Associate editor: V. Schini-KerthEstrogen therapy and thrombotic risk
Introduction
Postmenopausal hormone treatment is an established risk factor for venous thromboembolism (VTE) and may increase myocardial infarction (MI) and stroke in older women (Perez Gutthann et al., 1997, Varas-Lorenzo et al., 1998, Varas-Lorenzo et al., 2000, Writing Group for the Women's Health Initiative Investigators, 2002). However, the vast majority of women so treated do not develop thrombosis. Despite decades of research into the characterization of how hormone treatments affect proteins of the hemostasis system, there still is no clinically viable method to establish thrombosis risk for a woman contemplating hormone therapy (for review, see Cosman et al., 2005). Propensity for thrombosis varies widely among individuals but is independent of vascular disease. The term “thrombophilia” has come to be used in this context. In principle, preventing thrombosis by avoiding or modifying risk exposures among individuals with thrombophilia could have the same outcome as preventing the progression of vascular disease. Strategies for prevention in clinical practice will depend on the morbidity associated with the intervention versus the effect on outcome. That is, the effectiveness of an intervention will be context-sensitive. This concept is exemplified by a recent study that identified age and sex as modifiers of effectiveness of aspirin as primary prophylaxis against MI and stroke: aspirin was effective in preventing MI independent of age in men, but prevented stroke only in older women (Ridker et al., 2005a). The challenge for the clinician-scientist is to define the context. For example, do women with arterial disease who experience thrombosis have features in common with those who experience venous thrombosis? Do drugs or interventions that increase risks of thrombosis, like hormone therapy, move characteristics of the hemostasis system in healthy individuals toward high-risk characteristics? Or is there a genotype that defines high risk and are there stimuli which affect expression of a high risk phenotype? This review will approach the context of thrombotic risk (propensity) in post-menopausal women by evaluating effects of estrogen on characteristics of the vascular wall and coagulability of the blood, by evaluating genetic characteristics of estrogen receptors and coagulation proteins and finally by considering how infection-induced inflammation, as a prototype for environmental exposure, might modulate both characteristics of the vessel wall and the blood toward a thrombogenic phenotype.
Section snippets
Arteries
Arteriosclerotic lesions, while necessary, are insufficient to cause MI or stroke. Many elderly patients develop claudication, stable angina, carotid bruit or renovascular insufficiency without progressing to MI or stroke. That is, arterial stenosis can cause disability without ever triggering thrombosis. Thus, some individuals appear resistant to thrombosis in the face of advanced disease of the arterial wall. Clearly, epidemiological and randomized clinical trials that use MI and stroke as
Effects of estrogen on characteristics of blood elements
To reiterate, understanding contexts contributing to thrombotic risk will require distinguishing factors operating in the blood vessel wall from those in the blood, and further to distinguish humoral from cellular factors. However, it is also important to remember that factors operating in or on the blood vessel wall may affect coagulability of the blood by affecting adhesion and activation of cellular elements.
Genetic characteristics of estrogen receptors and coagulation proteins
Epidemiology of coronary disease and stroke and VTE has established familial risk for occurrence of events. Both arterial and venous thrombosis have been linked to estrogen therapy. Genetic variation in estrogen (or other sex-steroid) receptors would alter receptor-mediated gene transcription of a variety of proteins and enzymes regulating intracellular processes. In addition, genetic variation in proteins of the coagulation cascade would have direct effects on acellular clot formation, that
Genotype meets environmental risk factors
Considering the previous sections, it is reasonable to suggest that individual thrombotic propensity would be a mix of phenotypes reflecting specific genetic polymorphisms in estrogen (and perhaps other steroids) receptors, endothelium-derived factors, proteins of the coagulation cascade, cytokines and enzymes which in turn are responsible for biological variability in anatomy of the vascular wall, cellular and humoral hemostasis. For example, “apparently healthy” individuals with levels of say
Conclusion and future directions
Over a century ago, it was postulated that thrombosis resulted from a combination of reduction in blood flow, changes in anatomy of the blood vessel wall and changes in coagulability of the blood. It is clear that estrogen and other sex steroid hormones affect functions of vascular endothelial and smooth muscle cells that define vascular anatomy and vascular tone, thus modulating regional blood flow. In addition, sex steroid hormones affect proteins of the coagulation cascade and
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