Anticoagulants and Thrombolytics in Pregnancy

Anticoagulants and Thrombolytics in Pregnancyhttp://emedicine.medscape.com/article/164069-overview#showall Medscape Reference Reference News Reference Education MEDLINE Anticoagulants and Thrombolytics in Pregnancy Author: Farheen M Shah-Khan, MD; Chief Editor: Richard A Lange, MD more... Updated: Jan 12, 2011 Overview Outline of antithrombotic agents Although the formation of a thrombus or clot within a blood vessel is important for maintaining hemostasis, pathological thrombosis can occur and cause deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, or myocardial infarction (MI). The images below show an overview of the process for diagnosing DVT and PE, respectively. Diagnosis of deep vein thrombosis during pregnancy. Diagnosis of pulmonary embolism during pregnancy. 1 of 9 30/12/2012 12:55 PM 8] VIII. and X and prolongation of clotting times (ie. 6 ] Pathophysiology Normal pregnancy is associated with a hypercoagulable state due. They are available in oral or parenteral forms. valvular heart disease. [7. Dabigatran is an orally administered direct thrombin inhibitor that results in prolongation of the aPTT. Unfractionated heparin. VII. The risk in pregnant women is 5 times higher than in Anticoagulant therapy is indicated in pregnancy for the treatment acute VTE. the safety and efficacy of the newer oral agents (rivaroxaban or dabigatran) in pregnancy has not been established. such as factor II. [13] Epidemiology of Venous Thromboembolism in Pregnancy 2 of 9 30/12/2012 12:55 PM . Thrombolytic agents promote thrombus lysis and are administered parenterally. 10] and fibrinogen. [5 . serum plasminogen activator inhibitor-1 (PAI-1) and placental plasminogen activator inhibitor-2 Venous stasis resulting from (PAI-2) increase with pregnancy which leads to a decreased fibrinolytic state. fondaparinux). [2] [1] This risk further increases if an underlying thrombophilia is present. at least in part. to increased serum levels of procoagulants. hirudin and argatroban) belong to this category. PE remains a [3] [4] leading cause of maternal mortality in the Western world.Anticoagulants and Thrombolytics in Pregnancy http://emedicine.com/article/164069-overview#showall Antithrombotic agents (ie. Anticoagulants interrupt the coagulation cascade to prevent thrombus formation and extension while endogenous thrombus lysis occurs. Traditional thrombolytic agents include streptokinase (SK). and recombinant tissue plasminogen activator (t-PA). Rivaroxaban is an orally active factor Xa inhibitor that prolongs prothrombin time (PT) and activated partial thromboplastin time (aPTT). Evidenced indications for the use of antithrombotic agents Indications of antithrombotic use have been recently published and include the following: Acute and chronic venous thromboembolism (including pulmonary embolism ) Atrial fibrillation Valvular and structural heart disease Ischemic stroke Acute coronary syndromes Peripheral artery occlusive disease Pregnancy is associated with 4 times increased risk of venous thromboembolism (VTE) and the risk increases to 14-fold during puerperium. thus. anisoylated plasminogen streptokinase activator complex (APSAC). 11] In addition. urokinase. trimesters of pregnancy. low molecular weight heparin (LMWH). Unlike warfarin. routine monitoring of coagulation parameters is not required when one of these agents is used. the pharmacokinetics of rivaroxaban and dabigatran are predictable. international normalized ratio [INR]). IX. 9. synthetic pentasaccharide inhibitors (eg. and for the prevention of pregnancy-related complications in women with antithrombin deficiency or antiphospholipid antibody syndrome (APLAs) and other thrombophilias who have had prior VTE. decrease during pregnancy.medscape. [7] X. [7. heparinoids.{Ref12} pressure of the gravid uterus on the inferior vena cava and decreased venous tone are additional predisposing factors to VTE. Although warfarin has been used extensively in pregnancy. anticoagulants and thrombolytic agents) are first-line therapy for pathological thromboses. 10] XII. which causes degradation of fibrin to fibrin degradation products. Warfarin is an oral anticoagulant that interferes with liver synthesis of vitamin K-dependent clotting factors. Thrombolytic agents mediate the dissolution of fibrin clots by promoting the conversion of plasminogen to plasmin. [12] [7] VII. The most commonly used parenteral anticoagulants inactivate thrombin and/or factor Xa without depleting circulating levels of clotting factors. [7. and direct thrombin inhibitors (ie. protein S levels and increased resistance to activated protein C is observed in the second and third Concomitantly. [9. nonpregnant women of the same age. which leads to depletion of factors II (prothrombin). 17] The risk is The [19] The risk of pregnancy-related VTE is particularly high in heterozygous carriers of factor V Leiden (4-fold to 16-fold increase).97 per 1000 women. or otherwise unexplained intrauterine growth retardation Women with antiphospholipid antibody syndrome and a history of multiple (≥ 2) early pregnancy losses or ≥ 1 late pregnancy losses. [20] [18] 4-fold to 50-fold higher in pregnant women than in nonpregnant women and is highest during puerperium. 15] The incidence of pregnancy-associated VTE is estimated at 1 in 500 to 2000 deliveries (0.05-0. ACCP Risk Factors and Recommendations (Open Table in a new window) Risk Factor Women with a single episode of VTE associated with a transient risk factor that is no longer present Women with a single episode of VTE and thrombophilia (confirmed laboratory abnormality) and a strong family history of thrombosis who are not receiving long-term anticoagulants Women with thrombophilia (other than antithrombin deficiency) and no previous VTE Women with multiple (≥ 2) episodes of VTE who are not receiving long-term anticoagulants Women with multiple (≥ 2) episodes of VTE who are receiving long-term anticoagulants All women with previous DVT. the prothrombin mutation (15-fold increase). the Subcutaneous LMWH can be used initially and for long-term treatment with dose adjustment based on monitoring of anti-Xa levels. incidence of VTE in puerperium and pregnancy is 7.19 and 0. preeclampsia. respectively. antenatal anticoagulant prophylaxis is recommended. [21] Prevention and Treatment of Venous Thromboembolism The following recommendations are part of the Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotics and Thrombolytics Therapy: Evidence Based Guidelines.Anticoagulants and Thrombolytics in Pregnancy http://emedicine. intermediate-dose or adjusted-dose UFH or adjusted-dose LMWH followed by long-term anticoagulation postpartum Adjusted-dose UFH or LMWH followed by resumption of long-term anticoagulation postpartum Use of graduated elastic compression stockings Screen for thrombophilia and antiphospholipid antibodies Women with antithrombin deficiency and no previous VTE Antepartum and postpartum prophylaxis Antepartum aspirin plus prophylactic or intermediate-dose UFH or LMWH Adjusted-dose LMWH or UFH therapy plus low-dose aspirin and resumption of long-term oral anticoagulation therapy postpartum In pregnant women with acute VTE. 3 of 9 30/12/2012 12:55 PM . antenatal and postpartum Women with recurrent pregnancy loss (≥ 3 miscarriages) and women with severe or recurrent preeclampsia. and women with antiphospholipid antibodies (5% incidence). or abruption Women with APLAs and a history of VTE who are usually receiving long-term oral anticoagulation therapy * If the previous risk factor is pregnancy or estrogenrelated or additional risk factors (such as obesity) are present. plus postpartum anticoagulation for at least 6 wk (for a total minimum duration of therapy of 6 mo) Clinical surveillance or prophylactic LMWH or UFH and anticoagulant prophylaxis postpartum* Prophylactic. This is attributed to the more tortuous course of the venous drainage of the left leg through the pelvis and compression of the left common iliac vein by the overlying right iliac artery. [16.com/article/164069-overview#showall [14. intrauterine growth retardation (IUGR). [22] Table 1. following 2 alternative approaches are reasonable: [22] Recommendations Clinical surveillance and anticoagulant prophylaxis postpartum* Prophylactic or intermediate-dose LMWH or unfractionated heparin (UFH).medscape. placental abruption.{{Ref 6} Most (approximately 85%) of DVT of the lower extremity occur on the left side during pregnancy. The following are ACCP recommendations for antithrombotic agents.2%). and anticoagulation with any agent is associated with an increased incidence of fetal wastage (approximately 30%). Anticoagulation During Pregnancy in Patients With Valvular Heart Disease Women with valvular heart disease who are pregnant or planning to conceive require careful evaluation and management. large-scale. randomized trials are warranted. Seshadhri et al reviewed 120 articles and concluded that LMWH. a consensus panel concluded that this recommendation was based on studies in which underdosing or inadequate monitoring of LMWH occurred.35-0. symptomatic or severe valvular lesions should be addressed before conception. protamine sulfate may be required to reduce the risk of bleeding. In women receiving dose-adjusted LMWH or UFH therapy. its use throughout pregnancy was associated with warfarin embryopathy in 6.medscape. If aPTT is markedly prolonged near delivery. and continued until 12 weeks. [28] [27] However. the US Food and Drug Administration (FDA) issued a warning that LMWH was not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves.4% of live births. compared with UFH. Consequently. However. LMWH is preferred over UFH for the prevention and treatment of VTE because of ease of use and better efficacy and safety profile. 26.2 U/mL 4 hours after injection or Adjusted dose bid subcutaneous UFH throughout pregnancy to achieve mid-interval aPTT at least twice control or an anti-Xa level of 0. Anticoagulants should be administered for at least 6 weeks postpartum (for a minimum total duration of therapy of 6 mo). Patients with mechanical prosthetic valve requiring anticoagulation are exposed to special risks during pregnancy. Physiologic changes associated with pregnancy are poorly tolerated in some cases of valvular heart disease. eliminated the risk of warfarin embryopathy. warfarin therapy in the first trimester of pregnancy is associated with a substantial increase in fetal anomalies. However. aortic regurgitation with New York Heart Association (NYHA) class 3-4 symptoms. prematurity (approximately 45%). valvular heart disease that results in severe pulmonary hypertension. followed by subcutaneous LMWH or dose-adjusted subcutaneous UFH for the remainder of pregnancy.2%). and low birth weight (approximately 50%). Therefore. the regimen associated with the lowest risk of valve thrombosis (3. the panel supports the use of LMWH as a treatment option with monitoring of anti-Xa levels. mitral regurgitation. [23] Treatment Anticoagulation is recommended in most pregnant patients with a mechanical prosthetic heart valve. change to warfarin until the middle of the third trimester. The substitution of heparin at or prior to 6 weeks. whenever possible.9%) was warfarin throughout pregnancy. mitral stenosis with NYHA class 2-4 symptoms. and left ventricular (LV) dysfunction with an ejection fraction (EF) less than 40%.com/article/164069-overview#showall Intravenous (IV) UFH bolus is followed by continuous infusion to maintain aPTT in the therapeutic range for at least 5 days. whereas those with a bioprosthetic valve do not require anticoagulation. Using heparin only from 6-12 weeks' gestation was associated with an increased risk of valve thrombosis (9. [25. Unfortunately.Anticoagulants and Thrombolytics in Pregnancy http://emedicine. discontinuing anticoagulant therapy 24 hours prior to elective induction of labor is recommended. These include aortic stenosis. If spontaneous labor occurs.70 U/mL or UFH or LMWH (as above) until 13 weeks' gestation. Warfarin (Coumadin) is more efficacious than UFH for thromboembolic prophylaxis of pregnant women with mechanical valves. may be a safe and effective agent in patients with mechanical prosthetic heart valves. and then restart UFH or LMWH 4 of 9 30/12/2012 12:55 PM . Recommendations Recommendations for anticoagulation of pregnant women with prosthetic heart valves is based on the Eighth ACCP Conference on Antithrombotics and Thrombolytics and are as follows: [22] Adjusted dose twice daily (bid) subcutaneous LMWH throughout pregnancy to achieve a peak anti-Xa level of 1-1. In 2002. careful monitoring of aPTT or anti-Xa levels is required. 22] [24] In a systematic review of fetal and maternal outcome of pregnancy with mechanical heart valves. High-risk women with prosthetic heart valves. Northwestern Memorial Hospital Disclosure: Nothing to disclose. with the latter occurring mainly during the first trimester. Consulting Staff. Coauthor(s) Nishith K Singh. Department of Nephrology. women using this drug should be encouraged to breastfeed. Department of Internal Medicine. Division of Cardiology. and Illinois State Medical Society Disclosure: Nothing to disclose. is a member of the following medical societies: American College of Physicians. Author Farheen M Shah-Khan.medscape. Thus. these agents do not cause fetal bleeding or teratogenicity. [29. American Heart Association. American Medical Association. 39. heparin-induced thrombocytopenia [HIT]). [29] Two reports show that maternal administration of warfarin does not induce an anticoagulant effect in the breastfed infant. 38. Department of Internal Medicine. Maternal and Fetal Complications Secondary to Anticoagulation Use of anticoagulants in the breastfeeding mother Heparin and LMWHs are not secreted into breast milk and can be safely administered to women who are breastfeeding. therefore. which predisposes to venous and arterial thrombosis. MD Resident Physician. should have the addition of low-dose aspirin 75-162 mg/d. 40. Ltd Contributor Information and Disclosures 5 of 9 30/12/2012 12:55 PM . MD. Southern Illinois University School of Medicine. 34] Neither UFH nor LMWH cross the placenta. [36] Heparin-induced osteoporosis causes vertebral fracture in 2-3% of patients and significant reduction in bone density is seen in about 30% of patients receiving long-term UFH. 41] [37. such as women with LV dysfunction and women with prior thromboembolic episodes. LMWH causes less osteoporosis and HIT than UFH. MBBS. MBBS. MD Fellow. Prairie Cardiovascular Consultants. MD. [32] [31] [33. [35] Approximately 3% of patients receiving UFH develop immune thrombocytopenia (so called. FACC Clinical Assistant Professor. Maternal complications of anticoagulants during pregnancy The rate of major bleeding in patients treated with UFH therapy is 2%.com/article/164069-overview#showall Long-term anticoagulants should be resumed postpartum with all regimens. Nasaraiah Nallamothu. 30] Fetal complications of anticoagulants during pregnancy Warfarin crosses the placenta and can cause both fetal bleeding and teratogenicity.Anticoagulants and Thrombolytics in Pregnancy http://emedicine. Southern Illinois University School of Medicine Nishith K Singh. although bleeding at the uteroplacental junction and fetal wastage is possible. University of Texas Health Science Center at San Antonio Richard A Lange. Department of Medicine. Society for Gynecologic Investigation. Massachusetts Medical Society. Penn State University College of Medicine Serdar H Ural. American College of Physicians. American Medical Association. Los Angeles. Sigma Xi. University of California. MD Leo J Dunn Distinguished Professor and Chair.133(6 Suppl):110S-112S. American College of Obstetricians and Gynecologists. MD. LungRx Clinical Trials + honoraria. FCCP Professor of Medicine. [Medline].Anticoagulants and Thrombolytics in Pregnancy http://emedicine. and Society for Maternal-Fetal Medicine Disclosure: GSK Honoraria Speaking and teaching. FACP. American Institute of Ultrasound in Medicine. MD is a member of the following medical societies: American College of Obstetricians and Gynecologists. Hirsh J. Liu Center for Pulmonary Hypertension. American College of Cardiology. Jun 2008. Teresa Marino. Phi Beta Kappa. Tufts Medical Center Disclosure: Nothing to disclose. Encysive Grant/research funds Clinical Trials + honoraria. Association of Professors of Gynecology and Obstetrics. Schünemann HJ. Bayer Grant/research funds Consulting David Chelmow. American Heart Association. MD Assistant Professor. Labor and Delivery Suite. J&J Honoraria Speaking and teaching Francisco Talavera. FACC. and Association of Subspecialty Professors Disclosure: Nothing to disclose. Harrington R. eMedicine Disclosure: eMedicine Salary Employment Ronald J Oudiz. Association of Professors of Gynecology and Obstetrics. FACP. Medical Director. and Society for Medical Decision Making Disclosure: Nothing to disclose. Chest. Gilead Grant/research funds Clinical Trials + honoraria. 6 of 9 30/12/2012 12:55 PM . American Medical Association. Director. Chief Editor Richard A Lange. PhD Senior Pharmacy Editor. Guyatt G. Division of Maternal-Fetal Medicine. Albers GW. References 1. FCCP is a member of the following medical societies: American College of Cardiology. Division of Cardiology. American College of Chest Physicians. MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists. MD is a member of the following medical societies: Alpha Omega Alpha.com/article/164069-overview#showall Disclosure: Nothing to disclose. Attending Physician. MD Professor and Executive Vice Chairman. FACC. Virginia Commonwealth University Medical Center David Chelmow. and American Thoracic Society Disclosure: Actelion Grant/research funds Clinical Trials + honoraria. Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Director. Department of Obstetrics and Gynecology. Division of Maternal-Fetal Medicine. Pfizer Grant/research funds Clinical Trials + honoraria. American Heart Association.medscape. Director. David Geffen School of Medicine. United Therapeutics Grant/research funds Clinical Trials + honoraria. PharmD. LA Biomedical Research Institute at Harbor-UCLA Medical Center Ronald J Oudiz. American College of Chest Physician. MD. MD Associate Professor of Obstetrics and Gynecology and Radiology. 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