Should We Screen Women for Thrombophilia?
C620R9043.rtf
Should We Screen Women for Thrombophilia?
B.A. Konkle
University of Pennsylvania School of Medicine,Philadelphia, PA, U.S.A.
Introduction
In their lifetime women are more likely to face situations of increased risk of thrombosis, be it through hormonal therapy or pregnancy. These risks may be further modulated by inherited by inherited and acquired risk factors for thrombosis. Also, thrombophilic states may be associated with poor pregnancy outcomes. In this presentation we will briefly review inherited and acquired thrombophilia and the impact of hormonal states on these risks. This will allow us to address the question of screening women for thrombophilia.
Inherited and Acquired Thrombophilia
Venous thromboembolism may results from inherited or acquired thrombophilia, or frequently both. In the past decade more common inherited thrombophilic risk factors, particularly in Caucasians, have been identified. These include factor V Leiden (FVL), a mutation in factor V at a cleavage site for activated protein C (APC), through which APC with free protein S naturally inhibits coagulation. The heterozygous state is found in approximately 5% of Caucasians. Relative risks for thrombosis with this and other inherited thrombophilias found in the Leiden Thrombophilia Study are shown in the Table below. The prothrombin variant (PT20210) is due to a nucleotide change at 20210 in the prothrombin gene, and result in an increased thrombotic risk by increasing prothrombin levels. This is also common in Caucasians with the heterozygous state affecting 2-4%. Mild to moderately increased homocysteine levels, if genetic, are usually due to a mutation in the MTHFR gene. They may also result from diets deficient in folic acid, vitamin B12 and B6, renal or liver failure, or certain medications. While most strongly associated with premature atherosclerosis, increased homocysteine levels may also increase the risk of VTE. Because some inherited factors such as FVL and PT 20210 are common, homozygous and double heterozygous states are seen and are associated with a significant thrombotic risk. FVL can also worsen the phenotype of protein C or S deficiency. At least one half of patients with inherited thrombophilias will develop their first thrombosis in conjunction with an acquired state of increased risk, such as with surgery, immobility, hormonal therapy or pregnancy. The antiphospholipid antibody syndrome is an important risk factor for VTE and pregnancy loss in women of childbearing age, but will not be reviewed here.
Oral Contraceptives (OCP) and Risk of VTE
Since their introduction, OCPs have been associated with an increased incidence of thromboembolic events (reviewed in #2). Because estrogen was suspected of increasing the risk for VTE, contraceptives that contained less than 50 mg of estrogen and a new progestin, levonorgestrel, were introduced – 2nd generation OCP. Compared with non-OCP users, women who take 2nd generation OCP have a ~4 fold increased risk for VTE. More recently, the newest progestins in combination with no more than 35 mg of ethinylestradiol have become available – 3rd generation OCP. Surprisingly, 3rd generation OCPs appear to impart an ~2 fold increased risk of VTE over that seen with 2nd generation products.
Inherited and acquired risk factors may interact with OCP use to further increase the risk of VTE. Patients heterozygous for FVL have a risk of VTE ~ 35-fold (95% CI: 7.8 to 154). This risk is further increased in users of 3rd generation OCPs to ~ 50-fold compared with non-users without the mutation (3). Antithrombin, protein C and protein S deficiency are rare and have been evaluated only in retrospective case review type analyses. However, they do appear to increase the risk of thrombosis with OCP use, particularly AT deficiency. Recently, elevated FVIII levels have been associated with an ~ 4 fold increased risk of VTE and OCP use is additive, with an ~ 10 fold risk (4). There is also an increased risk with OCP use in women with PT20210. Martinelli et al found an ~ 16 fold increased risk of VTE in patients heterozygous for PT20210 who also took OCP, compared to a ~ 6 fold increased risk for those not taking OCP (5).
Women with thrombophilia are also more likely to develop VTE earlier in their use of OCP. Among women with thrombophilia, the risk of developing deep vein thrombosis during the first six months of OCP use (compared with prolonged use) was increased 19-fold (95% CI: 1.9-175.7) and in the first year of use, it was increased 11-fold (95% CI: 2.1-57.3) (6). Patients and controls in this study were considered thrombophilic when they had protein C, S or AT deficiency, or heterozygosity for FVL or PT20210.
Postcoital contraception is accomplished using either higher dose combination ethinyl estradiol and levonorgestrel or levonorgestrel only. While these products contain higher dosages of the hormones, they are taken for only 24 hours. Using the UK general practice data base, Vasilakis et al reported on 73,302 women < 50 years of age who collectively received 100,615 prescriptions for PCP at sometime between 1/1/1989 and 10/31/96 (7). No women in this group were diagnosed with VTE, suggesting that short term PCP use is not associated with a substantially increased risk for developing VTE.
Progesterone-only contraceptives are often considered for women with VTE risks. A study of VTE associated with progesterone only use evaluated 74,086 women. A nested case controlled study of 59 women with idiopathic VTE, found an overall 2.4 increased relative risk (8). When they separated those who used progestins only for contraception the risk was 1.3 (0.3 – 6.8) compared to 5.3 (1.5 – 18.7) for those who used progestins for other reasons. Progestins are used at higher doses for other indications, raising the question of whether there is a dose-dependent effect. A WHO international, multicenter, case-control study of progesterone only contraception found an adjusted odds ratio of 1.74 for oral progestins and of 2.19 for injectable progestins (9). Thus the data we currently have suggests that, when used as contraception, progestins used alone carry a lower risk than estrogen containing compounds. Since progestin-only containing compounds are more likely to produce irregular bleeding, special monitoring for pregnancy may be needed if used in women on warfarin therapy.
Hormone Replacement Therapy (HRT) and VTE Risk
HRT is used in peri- and post-menopausal women for a number of indications including cardiovascular disease prevention, osteoporosis, and menopausal symptoms. Recent studies have questioned the role of estrogen therapy in cardiovascular disease treatment, prompting reconsideration of risk/benefit ratios in considering hormonal therapy. The 2-3 fold increased relative risk for thromboembolic events reported in observational studies have been confirmed by clinical trial data from the Heart and Estrogen/Progestin Replacement Study (HERS) (10). There are much less data in for the risk of HRT in women with thrombophilia than for OCP use. One case controlled study of 66 women with HRT-associated VTE found a 13 fold increased risk in women with APC resistance on HRT, compared to unaffected women not on HRT (11). This needs to be confirmed, but suggests a risk similar to that seen with OCP in this setting.
DVT and PE in Pregnancy
Pregnancy is associated with a 5 to 6 fold increased risk of VTE. Most DVT in pregnancy involves the left leg (90%) and there is a greater proportion of ileofemoral DVT which may predispose to more pulmonary embolism (reviewed in #12) Thrombophilia appears to further increase the risk in pregnancy. In a study of 119 women with VTE during pregnancy, in multivariate analysis Gerhardt et al reported a 6.9 fold (95% CI: 3.3-15.2) and 9.5 fold (95% CI: 2.1-66.7) relative risk in carriers of the Factor V Leiden and the prothrombin mutations, respectively (13). Another study estimated the risk of VTE to be 1 in 400 to 500 pregnancies. Because the numbers of patients affected by ATIII, protein C and protein S deficiency, studies have involved smaller numbers of women and have been variable in their results, particularly for protein C and protein S. ATIII deficiency, probably because it carries such a strong risk for thrombosis, has been associated with thrombosis during the pregnancy. Studies have given conflicting results in terms of the highest times of risk of thrombosis for other thrombophilic defects, with some suggesting that the post-partum period as the period of highest risk (14).
Women with a prior history of thrombosis have often been anticoagulated through subsequent pregnancies, because of a presumed increased risk of recurrence. A recent study evaluated antepartum recurrence in 125 pregnant women with a single previous episode of VTE (15). All women received anticoagulation for 4 – 6 weeks post-partum, thus recurrences during that time could not be assessed. There were no antepartum recurrences in 45 women who had neither a laboratory finding of thrombophilia nor an idiopathic VTE. Of the 51 women with thrombophilia or a history of an idiopathic event, 3 had a antepartum recurrences. These findings suggest that therapy could safely be withheld in certain circumstances. Further studies will be needed to evaluate the best approach in thrombophilic women.
Thrombophilia and Poor Pregnancy Outcomes
Several pregnancy complications, including recurrent miscarriage, intrauterine fetal growth retardation, intrauterine death and possibly abruption and eclampsia, have been found to be more common in within with thrombophilic defects. This has been most strongly associated with second or third trimester fetal loss and is not a risk factor for first trimester loss. Women with factor V Leiden or the prothrombin mutation appear to have a 2 – 3 fold increased risk of late fetal loss. This risk may be significantly greater in women with multiple thrombophilic defects. Whether anticoagulation will prevent any or all of these associated risks is unknown. One study evaluated enoxaparin in 50 women with a history of fetal loss and thrombophilia and demonstrated a higher success rate in treated women (16). Larger prospective studies are needed to confirm these findings.
Conclusion
Women with thrombophilia are more at risk for VTE with hormonal therapy or with pregnancy and for poor pregnancy outcomes. Because the baseline risk of VTE in young women is so low, screening for thrombophilic mutations prior to OCP use is not cost-effective. Most clinicians would advise screening in women with a personal or family history of thrombosis. Institution of anticoagulation in women without a history of thrombosis is not warranted, except possibly in pregnancy for women with inherited AT deficiency. There may be a benefit in counseling women to educate them on the risk/benefit ratio of therapy, for general DVT precautions and for education on recognition of symptoms. The relative risk of thrombosis associated with the identified thrombophilia needs to be considered when assessing the risk of hormonal therapy or pregnancy. With the data we have, if a women with thrombophilia elects to use OCP, a 2nd generation, rather than a 3rd generation product should be used.
Advising whether or not a women should use HRT is, at present, very difficult, considering the questions that have been raised concerning cardiovascular benefits. In addition, we now have more effective treatment for osteoporosis, with the use of bisphosphanates. Still not all women can use those therapies nor are they always effective. It would seem most likely that women with a history of a hormonally-induced thrombosis would be at most risk of thrombosis. Laboratory data may aid in this decision but one must remember that most data apply to Caucasian women. If HRT is strongly indicated in a women with a risk of thrombosis, one could consider co-incident anticoagulation, taking into account associated risks associated.
Selected References
1. van der Meer FJM, Koster T, Vandenbroucke JP, et al. The Leiden Thrombophilia Study. Thromb Haemost 1997;78:631-635.
2. Vandenbroucke JP, Rosing J, Bloemenkamp KWM, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med. 2001;344:1527-1535.
3. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Colly LP, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third generation progestagen. Lancet 1995; 346: 1593-1596.
4. Bloemenkamp KWM, Helmerhorst FM, Rosendaal FR, Vandenbroucke. Venous thrombosis, oral contraceptives and high factor VIII levels. Thromb Haemost 1999;82:1024-1027.
5. Martinelli I, Taioli E, Bucciarelli P, Akhavean S, Mannucci PM. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep venous thrombosis. Arterioscler Thromb Vasc Biol. 1999;19:700-703.
6. Bloemenkamp KWM, Rosendaal FR, Kelmerhost FM, Vandenbroucke JP. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Arch Intern Med. 2000;160:49-52.
7. Vasilakis C, Jick SS, Jick H. The risk of venous thrombembolism in users of postcoital contraceptive pills. Contraception. 1999;59:79-83.
8. Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet 1999;354:1610-1611.
9. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception. 1998;57:315-324.
10. Hulley S, Grady D, Bush T, Furberg C, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280:605-613.
11. Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables and risk of idiopathic thromboembolism in women aged 45-64 years. Relationships to hormone replacement therapy. Thromb Haemost. 2000;83:530-535.
12. Ginsberg JS, Greer I, Hirsh J. Use of thrombotic agents during pregnancy. Chest. 2001;119 (Suppl 1):122S-131S.
13. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann W, Zotz RB. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000;342:374-379.
14. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999;353:1258-1265.
15. Brill-Edwards P, Ginsberg JS, Gent M, Hirsh J et al. Safety of withholding heparin in pregnant women with a history of venous thrombosis. N Engl J Med. 2000;343:1439-1444.
16. Meinardi JR, Middeldorp S, de Kam PJ, Koopman MMW et al. Increased risk for fetal loss in carriers of the factor V Leiden. Ann Intern Med. 1999;130:736-739.
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