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Thromb Haemost 2001; 86(06): 1379-1384
DOI: 10.1055/s-0037-1616739
Review Article
Schattauer GmbH

Low Molecular Weight Heparin and Warfarin in the Treatment of Patients with Antiphospholipid Syndrome during Pregnancy

Rachel Pauzner
Sheba Medical Center, Sackler School of Medicine and School of Engineering, Tel-Aviv University, Israel
,
Mordechai Dulitzki
Sheba Medical Center, Sackler School of Medicine and School of Engineering, Tel-Aviv University, Israel
,
Pnina Langevitz
Sheba Medical Center, Sackler School of Medicine and School of Engineering, Tel-Aviv University, Israel
,
Avi Livneh
Sheba Medical Center, Sackler School of Medicine and School of Engineering, Tel-Aviv University, Israel
,
Ron Kenett
Sheba Medical Center, Sackler School of Medicine and School of Engineering, Tel-Aviv University, Israel
,
Amira Many
Sheba Medical Center, Sackler School of Medicine and School of Engineering, Tel-Aviv University, Israel
› Author Affiliations
Further Information

Publication History

Received 10 February 2001

Accepted after resubmission 06 August 2001

Publication Date:
12 December 2017 (online)

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Summary

Fifty-seven pregnancies in women with antiphospholipid syndrome (APS) are presented. These were treated with s.c. enoxaparin and low dose aspirin. In fourteen pregnancies warfarin was prescribed between weeks 15-34 (warfarin group). The decision to switch to warfarin depended on a morbidity score, and the patient’s consent. Neither teratogenicity nor significant maternal, fetal or neonatal hemorrhage was observed. Despite the higher pretreatment morbidity score of the warfarin group, the live birth rate was high in both groups: 86% in the warfarin group and 87% in the non-warfarin group. There was no significant difference in week of delivery, birth weight, or incidence of thrombosis between the groups. The study demonstrates the efficacy and safety of anticoagulants during pregnancy. The use of LMWH in pregnant women with APS not being moot, warfarin might be justified in selected patients.

Keywords

Antiphospholipid syndrome - pregnancy - low molecular weight heparin - warfarin
 

  • References

  • 1 Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-4.
    CrossrefPubMedGoogle Scholar
  • 2 Lockwood CJ, Rand JH. The immunobiology and obstetrical consequences of antiphospholipid antibodies. Obstet Gynecol Survey 1994; 49: 432-41.
    CrossrefPubMedGoogle Scholar
  • 3 Lockwood CJ, Romero R, Feinberg RF, Cycline LP, Coster B, Hobbins JC. The prevalence and biologic significance of lupus anticoagulant and anti-cardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 1989; 161: 369-73.
    CrossrefPubMedGoogle Scholar
  • 4 Rai RS, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and anti-phospholipid antibodies. Hum Reprod 1995; 10: 3301-4.
    CrossrefPubMedGoogle Scholar
  • 5 Branch DW, Scott JR, Kochenour NK, Hershgold E. Obstetric complications associated with the lupus anticoagulant. N Eng J Med 1985; 313: 1322-6.
    CrossrefPubMedGoogle Scholar
  • 6 Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol 1995; 86: 555-9.
    CrossrefPubMedGoogle Scholar
  • 7 Polzin WJ, Kopelman JN, Robinson RD, Read JA, Brady K. The association of antiphospholipid antibodies with pregnancies complicated by fetal growth restriction. Obstet Gynecol 1991; 78: 1108-11.
    PubMedGoogle Scholar
  • 8 Alsulyman OM, Castrto MA, Zuckerman E, McGehee W, Goodwin TM. Preeclampsia and liver infarction in early pregnancy associated with antiphospholipid syndrome. Obstet Gynecol 1996; 88: 644-6.
    CrossrefPubMedGoogle Scholar
  • 9 Ilbery M, Jones AR, Sampson J. Lupus anticoagulant and HELLP syndrome complicated by placental abruption, hepatic, dermal and adrenal infarction. Aust N Z J Obstet Gynaecol 1995; 35: 215-7.
    CrossrefPubMedGoogle Scholar
  • 10 Ornstein MH, Rand JH. An association between refractory HELLP syndrome and antiphospholipid antibodies during pregnancy; a report of 2 cases. J Rheumatol 1994; 21: 1360-4.
    PubMedGoogle Scholar
  • 11 Harris EN, Bos K. An acute disseminated coagulopathy-vasculopathy associated with the antiphospholipid syndrome. Arch Intern Med 1991; 151: 231-3.
    CrossrefPubMedGoogle Scholar
  • 12 Out HJ, Kooijman CD, Bruinse HW, Derksen RH. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies. Eur J Obstet Gynecol Reprod Biol 1991; 41: 179-86.
    CrossrefPubMedGoogle Scholar
  • 13 Rand JH, WU XX, Andree HAM, Lockwood CJ, Guller S, Scher J, Harpel PC. Pregnancy loss in the antiphospholipid antibody syndrome – a possible thrombogenic mechanism. N Eng J Med 1997; 337: 154-60.
    CrossrefPubMedGoogle Scholar
  • 14 Santoro SA. Antiphospholipid antibodies and thrombotic predisposition: underlying pathogenic mechanisms. Blood 1994; 83: 2389-91.
    PubMedGoogle Scholar
  • 15 Greaves M. Antiphospholipid antibodies and thrombosis. Lancet 1999; 353: 1348-53.
    CrossrefPubMedGoogle Scholar
  • 16 Katsuragawa H, Rote NS, Inoue T, Narukawa S, Kanzaki H, Mori T. Monoclonal antiphosphatidylserine antibody reactivity against human first-trimester placental trophoblasts. Am J Obstet Gynecol 1995; 172: 1592-7.
    CrossrefPubMedGoogle Scholar
  • 17 Grimmer D, Landas S, Kemp JD. IgM antitrophoblast antibodies in a patient with a pregnancy-associated lupus-like disorder, vasculitis and recurrent intrauterine fetal demise. Arch Pathol Lab Med 1988; 112: 191-3.
    PubMedGoogle Scholar
  • 18 Stirling Y, Woolf L, North WRS, Seghatchian MJ, Meade TW. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52: 176-82.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Clark P, Brennand J, Conkie JA, McCall F, Greer IA, Walker ID. Activated protein C sensitivity, protein C, protein S, and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 1166-70.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Branch DW, Peaceman AM, Druzin M, Silver RK, El-Sayed Y, Silver RM, Esplin MS, Spinato J, Harger J. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. Am J Obstet Gynecol 2000; 182: 122-7.
    CrossrefPubMedGoogle Scholar
  • 21 Lubbe WF, Butler WS, Palmer SJ, Liggins GC. Fetal survival after prednisone suppression of maternal lupus-anticoagulant. Lancet 1983; 1: 1361-6.
    PubMedGoogle Scholar
  • 22 Ordi J, Barquinero J, Vilardell M, Jordana R, Tolosa C, Selva A, Genover E. Fetal loss treatment in patients with antiphospholipid antibodies. Annals Rheum Dis 1989; 48: 798-802.
    CrossrefPubMedGoogle Scholar
  • 23 Silveria LH, Hubble CL, Jara LJ, Saway S, Martinez-Osuna P, Seleznick MJ, Angel J, O’ Brien W, Espinoza LR. Prevention of anticardiolipin antibody related pregnancy losses with prednisone and aspirin. Am J Med 1992; 93: 403-11.
    CrossrefPubMedGoogle Scholar
  • 24 Silver RK, MacGregor SN, Sholl JS, Hobart JM, Neerhof MG, Ragin A. Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody positive obstetric patients. Am J Obstet Gynecol 1993; 169: 1411-7.
    CrossrefPubMedGoogle Scholar
  • 25 Rosove MH, Tabsh K, Wasserstrum N, Howard P, Hahn BH, Kalunian KC. Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 1990; 75: 630-4.
    PubMedGoogle Scholar
  • 26 Many A, Pauzner R, Carp H, Langevitz P, Martinovitz U. Treatment of patients with antiphospholipid antibodies during pregnancy. Am J Reprod Immunol 1992; 28: 216-8.
    CrossrefPubMedGoogle Scholar
  • 27 Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative trial comparing prednisone with low dose heparin treatment. Am J Obstet Gynecol 1992; 166: 1318-23.
    CrossrefPubMedGoogle Scholar
  • 28 Lima F, Khamashta MA, Buchanan NMM, Kerslake S, Hunt BJ, Hughes GRV. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 1996; 14: 131-6.
    PubMedGoogle Scholar
  • 29 Kutteh WH. Antiphospholipid antibody associated recurrent pregnancy loss: Treatment with heparin and low dose aspirin is superior to low dose aspirin alone. Obstet Gynecol 1996; 174: 1584-9.
    CrossrefPubMedGoogle Scholar
  • 30 Ruffatti A, Orsini A, Di Leonardo L, Nardelli GB, Patrassi GM, Truscia D, Brigato G, Grella P, Todesco S. A prospective study of fifty-three consecutive calcium heparin treated pregnancies in patients with anti-phospholipid antibody-related fetal loss. Clin Exp Rheumatol 1997; 15: 499-505.
    PubMedGoogle Scholar
  • 31 Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 53-7.
    PubMedGoogle Scholar
  • 32 Backos M, Rai R, Baxter N, Chilcott IT, Cohen H, Regan L. Pregnancy complications in women with recurrent miscarriage associated with anti-phospholipid antibodies treated with low dose aspirin and heparin. Br J Obstet Gynecol 1999; 106: 102-7.
    CrossrefPubMedGoogle Scholar
  • 33 Kutteh WH, Rote NS, Silver R. Antiphospholipid antibodies and reproduction: The antiphospholipd antibody syndrome. AJRI 1999; 41: 133-52.
    PubMedGoogle Scholar
  • 34 Ginsberg JS, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1998; 114: 524S-30S.
    CrossrefPubMedGoogle Scholar
  • 35 Greaves M, Cohen H, Machin SJ, Mackie I. Guidelines on the investigation and management of the antiphospholipid syndrome. BJH 2000; 109: 704-15.
    CrossrefPubMedGoogle Scholar
  • 36 Bazzan M, Donvito V. Low molecular weight heparin during pregnancy. Throm Res 2001; 101: 175-186.
    CrossrefPubMedGoogle Scholar
  • 37 Oakley CM. Anticoagulants in pregnancy. Br Heart J 1995; 74: 107-11.
    CrossrefPubMedGoogle Scholar
  • 38 Lécuru F, Desnos M, Taurelle R. Anticogulant therapy in pregnancy: report of 54 cases. Acta Obstet Gynecol Scand 1996; 75: 217-21.
    CrossrefPubMedGoogle Scholar
  • 39 Ramin SM, Ramin KD, Gilstrap LC. Anticoagulants and thrombolytics during pregnancy. Semin Perinatol 1997; 21: 149-53.
    CrossrefPubMedGoogle Scholar
  • 40 Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve prostheses. Br Heart J 1994; 71: 196-201.
    CrossrefPubMedGoogle Scholar
  • 41 Frewin R, Chisholm M. Anticoagulation of women with prosthetic heart valves during pregnancy. Br J Obstet Gynecol 1998; 105: 683-6.
    CrossrefPubMedGoogle Scholar
  • 42 Hunt BJ, Khamashta M, Lakasing L, Williams FMK, Nelson-Piercy C, Bewley S, Hughes GRV. Thromboprophylaxis in antiphospholipid syndrome pregnancies with previous cerebral arterial thrombotic events: is warfarin preferable?. Thromb Haemost 1998; 79: 1060-1.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Ruiz-Irastorza G, Kamashta MA, Hughes G. Antiaggregating and anticoagulant therapy in systemic lupus erythematosus and Hughes’ syndrome. Lupus 2001; 10: 241-5.
    CrossrefPubMedGoogle Scholar
  • 44 Hirsh J. Heparin. N Engl J Med 1991; 324: 1565-74.
    CrossrefPubMedGoogle Scholar
  • 45 Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. JACC 1996; 27: 1698-703.
    CrossrefPubMedGoogle Scholar
  • 46 Sanson BJ, Lensing AWA, Prins MH, Ginsberg JS, Barkagan ZS, LavennePardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, Mac Gillavry MR, Hamulyak K, Theunissen IM, Hunt BJ, Büller HR. Safety of low- molecular weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-72.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Ensom MHH, Stephenson MD. Low-molecular weight heparins in pregnancy. Pharmacotherapy 1999; 19: 1013-25.
    CrossrefPubMedGoogle Scholar
  • 48 Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG. Heparin-induced thrombocytopenia in patients treated with low-molecular weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-5.
    CrossrefPubMedGoogle Scholar
  • 49 Sivakumaran M, Ghosh K, Zaidi Y, Hutchinson RM. Osteoporosis and vertebral collapse following low-dose, low molecular weight heparin therapy in a young patient. Clin Lab Haematol 1996; 18: 55-7.
    PubMedGoogle Scholar
  • 50 Hunt BJ, Doughty HA, Majumdar G, Copplestone A, Kerslake S, Buchanan N, Hughes G, Khamashta M. Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies. Thromb Haemost 1997; 77: 39-43.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Rosner E, Pauzner R, Lusky A, Modan M, Many A. Detection and quantitative evaluation of Lupus circulating anticoagulant activity. Thromb Haemost 1987; 57: 144-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Melissari E, Parker CJ, Wilson NV, Kanthou C, Pemberton KD, Nicolaides KH, Barret JJ, Kakkar VV. Use of low molecular weight heparin in pregnancy. Thromb Haemost 1992; 68: 652-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Dulitzki M, Pauzner R, Langevitz P, Pras M, Many A, Schiff E. Low molecular weight heparin during pregnancy and delivery: Preliminary experience with 41 pregnancies. Obstet Gynecol 1996; 87: 380-3.
    CrossrefPubMedGoogle Scholar
  • 54 Nelson-Piercy C, Letsky EA, De Swiet M. Low molecular weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk. Am J Obstet Gynecol 1997; 176: 1062-8.
    CrossrefPubMedGoogle Scholar
  • 55 Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-7.
    Article in Thieme ConnectPubMedGoogle Scholar