The mechanism for considering female sex as a factor for developing thromboembolic stroke in atrial fibrillation

Abstract

Introduction: Women with AF are at a higher overall risk for thromboembolic stroke when compared to men with AF. Recent evidence suggests that female sex, after adjusting for stroke risk profile and sex differences in utilization of anticoagulation, is an independent stroke risk factor in AF. Underutilization or inadequate oral anticoagulation in women could potentially explain part of these sex-differences in stroke risk. However, a more recent study found a persistently higher risk of stroke among women as compared to men despite similar warfarin adherence rates. Objective: To describe the potential mechanisms behind the increased risk of stroke in AF associated with female sex. Materials and Methods: General mechanisms of thromboembolism in AF - Rudolf Virchow postulated that thrombosis arises from three co-existing phenomena: abnormalities in the vessel wall, blood stasis, and a hypercoagulable state. Virchow’s triad can be applied to throm bogenicity in AF. Structural changes in the left atrium (LA) and left atrial appendage (LAA), blood stasis induced by left atrial dilatation and inhibited forward flow contributes to throm bus formation in patients with and without AF. As a consequence of structural and blood flow changes, prothrombotic conditions develop with activation of coagulation proteins. Potential mechanisms for higher stroke risk in women with AF Hormone therapy and menopause - the risk for ischemic stroke in women doubles between the ages of 55 and 65, the menopausal transition period during which estradiol levels decrease by about 60%. Endogenous estrogen has favorable outcomes on lipid metabolism, coagulation and vascular tone, and even incident AF. In a meta-analysis of seven major randomized trials analyzing hormone therapy (HT) reported an increased risk of stroke in both combination HT trials and estrogen-only trials. Conclusion: Sex-related differences in the vasculature and myocardial structure may predispose to alterations in blood flow, shear stress, and altered endothelial function. Further, there is evidence suggesting a potential sex-based increase (especially in the post-menopausal state) in systemic inflammatory and procoagulant markers, thrombogenic particles and platelet aggregation, all of which contribute to a prothrombotic circumstance. Observational data suggest sex-based differences in stroke outcomes are related to differences in stroke risk factor profile and management, in addition to underutilization of anticoagulant therapy in women. However, recent study results demonstrate an increased stroke risk in women despite baseline anticoagulant use.