randomized clinical trial.

Abciximab↗
PubMed2004

Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin)-its relation to metabolic control.

Aspirin (acetylsalicylic acid, ASA), which is recommended for primary and secondary prevention in diabetes mellitus (DM), has been shown to have a lower antiplatelet activity in diabetic patients. We conducted a crossover designed observational study to evaluate whether there is an association between the parameters relevant to metabolic control of diabetes and platelet sensitivity to aspirin in type 2 diabetic patients. Platelets' ability to adhere and aggregate was monitored with the use of platelet function analyser (PFA-100 collagen/epinephrine closure time, CT(CEPI) or collagen/ADP closure time, CT(CADP)), classical turbidimetric aggregometry and whole blood electrical aggregometry (WBEA), using collagen (WBEA(coll)), ADP (WBEA(ADP)) and arachidonic acid (WBEA(AA)) as platelet agonists, in 48 control healthy volunteers (mean age+/-S.D., 49+/-9 years) and 31 type 2 DM patients (50+/-9 years; HbA(1c) 9.4+/-1.6%). In majority of control subjects (69%) and minority of diabetic patients (29%, p=0.0006), the use of 150 mg aspirin daily for 1 week significantly reduced platelet adhesiveness and reactivity (by 14.1% in diabetes vs. 78.6% in control, p(np)=0.0035, as expressed by the relative changes in CT(CEPI)). Aspirin reduced WBEA(coll) and WBEA(AA) to a lesser extent in diabetic patients (by 2.1% vs. 8.3% in controls, p(np)=0.0397, and by 97.3+/-12.8% vs. 100% in controls, p(np)=0.0383, respectively), which corresponded to ASA-mediated decreased aggregation in platelet-rich plasma (PRP, r(S)=0.45 and r(S)=0.78 for collagen- or arachidonate-agonized platelets, p<0.01 or lower). The maximal inhibition of platelet aggregation was lower and IC(50) higher in diabetic compared to control subjects, both in the presence of arachidonic acid (71% vs. 39%, p(np)0.0001; 0.5 microg/ml vs. 1.3 microg/ml, p<0.0001) and collagen (52% vs. 35%, p<0.0004; 1.6 microg/ml vs. 2.1 microg/ml, p<0.01). The reduced response of platelets from diabetic subjects to aspirin was associated with a higher level of HbA(1c), lower concentration of HDL-cholesterol and a higher total cholesterol concentration. Overall, there is evidence that reduced platelets response to aspirin may occur more often in diabetic patients. Poor metabolic control may play a role in the reduced platelet sensitivity to aspirin in DM patients. Thus, our findings strongly support the requirements for an excellent near-normal metabolic control and may suggest a need for alternative ASA dosing schedules in DM patients.

Adult↗
PubMed2005

The difference between clopidogrel responsiveness and posttreatment platelet reactivity.

BACKGROUND: Aggregation is the most common measure of platelet reactivity. The relative inhibition of platelet aggregation between pretreatment and posttreatment is the most common estimate of clopidogrel responsiveness. However, patients responsive to clopidogrel may remain with highly reactive platelets and thus have increased thrombotic risk. METHODS: Platelet reactivity was determined by ADP-induced aggregation (%) in 62 patients undergoing elective coronary stenting at pretreatment and 5 days postprocedure. All patients were on aspirin (325 mg) and received 300 mg of clopidogrel immediately poststenting and 75 mg qd. Pretreatment reactivity was divided into tertiles. Based on clopidogrel drug responsiveness, nonresponders were defined as <10% relative inhibition of pretreatment aggregation, semiresponders as 10-30%, and responders as >30%. We determined the relation between clopidogrel responsiveness and platelet reactivity. RESULTS: Pretreatment reactivity tertiles by 5 microM ADP were: low (47+/-9%), moderate (64+/-4%), and high (78+/-6%). Eight patients were nonresponders, 18 were semiresponders, and 36 were responders. Clopidogrel responsiveness directly correlated with pretreatment reactivity, 86% of responders had moderate or high pretreatment reactivity, whereas 75% of nonresponders had low pretreatment reactivity. Despite being more responsive, 16% of patients with high pretreatment reactivity and 17% with moderate pretreatment reactivity remained with moderate posttreatment reactivity. CONCLUSION: Measuring clopidogrel responsiveness may overestimate the risk of stent thrombosis in nonresponders with low pretreatment reactivity and underestimate risk in those responders who remain with high posttreatment platelet reactivity. Posttreatment platelet reactivity is a better measure of thrombotic risk than responsiveness to clopidogrel.

Adenosine Diphosphate↗
PubMed2005

Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance.

BACKGROUND: Late venous graft thrombosis, leading to recurrent ischemia, is frequently encountered in old, degenerated vein grafts with advanced atherosclerotic plaque formation. Aspirin has been indicated to maintain venous graft patency in the post-operative period. However, there is considerable evidence that aspirin resistance is of concern in patients with venous grafts. MATERIAL AND METHOD: Prospectively enrolled 14 patients (11 male, 3 female, Group 1), who were shown to have at least one occluded saphenous vein graft on their late control coronary angiogram after bypass operation, were compared for the presence of aspirin resistance by PFA-100 with age- and sex-matched 14 patients (10 male, 4 female, Group 2), who were found patent and well-functioning vein grafts without wall irregularities on late post-operative coronary angiograms (mean 6.5+/-2.5 years), enrolled as a control group. RESULTS: Mean CT of collagen/epinephrine cartridge in Group 1 was 197+/-85 s and significantly less than in Group 2 (279+/-44 s; p=0.011). It was found that 50% of patients in Group 1 were so-called aspirin resistant, whereas in Group 2, this ratio was 7.1% (p=0.033). BMI (p=0.038, Beta=-0.322), uric acid level (p=0.023, Beta=-0.355), and CT by collagen/epinephrine cartridge (p=0.008, Beta=0.431) were independently predicting late occlusion of saphenous vein graft. CONCLUSION: Aspirin resistance is highly prevalent in patients with occluded venous grafts at a relatively late period.

Aged↗