Platelet Activation Differs Between Men and Women in Myocardial Infarction and Beyond

New research is revealing fundamental differences in platelet activity between the sexes, both in health and during myocardial infarction (MI). The findings suggest clues to why men and women often present differently with acute coronary syndromes and differ in treatment response.

The research, published online in Arteriosclerosis, Thrombosis, and Vascular Biology, focused on protease-activated receptors (PARs), membrane proteins that are abundantly expressed on platelets. Four PARs have been recognized, with PAR1 of special interest for drug therapy in MI, as it is activated by thrombin and stimulates inflammatory activity and platelet aggregation. The investigators found that during MI, activation of PAR1 is enhanced in men but muted in women, with the opposite pattern seen in health.

“Our findings call into question whether current treatment recommendations for MI, which are identical for men and women, benefit the sexes equally,” says the study’s principal investigator, Scott Cameron, MD, PhD, Section Head of Vascular Medicine at Cleveland Clinic. “Both preclinical and clinical research should put more emphasis on enrolling enough females to enable sex-specific analysis and the development of personalized therapy in heart disease.”

A focus on platelet activation

Antiplatelet therapy routinely administered to patients for MI includes aspirin (which blocks thromboxane production, inhibiting platelet activity) and clopidogrel, a P2Y12 platelet receptor antagonist. But preclinical research of platelet activity and drug effects rarely accounts for sex and often does not consider platelet activity in both health and MI settings.

Excessive platelet activation has been implicated in recurrent atherothrombotic events, as seen in non-ST-elevation MI (NSTEMI). Although NSTEMI is not considered as acutely dangerous as STEMI, it confers a poorer prognosis in the long term.

The research led by Dr. Cameron investigated platelet signaling pathways for which antiplatelet agents exist in order to maximize the relevance and translational potential of findings. The work was conducted primarily on human platelets, with murine models used to confirm and extend findings.

Study design and findings

The human study arm enrolled 38 healthy volunteers and 117 subjects with acute MI. The post-MI cohort included patients with STEMI (n = 57) and NSTEMI (n = 60), with females constituting about one-third of each group. In patients with acute MI, platelets were collected before a P2Y12 receptor antagonist was administered.

Mouse platelets were studied in health and after induction of a mild MI.

Platelets were exposed ex vivo to agonists of PAR1, thromboxane receptor and P2Y12 receptor pathways.

Highlights of the study findings include the following:

• In health, platelets from women were more reactive to agonists in all three signaling pathways than were platelets from men.
• In MI, platelet PAR1 signaling decreased in women and increased in men; in health, trends were the opposite.
• Independent predictors of enhanced human platelet PAR1 activation were male sex and NSTEMI.
• During MI in mice and humans, thrombin-mediated platelet activation was augmented in males and attenuated in females.

A path to personalized therapy?

“This is the first study we know of to assess differences in platelet signaling between sexes in both health and myocardial infarction, and it revealed clear differences,” observes Dr. Cameron.

He highlights several key takeaways from this research:

• Platelet activation differs in important ways between men and women both in health and in response to MI. This general finding has significant implications for research in therapeutics. Dr. Cameron notes that drug trials for heart disease often are biased toward men in enrollment — most likely because patients presenting with acute MI are more frequently male — yet conclusions are drawn from overall rather than sex-specific results.
• Findings have implications for better understanding of NSTEMI. Augmented platelet activation through PAR1 following MI was pronounced in NSTEMI but not STEMI, supporting previous findings from Dr. Cameron’s group that platelet signaling differs between these conditions. “I suspect NSTEMI is predominantly a platelet disorder, and we know that STEMI, which results in complete occlusion of an epicardial coronary artery, is caused by abnormalities in both platelet activation and vascular wall biology,” Dr. Cameron says. “Focusing future research on platelet PAR1 inhibition may prove useful for treating this condition.”
• The thrombin pathway was particularly reactive for men. Blocking platelet thromboxane production with aspirin and inhibiting the platelet PAR1 pathway directly with a PAR1 antagonist (or indirectly with a factor Xa inhibitor that prevents pro-thrombin conversion to thrombin in the circulation) may be helpful, especially for men.
• Sex differences in platelets have been demonstrated across species and are therefore likely important. The fact that sex-specific signaling in platelets occurs in both humans and mice points to an important biological mechanism rather than an isolated species-limited observation, Dr. Cameron notes, although the reasons are unknown.

“Symptoms of women presenting with MI are too often dismissed because they are deemed ‘atypical,’” Dr. Cameron concludes. “What if fundamental processes between the sexes are different? Better definition of sex-specific cardiac disease prevention and treatment strategies is likely to be an important path to improved clinical outcomes.”