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The influence of sex on cardiovascular biology is gaining recognition as differences between the sexes -from the basic anatomic level to physiologic response -become apparent [1-4]. Men and women are also thought to significantly differ at the cellular and molecular levels, with sex differences reported in platelet function and coagulation factor activities [5-10]. In addition, there are substantial sex differences in the rate of cardiovascular events, such as myocardial infarction, stroke and venous thromboembolism (VTE), supporting the notion that sex is an important variable in cardiovascular disease risk [11-13].
Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, affects one in every 1000 people annually, accounting for approximately 250,000 cases in the USA per year [14]. Risk factors for VTE include decreased blood flow, altered blood components and/or modifications of the vessel wall [15]. Although the existence of sex differences for incident VTE remains controversial, men are 50% more likely to suffer recurrent VTE than women [12,13,16]. In addition, several clinical risk factors for VTE differ between the sexes, such as cancer and congestive heart failure, which have strong epidemiologic sex differences. Trauma is also an established risk factor for VTE and occurs more often in males than females. Some risk factors for thrombosis are unique to women, such as pregnancy, oral contraceptive use, hormone-replacement therapy and estrogen antagonist therapies [17]. Considering the prevalence of thrombotic diseases, an improved understanding of how sex functions as a disease modifier is highly desirable. Recently, our laboratory, as well as others, have reported sex differences in thrombosis in rodent models, thus providing the opportunity for mechanistic investigation of sex-dependent cardiovascular phenotypes in these systems [18-20]. It is expected that important sexually dimorphic characteristics will continue to emerge as the field gains greater appreciation for the influence of sex on cardiovascular disease; these insights will lead to improved approaches to thrombotic disorders in patients.
Estrogen
The precise mechanisms underlying sex differences in thrombosis remain unknown; however, differences in cardiovascular risk have been broadly attributed to the distinct hormonal profiles of men and women. The actions of estrogen within the female cardiovascular system have long been implicated in the relative protection of premenopausal women from cardiovascular events. Evidence for this protective effect is demonstrated in the increased cardiovascular...