Sex-related differences in the effects of aspirin on the interaction of platelets with subendothelium

doi:10.1016/0049-3848(86)90029-0

Thrombosis Research

Volume 44, Issue 6, 15 December 1986, Pages 837-847

https://doi.org/10.1016/0049-3848(86)90029-0 Get rights and content

Abstract

Using the Baumgartner perfusion technique, marked sex-related differences in the extent of platelet-subendothelium interaction and in the effect of aspirin (ASA) have been observed. The administration of ASA (150 mg daily for 15 days) to two groups of healthy volunteers, one composed of males and the other of females, proved to block the generation of TXB₂ in both cases. The basic pattern of platelet subendothelium interaction, however, was found to be markedly different in both groups studied. In men, aspirin treatment induced a significant reduction in the percentage of platelet thrombi, whereas in women, post ASA values remained at the same level as in control experiments. These results show that in the Baumgartner perfusion system women display a less thrombogenic tendency than men and that 150 mg of ASA administered daily are effective in reducing the extent of platelet-subendothelium interaction in the male group but not in the female group. These findings could explain the absence of benefit observed for women in clinical trials with aspirin.

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Cited by (33)

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Although the guidelines have been revised recently, the effect of aspirin for the primary prevention of cardiovascular disease (CVD) is still controversial. Thus, we aimed to evaluate the effect of aspirin on primary prevention in the real world.
Among the 4,266,268 participants without a history of CVD or previous prescription of aspirin and other antiplatelet agents who were screened between 2002 and 2008, 268,963 persons who were prescribed low-dose aspirin (≤100 mg/day) over 90 days in 2002–2008 and 1,075,852 persons who did not receive aspirin were selected after propensity score matching. A Cox proportional-hazards model was used to evaluate the effect of low-dose aspirin on the development of CVD and bleeding episodes.
Aspirin showed a protective effect on total CVD events (hazard ratio (HR); 0.737, 95% confidence interval; 0.729–0.745). The protective effect of aspirin on total CVD events was significant in men, women and even in young participants (<65 years). Aspirin had a protective effect in participants with diabetes or hypertension against all subcategories of CVD. The HR of bleeding risk was 1.4–1.5 in aspirin group.
Low-dose aspirin generally showed a protective effect against CVD regardless of age, sex, and underlying comorbidities in the real world. Though, the effect of aspirin was evident at a young age, the risk of bleeding was also high (1.4–1.5 times), and thus, careful prescription is required.
Does gender have an influence on platelet function and the efficacy of oral antiplatelet therapy?
2012, Interventional Cardiology Clinics
Citation Excerpt :
The investigators suggested that higher levels of COX activity caused by (1) higher concentrations of testosterone in men, (2) less effectiveness of aspirin in acetylating COX in women, or (3) gender-dependent effects of aspirin that are independent of COX-1 inhibition may explain the attenuated effect of aspirin in women.39 In support of the latter non–COX-1 effects of aspirin, greater inhibition of thrombus formation in male rats and ex vivo thrombus generation in a Baumgartner chamber with blood isolated from men were demonstrated in the presence of complete inhibition of COX-1 in both genders by aspirin.40,41 Becker and colleagues32 studied platelet reactivity in healthy subjects who were siblings of patients with documented coronary heart disease, and showed in women a significantly higher platelet reactivity to multiple agonists compared with men, in the absence of antiplatelet therapy.
The Relative Efficacy and Safety of Clopidogrel in Women and Men. A Sex-Specific Collaborative Meta-Analysis
2009, Journal of the American College of Cardiology
Citation Excerpt :
To obtain net clinical benefit over a weighted mean follow-up of 8.3 months, one needed to treat ≈101 men and ≈435 women. Several (9–13,31), although not all (32–34), previous studies have reported a sex-specific response to antiplatelet medications. In a sex-specific meta-analysis of aspirin for the primary prevention of cardiovascular disease, aspirin was shown to be effective in reducing cardiovascular events in both women and men (9).
This study sought to investigate the efficacy and safety of clopidogrel in women and men.
Previous analyses have shown sex-based differences in response to several antiplatelet medications. Little is known about the efficacy and safety of clopidogrel in women and men.
This study performed a meta-analysis of all blinded randomized clinical trials comparing clopidogrel and placebo (CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events], CREDO [Clopidogrel for the Reduction of Events During Observation], CLARITY–TIMI 28 [Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28], COMMIT [Clopidogrel and Metoprolol in Myocardial Infarction Trial], and CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance] trials), involving a total of 79,613 patients, of whom 30% were women. The relative efficacy and safety of clopidogrel at reducing cardiovascular events (cardiovascular death, myocardial infarction [MI], or stroke) in women and men was estimated using random-effects modeling.
Overall, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93), with no significant differences in treatment effect between women and men. Among the 23,533 women enrolled, there were fewer cardiovascular events in the clopidogrel group compared with the placebo group (11.0% vs. 11.8%; OR: 0.93; 95% CI: 0.86 to 1.01). In women the risk reduction with clopidogrel seemed to be greatest for MI (OR: 0.81; 95% CI: 0.70 to 0.93), with the effects on stroke (OR: 0.91; 95% CI: 0.69 to 1.21) or total death (OR: 0.99; 95% CI: 0.90 to 1.08) not statistically significant. Among the 56,091 men enrolled, there were fewer cardiovascular events in those receiving clopidogrel compared with placebo (7.8% vs. 9.0%; OR: 0.84; 95% CI: 0.78 to 0.91), and the risk reduction was significant for MI (OR: 0.83; 95% CI: 0.76 to 0.92), stroke (OR: 0.83; 95% CI: 0.71 to 0.96), and total death (OR: 0.91; 95% CI: 0.84 to 0.97). Clopidogrel increased the risk of major bleeding in both women (OR: 1.43; 95% CI: 1.15 to 1.79) and men (OR: 1.22; 95% CI: 1.05 to 1.42).
Clopidogrel reduces the risk of cardiovascular events in both women and men.
Gender differences in the effect of aspirin on retinal ischemia, prostanoid synthesis and nitric oxide production in experimental type 1-like diabetes
2007, Vascular Pharmacology
The protective effect of acetylsalicylic acid (aspirin) against cardiovascular events is known to be weaker in women than in men. The present study was designed to test whether this effect of aspirin differed between sexes in an experimental model of diabetes with retinal ischemia.
We compared nondiabetic rats and rats after 1, 2 and 3 months of diabetes that were given 2 mg/kg/day p.o. of aspirin from the first day of diabetes. The variables recorded were platelet aggregation, production of thromboxane B₂ (TxB₂), 6-keto-prostaglandin F_1α and aortic nitric oxide, and the percentage of the retinal surface occupied by horseradish peroxidase (HRP)-permeable vessels.
In female rats made diabetic, TxB₂ synthesis was more markedly reduced, and the percentage of HRP-permeable retinal vessels was less markedly reduced, than in their male counterparts. The response to aspirin treatment was weaker in female than in male diabetic rats in terms of inhibition of TxB₂ synthesis, increased nitric oxide production, and prevention of the increase in the percentage of retinal surface covered by HRP-permeable vessels.
Aspirin was less effective in preventing retinal ischemia in experimental diabetes in female than in male rats.
Interactions of aspirin and salicylic acid with prednisolone for inhibition of lymphocyte proliferation
2001, International Immunopharmacology
The anti-inflammatory properties of salicylates and prednisolone were investigated using inhibition of in vitro phytohemagglutinin-stimulated lymphocyte proliferation in human whole blood from healthy male and female subjects. Steroids and salicylates are used in conjunction for the treatment of inflammatory disorders such as rheumatoid arthritis and inhibit the proinflammatory transcription factor, NFκB, by different mechanisms. Data generated using various combinations of these drugs were analyzed using isobolograms and the universal surface response approach based on the Loewe additivity principle. The interaction between aspirin and prednisolone was mildly antagonistic while that between salicylic acid and prednisolone was modestly synergistic at therapeutic concentrations. Further, aspirin was slightly more potent in males, but the nature of the steroid–salicylate interaction was similar across genders. This study helps rationalize part of the beneficial effects of steroids and salicylates in treatment of inflammatory disorders.
Effect of aspirin on mortality in women with symptomatic or silent myocardial ischemia
1996, American Journal of Cardiology
The benefit of aspirin therapy among women with coronary artery disease (CAD) is not well established. Previous studies have shown conflicting results among women. Data from 2,418 women with CAD screened for participation in the ongoing Bezafibrate Infarction Prevention (BIP) study were analyzed: 45% reported aspirin therapy. Baseline characteristics were similar in both groups. Cardiovascular mortality at 3.1 ± 0.9 years of follow-up was 2.7% in the aspirin treated group versus 5.1% in the non-aspirin-treated women (p = 0.002). All cause mortality was 5.1% and 9.1%, respectively (p = 0.0001). Treatment with aspirin emerged as an independent predictor of reduced cardiovascular (RR = 0.61, 95% confidence interval [CI] 0.38 to 0.97) and all cause (RR = 0.66, 95% CI 0.47 to 0.93) mortality after multiple adjustment for possible confounders such as age, history of myocardial infarction, systemic hypertension, diabetes mellitus, peripheral vascular disease, current smoking, New York Heart Association classification, and concomitant treatment with digitalis. Women who benefited the most from aspirin therapy were older, diabetic, symptomatic, or had a previous myocardial infarction. Thus, treatment with aspirin was associated with reduced mortality among women with CAD. This study suggests that women with CAD should be treated with aspirin, unless specific contraindications exist.

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PaperSex-related differences in the effects of aspirin on the interaction of platelets with subendothelium

Abstract

Lancet

Lancet

Thrombosis Res.

Thromb.Res

Lancet

Aspirin selectively inhibits prostaglandin production in human patients

Nature (New Biol)

Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects

J.Clin.Invest.

Endogenous biosynthesis of prostacyclin and thromboxane and platelets function during chronic administration of aspirin in man

J.Clin.Invest.

Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients

N.England J.Med.

A randomized controlled trial of aspirin in persons recovered from myocardial infarction

J.Am.Med.Assoc.

A platelet-inhibitor drug trial in coronary-dipyridamole and aspirin therapy on early postoperative vein-graft patency

N.Engl.J.Med.

Paper
Sex-related differences in the effects of aspirin on the interaction of platelets with subendothelium