Cyclooxygenase-1 haplotype C50T/A-842G does not affect platelet response to aspirin

SummaryCOX-1 polymorphism C50T, in complete linkage disequilibrium with the other polymorphism A-842G, has been depicted as a determinant of pharmacological response to aspirin treatment. Whether these polymorphisms exert an effect on response to aspirin both in vitro and ex vivo is still controversial. We geno-typed a population of 148 healthy individuals for the C50T/A-842G haplotype. Thirty of them underwent low-dose aspirin (100 mg daily) treatment for four weeks and were followed up for seven days after withdrawal. In this subgroup, we evaluated the thromboxane-dependence of biochemical and functional indexes used to monitor the antiplatelet effect of low-dose aspirin. Among the 148 subjects studied, 10 were heterozygous for the C50T/A-842G haplotype (6.7%) and only one was homozygous for the 50T/-842G haplotype (0.67%). In the group on low-dose aspirin, serum thromboxane (TX) B2 as well as urinary 11-dehydro-TXB2 and arachidonic acid (AA)-induced aggregation were similarly suppressed in carriers and non-carriers of the 50T/-842G haplotype, with an increase until basal levels of all the parameters within seven days after withdrawal. We found no relationship between the 50T/-842G haplotype and the so-called phenomenon of aspirin resistance. Platelet cyclooxygenase activity, as reflected by serum TXB2, was uniformly and persistently suppressed by low-dose aspirin in both carriers and non carriers of these polymorphisms.

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Effect of Diltiazem and Low-Dose Aspirin on Platelet Aggregation and ATP Release Induced by Paired Agonists

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649575 ◽

1993 ◽

Vol 70 (02) ◽

pp. 332-335 ◽

Cited By ~ 12

Author(s):

Marjorie L Zucker ◽

Susan E Budd ◽

Lawrence E Dollar ◽

Steven B Chernoff ◽

Raul Altman

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Low Dose ◽

Atp Release ◽

Thromboxane B2 ◽

Platelet Response ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Significant Difference

SummaryThe authors studied the effects of diltiazem, administered alone and together with low-dose aspirin, on the platelet response to paired agonists. After a baseline period, 25 healthy volunteers were given oral diltiazem for 1 week (120, 240, or 360 mg/day), and then crossed over randomly between 1 week on diltiazem plus aspirin (81 mg/day), and 1 week on aspirin (81 mg/day) alone. Platelet function was tested on 2 consecutive days in each period. Synergistic platelet aggregation and ATP release were obtained at baseline using a subthreshold concentration of arachidonic acid combined with platelet activating factor, ADP, or epinephrine. Diltiazem resulted in a significant decrease from baseline in platelet aggregation and ATP release using the arachidonic acid-epinephrine combination (35% and 40% decrease, respectively, p <0.01) and a significant decrease in aggregation using the arachidonic acid-ADP combination (22% decrease, p <0.01). The effects were neither dose-related, nor accompanied by any significant change in serum thromboxane B2 levels or bleeding times. There was no significant difference between the effects of aspirin alone and aspirin plus diltiazem on the synergistic platelet aggregation and ATP release induced by the paired agonists, or on thromboxane B2 levels or bleeding times. Diltiazem administered in vivo partially inhibits the synergistic platelet aggregation and ATP release induced by paired agonists; however, in contrast to a previous in vitro study it does not potentiate the platelet-inhibitory effect of aspirin.

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Low-Dose Aspirin Inhibits Serum Thromboxane B2 Generation More Than 99 Percent.

Blood ◽

10.1182/blood.v110.11.3897.3897 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3897-3897 ◽

Cited By ~ 1

Author(s):

Sofie S. Thygesen ◽

Anne-Mette Hvas ◽

Steen D. Kristensen

Keyword(s):

Coronary Artery Disease ◽

Low Dose ◽

Stable Coronary Artery Disease ◽

Aspirin Resistance ◽

Thromboxane B2 ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Serum Thromboxane ◽

Artery Disease ◽

Cox 1

Abstract Low dose aspirin is widely used as a well-documented antiplatelet drug in patients with cardiovascular disease. However, several laboratories report a highly variable platelet response to aspirin treatment when assessed by different methods, referred to as ’aspirin resistance’. Aspirin resistance may in part be explained by different degrees of compliance, and also by different doses of aspirin used. In a prospective study we measured serum thromboxane B2 (se-TxB2) in order to investigate whether 75 mg daily of aspirin was sufficient to inhibit the enzyme COX-1. Furthermore, the endogenous production of thromboxane A2, urinary-11-dehydro-thromboxane B2 (U-TxM), was determined. Finally, we measured platelet function by optical platelet aggregometry (OPA) in platelet-rich plasma induced by arachidonic acid (AA) 1.0mM and by adenosine diphosphate (ADP) 5.0 μM. Twenty-two healthy individuals ≥18 years and 44 patients with stable coronary artery disease were included. All subjects had been treated with 75 mg of plain aspirin daily for at least 7 days to achieve steady state before blood sampling. At inclusion the participants received a pill box with the study medication and careful instruction regarding the medication. Compliance was optimized by interview and pill counting at each visit. Reading through all case report forms we found that every participant was 100% compliant stated by every-day interviewing and pill-counting. We found that low-dose aspirin inhibited se-TxB2 more than 99% and U-TxM by 74% on average. Table 1 Group se-TxB2, baseline se-TxB2, aspirin U-TxM, baseline U-TxM, aspirin Healthy (n=22) 326 [277;377] 1.2[0.9;1.5] 295 [248;343] 77 [65;90] Patients (n=44) - 1.0 [0.9;1.2] - 68 [61;76] All of the participants had a complete inhibition of their COX-1 pathway evaluated by measurements of se-TxB2 (<4.5 ng/mL). However, 5 of the 66 (7.5%) individuals had less than 60% inhibition of the U-TxM. Figure 1: Relationship between se-TxB2 and U-TxM day 9. The line indicates 60% of inhibition U-TxM after aspirin treatment. Figure 1:. Relationship between se-TxB2 and U-TxM day 9. The line indicates 60% of inhibition U-TxM after aspirin treatment. The high U-TxM indicates that other pathways synthesizing TxA2 were not completely inhibited. After treatment with aspirin the OPA induced by AA and by ADP decreased significantly. By using limits of > 20% aggregation with AA 1.0 mM and > 70% aggregation for ADP 5 μM as suggested in the literature, we identified three participants (4.5%) who were aspirin resistant. Our finding, that 4.5% of the participants were identified as aspirin resistance by OPA, despite 100% compliance, is interesting and makes the concept ’aspirin resistance’ even more complicated. Even though the COX-1 pathway was completely inhibited, insufficient suppression of OPA and U-TXM, were observed. In conclusion, our findings support that low-dose aspirin of 75 mg daily, was sufficient to suppress se-TxB2 > 99% in patients with stable coronary artery disease. High level of se-TxB2 in patients on low dose aspirin as reported in other studies may be due to poor compliance.

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In vitro and ex vivo effects of aspirin in patients on a low-dose aspirin therapy

Thrombosis Research ◽

10.1016/0049-3848(93)90172-k ◽

1993 ◽

Vol 72 (1) ◽

pp. 49-57 ◽

Cited By ~ 4

Author(s):

R. Voss ◽

B.S. Geissler ◽

H. Tillmanns ◽

F.R. Matthias

Keyword(s):

Low Dose ◽

Ex Vivo ◽

Aspirin Therapy ◽

Dose Aspirin ◽

Low Dose Aspirin

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The use of low-dose aspirin and prednisone does not improve the pregnancy rates in patients undergoing in vitro fertilization or intracytoplasmic sperm injection in antagonist cycle regimen

Fertility and Sterility ◽

10.1016/j.fertnstert.2007.07.550 ◽

2007 ◽

Vol 88 ◽

pp. S158-S159

Author(s):

F.P. Ferreira ◽

R. Fraietta ◽

J. Haddad Filho ◽

A.P. Cedenho

Keyword(s):

In Vitro Fertilization ◽

Intracytoplasmic Sperm Injection ◽

Low Dose ◽

Pregnancy Rates ◽

Vitro Fertilization ◽

Dose Aspirin ◽

Low Dose Aspirin

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Treatment with Simvastatin and Low-dose Aspirin Depresses Thrombin Generation in Patients with Coronary Heart Disease and Borderline-high Cholesterol Levels

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615701 ◽

2001 ◽

Vol 85 (02) ◽

pp. 221-225 ◽

Cited By ~ 16

Author(s):

Anetta Undas ◽

Robert Undas ◽

Jan Brożek ◽

Andrzej Szczeklik ◽

Jacek Musiał

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Thrombin Generation ◽

Low Dose ◽

Ex Vivo ◽

Blood Cholesterol ◽

High Cholesterol ◽

Cholesterol Levels ◽

Dose Aspirin ◽

Low Dose Aspirin

SummaryAspirin and statins are beneficial in coronary heart disease across a broad range of cholesterol levels. We assessed the effects of low-dose aspirin (75 mg daily) on thrombin generation in patients with coronary heart disease and average blood cholesterol levels. We also investigated whether in patients with borderline-high cholesterol level who have been already taking aspirin, additional treatment with simvastatin would affect thrombin generation.Seven-day treatment with low-dose aspirin decreased thrombin generation ex vivo only in patients with total cholesterol 5.2 mmol/L. In patients with higher cholesterol levels aspirin had no effect. In these patients, already taking low-dose aspirin, additional three-month simvastatin treatment resulted in a reduction of thrombin generation. This demonstrates that low-dose aspirin depresses thrombin generation only in subjects with desirable blood cholesterol levels, while in others, with borderline-high cholesterol, thrombin formation is being reduced following the addition of simvastatin.

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