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    Thrombophilias in ob/gyn: Part II: treatment strategies

     

    TREATING THROMBOPHILIAS

    Thrombophilias in ob/gyn:
    Part II: treatment strategies

    Jump to:

    By Vern L. Katz, MD

    Will heparin prevent adverse pregnancy outcomes among women with thrombophilia? Can patients prone to clotting safely take OCs and HRT? The author's concluding article addresses these and related treatment issues.

    The thrombophilias are acquired or inherited predispositions to clotting that can threaten a woman's life or compromise her pregnancy. Any patient who is prone to clotting should know that whenever she faces a thrombogenic situation like surgery, pregnancy, or immobilization, she is at increased risk for thrombosis—and it behooves the obstetrician/gynecologist to so advise her and to prescribe appropriate therapy when necessary. In Part I, I discussed the various types of thrombophilias and how to test for them. In this article, I will focus on management strategies, and look at a question currently being debated: "Will heparin therapy prevent adverse outcomes?"

    As I mentioned previously, the most common inherited thrombophilias include heterozygosity for the factor V Leiden mutation, the prothrombin (G20210A) mutation, mutations in the PAI-1 gene, and a variant of methylenetetrahydrofolate reductase (MTHFR). The latter is of special interest to obstetricians because it is the most frequent cause of hyperhomocysteinemia, a condition that—unlike the other inherited thrombophilias—may be associated with recurrent embryonic and fetal loss. More serious—albeit less common—thrombophilias include Protein C deficiency, Protein S deficiency, and antithrombin III deficiency. In contrast to the aforementioned thrombophilias, the antiphospholipid antibody syndrome is an acquired thrombophilia.

    Thrombophilias may arise from defects in any of three physiologic mechanisms that keep clot formation in check: (1) inhibition of thrombin, (2) inactivation of factor V, and (3) the breakdown of fibrin. Once identified via appropriate screening, management of patients with thrombophilias falls into two categories: (1) counseling and (2) prevention—through either anticoagulant prophylaxis or full anticoagulation.

    The role of counseling

    As mentioned earlier, after identifying women who have thrombophilias, you should advise them of their heightened risk of thrombosis whenever they face surgery or are pregnant or immobilized. (Educating women on the topic with materials like the Patient Information handout included in Part I can help. It's in the October 2002 issue.) In these situations, consider anticoagulant prophylaxis and advise family members of the thrombophilia. By way of illustration, a recent patient of ours who'd screened positive for factor V Leiden was the daughter of a women scheduled for gallbladder surgery. Her mother, who was then tested, was also found to be positive for factor V Leiden and given anticoagulant prophylaxis.

    Also advise women with thrombophilias not to take oral contraceptives or estrogen replacement therapy, including selective estrogen-receptor modulator (SERM) medications.1,2 The exception is women with the MTHFR mutation with normal homocysteine levels on vitamin therapy. For these women, in fact, HRT often improves homocysteine levels.3 Estrogen plus progesterone leads to a more profound drop in homocysteine levels than does estrogen alone.

    The risk for thrombosis increases over a person's lifetime.4 Older individuals become more susceptible, presumably because their blood vessels are more diseased. Any coexisting disease that damages blood vessels will increase the patient's risk of significant morbidity. Women with thrombophilias should be counseled regarding high-risk behaviors, such as smoking. Make them aware that individuals with thrombophilia are more prone to coronary artery disease, stroke, and peripheral vascular disease. It is therefore essential to pay careful attention to a woman's lipid levels, hypertension, smoking, and glucose intolerance.

    Two approaches to prevention

    The second category of management involves prevention through either anticoagulant prophylaxis or full anticoagulation (Figure 1).

     


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    Anticoagulant prophylaxis. This approach includes heparin to prevent DVT or adverse pregnancy outcomes. The dosing, duration of therapy, and selection of patients is based on clinical judgment—and not all women with thrombophilia will need prophylaxis. The evidence regarding whom to treat is primarily levels II and III (nonrandomized studies and case series).5-15 Though multiple series have found that anticoagulant prophylaxis improves pregnancy outcomes, there are no randomized trials.

    Anticoagulant prophylaxis is indicated for patients with a personal history of DVT and the less potent thrombophilias (for example, factor V Leiden, the prothrombin mutation, hyperhomocysteinemia, and mutations in the PAI-1 gene). On the other hand, an incidental finding of thrombophilia—without a personal history of DVT or other thrombotic events—does not warrant prophylaxis.6 Since the most thrombogenic time associated with pregnancy are the first several weeks postpartum, most authors recommend offering anticoagulant prophylaxis to women with thrombophilia for the 6 weeks following delivery.

    With respect to changes in pregnancy management for women with thrombophilia, we consider obtaining an ultrasound at 30 to 32 weeks to look at fetal growth. Doppler studies are not helpful in these patients in the absence of growth restriction. Unexplained elevated maternal serum alpha-fetoprotein levels suggest placental disease.16

    There are two types of heparin, unfractionated (traditional) heparin, and low-molecular weight heparin (LMWH). While both LMWH and unfractionated heparin are metabolized more quickly in pregnancy, LMWH remains at pharmacologic levels significantly longer.17,18 LMWH dosing is usually twice a day during pregnancy, as single-day dosing may not achieve adequate trough levels. LMWHs have several advantages in terms of flexibility and fewer side effects compared to unfractionated heparin (see Table 1).14,15,19

     

    TABLE 1
    Dosing of LMWH for prophylaxis and full anticoagulation

    For anticoagulant prophylaxis
    Enoxaparin 30 to 40 mg q 12 h; raise in 10-mg increments
    Dalteparin 2,500 units q 12 h; raise in 1,000 unit increments
    Titrate these medications until trough levels are >0.2 units per mL of the antifactor Xa activity assay
    For full anticoagulation, begin dosing at
    Enoxaparin 1 mg/kg q 12 h
    Dalteparin 100 units/kg q 12 h
    Titrate these medications until trough levels are > 0.4 units per mL of the antifactor Xa activity assay
    LMWH—low-molecular weight heparin*
    *Advantages of LMWH are less thrombocytopenia, less osteoporosis, less bleeding, and less recurrent DVT

     

    Because unfractionated heparin is metabolized so quickly, a patient needs a high level of the drug initially to achieve an effective trough level 8 to 12 hours later. Thus, to obtain effective trough levels with unfractionated heparin, either patients become prone to bleeding shortly after dosing or they need to receive the medication three to four times a day. Unfractionated heparin is associated with higher incidences of osteoporosis, fractures, and thrombocytopenia. The dosing technique we use is to check a trough level one-half hour prior to the next dose. For unfractionated heparin, we try to achieve an activated partial thromboplastin time (aPTT) of approximately one and a half to two times normal. We check platelet counts for the first 2 weeks and then every month after and we check aPTTs on a weekly basis.

    We measure the activity of the LMWHs enoxaparin sodium and dalteparin by specific assays that look at anti-Factor Xa activity levels—not aPTT. For prophylaxis with LMWH, we recommend a trough level of approximately 0.2 U (Table 1). Once the appropriate trough levels of LMWH are obtained, they don't need to be checked unless the patient gains more than 30 or 40 lb. or renal function changes drastically. As with most pharmacologic agents, anticoagulants produce different effects in different individuals. Because of the increased and variable metabolism from one patient to another, peak and trough levels are not the same. Thus, standard doses of heparin need to be evaluated for effective levels on an individual basis, because each patient metabolizes heparin differently. For prophylactic purposes, we usually start with 30 to 40 mg of enoxaparin every 12 hours or dalteparin at 2,500 units every 12 hours. While dalteparin can be given only once a day to a nonpregnant person, it usually does not achieve effective trough levels when given in a single-day dose during pregnancy. We increase by 10 mg, or 1,000 units, respectively.

    At our institution, if we are anticipating a vaginal delivery for women taking LMWH, we change them over to unfractionated heparin at 38 weeks. An epidural should not be given to women who have used LMWH in the previous 24 hours. Heparin is stopped when the patient goes into labor and LMWH and warfarin are re-started 8 to 12 hours after delivery. Once an INR (International Normalized Ratio) of 1.75 to 2.0 is reached, LMWH can be stopped if the patient has had at least 4 days of LMWH therapy. Never start warfarin without giving heparin at the same time. Anticoagulation prophylaxis is continued for up to 6 weeks. If a C/S delivery is performed or epidural anesthetic is used, there is increased immobilization. For these patients, we order compression stockings, which they continue to use until they're fully ambulatory.

    One common situation is a woman with a history of a DVT, who after evaluation, is found to not have a thrombophilia. In this situation, prophylactic anticoagulation may be withheld.11,19 However, many researchers recommend offering these patients prophylaxis for the first 6 weeks postpartum, and such therapy is strongly recommended if the patient delivers by C/S and perhaps if she has an affected first-degree relative.

    Women with adverse outcomes, and whose only hematologic finding is hyperhomocysteinemia due to the MTHFR mutation, are given 4 mg of folic acid, in addition to their prenatal vitamins, 250 µg of B12 and 25 mg of B6. We check a fasting homocysteine level 2 weeks later and, if that is abnormal, we increase the folic acid to 5 mg a day and the B6 up to 100 mg. Women who fit this profile do not need heparin therapy. We continue the folic acid, B6, and B12 throughout their childbearing years, since the MTHFR mutation is associated with fetal anomalies. Women who have antiphospholipid antibodies should receive both heparin prophylaxis and 81 mg of aspirin a day. In contrast, women who have antiphospholipid antibodies and recurrent or severe DVT, or women with antithrombin III deficiency, should be offered continued warfarin therapy indefinitely (when not pregnant), as their risk for significant thromboembolism is extremely high.

    Full anticoagulation treatment. A second strategy for prevention is full anticoagulation treatment for women who present with acute DVT. Again, we prefer LMWH, as it has been associated with the lowest rates of recurrent DVT and of bleeding complications. We start patients on 100 units/kg twice a day of dalteparin, or 1 mg/kg twice a day of enoxaparin. After 1 day of therapy, we check a trough level. We want to achieve a trough level between 0.4 and 0.7—as opposed to levels associated with increased bleeding, which are usually in the 0.8 to 1.1 range.

    In addition, offer therapeutic anticoagulation, regardless of antecedent thromboembolic history to the following patients: women with the most potent thrombophilias, those who are homozygous for factor V Leiden or for the prothrombin mutation, women with two co-existing thrombophilias, women with antithrombin III deficiency, and those having the antiphospholipid antibody syndrome. Moreover, most authorities recommend offering full anticoagulation to those women with antiphospholipid antibody syndrome who have had a previous DVT.

    Although patients will need to be treated with anticoagulants for 6 months, or up to 6 weeks postpartum, the duration of follow-up therapy is affected by the type of thrombophilia. For example, women with antiphospholipid antibody syndrome associated with DVT should be offered anticoagulation for life because of the risk of subsequent severe DVTs.

    Conclusion

    In Part I of this article, I discussed the types of inherited and acquired thrombophilias and the importance of screening, especially to detect fetal disease in women with thrombophilias. Because second- and third-trimester losses, as well as growth restriction, abruption, and severe preeclampsia, may result, all women should be screened by history. Assess them both for a family history of blood clots or vascular disease and a history of significant adverse pregnancy outcomes, and evaluate women who screen positive by history with a hematological workup. Patients with positive histories and thrombophilia may be offered heparin prophylaxis. Although low-molecular-weight heparin appears to be the medication of choice at this time, there are no randomized clinical trials to support this approach.

    We are just beginning to understand why the thrombophilias produce disease. Up to 20% of the population (depending on ethnic background) has a thrombophilia, yet a much smaller proportion will develop pathology. Much of our management is based on series, case reports, and expert opinion. The goal of future research will be to delineate which patients are at risk for either deep vein thrombosis or adverse pregnancy outcomes.

    REFERENCES

    1. Meschia JF, Biller J, Witt T, et al. Is hormone replacement a risk factor for ischemic stroke in women with factor V Leiden mutation? Arch Neurol. 1998;55: 1137-1139.

    2. Vandenbroucke JP, Koster T, Brest E, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;334:1453-1457.

    3. Van Baal WM, Smolders RG, Van Der Mooren MJ, et al. Hormone replacement therapy and plasma homocysteine levels. Obstet Gynecol. 1999;94:485-491.

    4. Ridker PM, Glynn RJ, Miletich JP, et al. Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med. 1997;126:528-531.

    5. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med. 1999;340:9-13.

    6. Lockwood CJ. Inherited thrombophilias in pregnancy patients: detection and treatment paradigm. Obstet Gynecol. 2002;99:333-341.

    7. Martinelli I, Taioli E, Cetin I, et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med. 2002;343:1015-1018.

    8. Brenner B. Inherited Thrombophilia and Pregnancy Loss. Thromb Haemost. 1999;82:634-640.

    9. Walker ID. Thrombophilia in pregnancy. J Clin Pathol. 2000;53:573-580.

    10. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000;342:374-380.

    11. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-1231.

    12. Hunt BJ, Doughty HA, Majumdar G, et al. Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies. Thromb Haemost. 1997;7:39-43.

    13. Brenner B, Hoffman R, Blumenfeld Z, et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost. 2000;83:693-697.

    14. Lepercq J, Conard J, Borel-Derlon A, et al. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. Br J Obstet Gynaecol. 2001;08:1134-1140.

    15. Thromboembolism in Pregnancy. ACOG Practice Bulletin. Number 19, August 2000.

    16. Ochshorn Y, Kupferminc MJ, Eldor A, et al. Second-trimester maternal serum alpha-fetoprotein (MSAFP) is elevated in women with adverse pregnancy outcome associated with inherited thrombophilias. Prenat Diagn. 2001;21:658-661.

    17. Casele HL, Laifer SA, Woelkers DA, et al. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol. 1999;181:1113-1117.

    18. Gibson JL, Ekevall K, Walker I, et al. Puerperal thromboprophylaxis: comparison of the anti-XA activity of enoxaparin and unfractionated heparin. Br J Obstet Gynaecol. 1998;105:795-797.

    19. Anticoagulation with Low-Molecular-Weight Heparin During Pregnancy. ACOG Committee Opinion. Number 211, November 1998.

    20. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med. 2000;343:1439-1444.

    SUGGESTED READING

    Dahlman TC, Sjoberg HE, Rinertz H. Bone mineral density during long-term prophylaxis with heparin in pregnancy. Am J Obstet Gynecol. 1994;170:1315-1320.

    Dizon-Townson DS, Meline L, Nelson LM, et al. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol. 1997;177:402-405.

    Grandone E, Margaglione M, Colaizzo D, et al. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. Am J Obstet Gynecol. 1998;179:1324-1328.

    Lee RV. Thromboembolic disease and pregnancy: are all women equal? Ann Intern Med. 1996;125:1001-1003.

    Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698-3703.

    Powers RW, Evans RW, Majors AK, et al. Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation. Am J Obstet Gynecol. 1998;179:1605-1611.

    Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;37:688-698.

    Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, et al. Resistance to activated protein C and the leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol. 1998;179:1565-1567.

    Dr. Katz is Medical Director, Perinatal Services, Sacred Heart Medical Center, Eugene, Ore.

    Key points

    • If your patient has thrombophilia, make her aware of the fact that she's at increased risk of thrombosis whenever she encounters a thrombogenic situation, including surgery, pregnancy, or immobilization.
    • Offer therapeutic anticoagulation, regardless of antecedent thromboembolic history to women with the most potent thrombophilias, those homozygous for factor V Leiden or for the PT mutation, those with two co-existing thrombophilias, patients with antithrombin III deficiency, and any woman with antiphospholipid antibody syndrome.
    • Because a woman with thrombophilia is more prone to coronary artery disease, stroke, and peripheral vascular disease, monitor her blood pressure, lipid levels, and glucose readings closely, and warn her that the detrimental effects of smoking are heightened.

     

    Vern Katz. Thrombophilias in ob/gyn: Part II: treatment strategies. Contemporary Ob/Gyn 2002;11:59-70.

    Vern Louis Katz, MD
    Dr. Katz is Medical Director, Perinatal Services, Sacred Heart Medical Center, Eugene, Ore.

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