Warfarin Institute of America
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ESTROGENS INTERACTIONS WITH WARFARIN
Because of the rapidity with which new data is being found and new opinions are being formed, this section will focus only on articles published in 2003-2004. While this is not a true interaction between warfarin and estrogens, I have placed it in this section because it does involve two medications.
Hormonal therapies are associated with a doubling or tripling increase in blood clots in the veins. The risk appears to be high right at the time that hormone therapy is started, among overweight women, those who smoke and those who have some type of clotting disorder. The more factors that are present, the more likelihood there is of clotting. For example an overweight woman who smokes and has a clotting disorder is likely to have a problem if she is started on high-estrogenic activity birth control pills.
In the past, estrogens were mostly lumped together as one group. As experience grows with newer agents, it is being discovered that there are some very significant differences between agents and even between the routes by which these are given. These are very important considerations because estrogens have been implicated in the formation of deep vein blood clots in the legs. They do not cause a change in the INR. Therefore, they give no advance warning that a clot is about to form. In some cases, a large blood clot from the leg can move through the veins into the lungs and be fatal within a few minutes.
Toorians et al published an interesting study using transsexual people. It has been observed that blood clots are common in people making the transition from males to females when they are given oral ethinyl estradiol than when given a similar estrogen using a skin patch. They found that the oral preparation caused a large increase in activated protein C resistance and a large decrease in Protein S. These are both indications of increased likelihood of forming clots. Oral ethinyl estradiol also caused a significant increase in plasma protein C. This would work in favor of not forming a clot. However, the factors that increased the likelihood of clots forming evidently outweighed this. They also compared oral ethinyl estradiol to another oral estrogen that is metabolized in the liver but has a lesser effect on clotting. This ruled out liver metabolism as a factor in clot forming. The authors state that it is the chemical structure of ethinyl estradiol that is responsible for its clot enhancing nature.
Cushman et al reported on the Women’s Health Initiative Estrogen plus Progestin clinical trial. The objective was to study the relationship of hormone therapy to clotting when women already had other clotting risk factors. The study was a double-blind, randomized, controlled trial involving 16,608 post menopausal women between the ages of 50 to 79. This involved 40 sites with an average follow-up of 5.6 years. The women were assigned to take either conjugated estrogens 0.625 mg/medroxyprohesterone acetate 2.5 mg (Prempro) every day or a placebo. Blood clots were diagnosed in 167 women in the treatment group and 76 in the placebo group. While the risk was rather small (about 3.5 clots per every 1000 person-years) it was doubled for women in the treatment group. The risk also increased with age. Women in their 60 were about 4 times more likely to develop a clot than those in their 50s. Women in their 70s were 7 to 8 times more likely to suffer a clot than women in their 50s. Being overweight was associated with about a four-fold increase in the risk of clotting, while obesity caused a six-fold increase in clotting risk. The genetic clotting disorder Factor V Leiden was associated with about a seven-fold increase in clotting risk. (Unfortunately whether a person has one set of genes – heterozygous – or two sets of genes – homozygous makes a lager difference in the risk but this was not given in the abstract that I read.) No other genetic variants were associated with an increased risk of clotting in this study.
Sidney et al studied blood clots in women (ages 15-44) who used low-estrogen/progestin oral contraceptives. Low-estrogen dose was defined as < 50 mcg of estrogen. Compared with controls, Factor V Leiden was associated with about a seven-fold increase in the risk of clotting. (Again no mention of heterozygous vs homozygous breakdown.) The Prothrombin G20210A mutation was associated with about a three-fold increased risk of clotting. Obese women appeared to be at the greatest risk of clotting with these birth control pills.
Smith et al compared the risk of blood clotting in the veins among users of esterified estrogens, conjugated equine estrogens and those who took neither. They studied a large group of women aged 30 to 89 years. When compared to women not using hormones, those using esterified estrogens had no increased risk of clots. Women taking conjugated estrogens were almost twice as likely as women taking no hormones to have a clot. Higher doses of conjugated estrogens were more likely to be associated with clots. Users of progestin with either type of estrogen were more likely to experience clots.
Scarabin et al. found that estrogen patches were not associated with a risk of blood clots in post-menopausal women
References:
Toorians AW et at. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab. 2003;88:5723-5729
Moores L et al. Sex and gender issues and venous thromboembolism. Clin Chest Med. 2004;25:281-297.
Cushman M et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.
Sidney S. Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. Contraception 2004;70:3-10.
Smith NL et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA. 2004;292:1581-1587.
Scarabin PY et al. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk Lancet. 2003;362:428-432.
Published studies about the benefits and risks of estrogen show mixed results. The opinions on the use of these medications are changing rapidly. Readers should seek up to date information before drawing conclusions.
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Last updated November 7, 2004