Platelet Responses in Cardiovascular Disease: Sex-Related Differences in Nutritional and Pharmacological Interventions

Abstract

Cardiovascular diseases (CVD) represent one of the biggest causes of death globally, and their prevalence, aetiology, and outcome are related to genetic, metabolic, and environmental factors, among which sex- and age-dependent differences may play a key role. Among CVD risk factors, platelet hyperactivity deserves particular mention, as it is involved in the pathophysiology of main cardiovascular events (including stroke, myocardial infarction, and peripheral vascular injury) and is closely related to sex/age differences. Several determinants (e.g., hormonal status and traditional cardiovascular risk factors), together with platelet-related factors (e.g., plasma membrane composition, receptor signaling, and platelet-derived microparticles) can elucidate sex-related disparity in platelet functionality and CVD onset and outcome, especially in relation to efficacy of current primary and secondary interventional strategies. Here, we examined the state of the art concerning sex differences in platelet biology and their relationship with specific cardiovascular events and responses to common antiplatelet therapies. Moreover, as healthy nutrition is widely recognized to play a key role in CVD, we also focused our attention on specific dietary components (especially polyunsaturated fatty acids and flavonoids) and patterns (such as Mediterranean diet), which also emerged to impact platelet functions in a sex-dependent manner. These results highlight that full understanding of gender-related differences will be useful for designing personalized strategies, in order to prevent and/or treat platelet-mediated vascular damage.

The Anti-Inflammatory and Antioxidant Properties of n-3 PUFAs: Their Role in Cardiovascular Protection

“…It was proposed that anti-platelet effect of n-3 PUFA could depend on gender. EPA seems to have more effectiveness in male while DHA in female as observed by an inverse correlation between testosterone levels and platelet aggregation after EPA administration and the observation of the higher levels of serum DHA in women independently from diet presence of DHA [85].…”

Evaluation of the Equivalence of Different Intakes of Fruitflow® in Affecting Platelet Aggregation and Thrombin Generation Capacity in a Randomized, Pilot Study in Male Subjects

“…Platelet behaviour varies in response to a wide range of factors -ethnicity, age, nutrition status, exposure to air pollution, exercise levels, etc. (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). No two individuals' platelets are precisely the same, something that can be clearly observed in the heterogeneity of their responses to agonist and to antiplatelet agents (20)(21)(22)(23)(24), Studies using antiplatelet drugs have shown that marked differences in platelet responses may be linked to such factors, with genomic and nutrigenomic reasons postulated (25,26).…”

Sex, Endothelial Cell Functions, and Peripheral Artery Disease

“…This difference in platelet reactivity may be due to sex hormones. Both female and male platelets express receptors for 17β-estradiol as well as androgen and progesterone receptors; however, their effect on platelet function is somewhat controversial [59,60]. Platelet receptors can also regulate platelet reactivity in a sex-dependent manner.…”

“…Platelet activation and aggregation is mediated through the G-protein receptors PAR1 (protease activated receptor 1) and PAR4 (thrombin receptors), P2Y12 receptors (ADP receptors), and the thromboxane A2 receptor, amongst others [61]. While there is no difference in the expression of glycoprotein IIb/IIIa between sexes, women show higher receptor reactivity [59]. Moreover, healthy women and female mice have higher reactivity to PAR1 and PAR4 agonists [62], suggesting sex-dependent expression or activation of these receptors.…”