Females showed higher platelet reactivity than males with aspirin therapy but similar reactivity with P2Y12 inhibitors, suggesting P2Y12 inhibitors better reduce female platelet activity.
Does female sex influence platelet reactivity in the presence or absence of antiplatelet therapy compared to male sex?
Females demonstrate higher baseline platelet reactivity to ADP and a lower response to aspirin compared to males, which is effectively mitigated by P2Y12 inhibitors, suggesting P2Y12 inhibitor monotherapy may be particularly beneficial for women.
Abstract Background Emerging evidence suggests sex-specific differences in platelet biology and responses to antiplatelet agents, yet no specific recommendations addressing these differences have been provided in international guidelines. Existing studies comparing platelet reactivity between men and women are limited by small sample sizes and methodological inconsistencies, which are susceptible to intra- and interlaboratory variability. Light transmission aggregometry (LTA) represents the historical gold standard for the assessment of platelet reactivity but is influenced by pre- and intra-analytical variables. Purpose We analyzed a large dataset of patients undergoing LTA using a standardized methodology to investigate the impact of sex on platelet reactivity with or without antiplatelet therapy. Methods Between 2004 and 2022, 11,913 patients sequentially underwent LTA following stimulation with ADP (2 µM), collagen (2 µg/ml), arachidonic acid (AA, 0.5 mM), and epinephrine (10 µM). Patients were categorized into five groups: 1) healthy volunteers (HV); 2) controls (CTR), with at least one cardiovascular risk factor; 3) patients on aspirin 75-150 mg/day (ASA); 4) patients on clopidogrel 75 mg/day (CLOP); 5) patients on DAPT with ASA and CLOP. The primary endpoint of the study was the difference in platelet aggregation (PA%) measured at 4-minute after exposure to the various agonists between females (F) and males (M) within each of the five groups. Patients affected by platelet disorders or diseases influencing platelet function, taking therapies affecting platelet function or using antithrombotic therapies different from aspirin 150 mg or clopidogrel 75 mg, were excluded. A pre-specified secondary analysis according to age (50 years old vs 50 years old) was performed within each of the five groups of patients. Results After applying study entry criteria, 5687 patients were included: 428 HV (F=273; M=155), 1055 CTR (F=725; M=330), 3289 ASA patients ASA (F=2058; M=1231), 430 CLOPI patients (F=272; M=158), and 485 DAPT patients (F=166; M=319). Females exhibited significantly greater PA% in response to ADP compared to males in the HV (p=0.004) (Figure 1), CTR (p0.0001), and ASA (p0.0001) groups, but not in the CLOP or DAPT groups (Figure 2a). Among aspirin-treated patients, females showed increased PA% (p0.0001) in response to collagen, compared with males (Figure 2b). Females in the HV group older than 50 exhibited increased platelet reactivity in response to epinephrine compared to those younger than 50. Conclusion The higher baseline platelet reactivity linked to the P2Y12 receptor pathway—effectively reduced by P2Y12 inhibitors—and the lower response to aspirin in females compared to males suggest that P2Y12 inhibitors may be the preferred antiplatelet therapy for women. These observations may explain findings from clinical studies showing that P2Y12 inhibitor monotherapy is especially effective in women compared to men.Figure 1 Figure 2
Galli et al. (2025) studied this question. Females showed higher platelet reactivity than males with aspirin therapy but similar reactivity with P2Y12 inhibitors, suggesting P2Y12 inhibitors better reduce female platelet activity.