Haemostasis and pregnancy

Summary

Normal pregnancy is associated with profound alterations in the coagulation and fibrinolytic systems. While these physiological procoagulant changes are aimed to minimise intrapartum blood loss, they do increase the risk of thromboembolism during pregnancy and the post-partum period. In contrast and more rarely, haemorrhage due to an underlying inherited or acquired bleeding disorder may occur and complicatea pregnancy. Based on an analysis of the literature data, this review presents an overview of the main thrombotic and haemorrhagic disorders complicating pregnancy.

Keywords

Haemostasis - thrombophilia - bleeding - pregnancy

• References

• 1 Stirling Y. et al. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52: 176-82.
• 2 Sattar N. et al. A longitudinal study of the relationships between haemostatic, lipid, and oestradiol changes during normal human pregnancy. Thromb Haemost 1999; 81: 71-5.
• 3 Gerbasi FR. et al. Increased intravascular coagulation associated with pregnancy. Obstet Gynecol 1990; 75: 385-9.
• 4 Gerbasi FR. et al. Changes in hemostasis activity during delivery and the immediate postpartum period. Am J Obstet Gynecol 1990; 162: 1158-63.
• 5 Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003; 16: 153-68.
• 6 O’Riordan MN, Higgins JR. Haemostasis in normal and abnormal pregnancy. Best Pract Res Clin Obstet Gynaecol 2003; 17: 385-96.
• 7 Holmes VA, Wallace JMW. Haemostasis in normal pregnancy: a balancing act?. Biochem Soc Trans 2005; 33: 428-32.
• 8 Persson BL. et al. Transamidating enzymes in maternal plasma and placenta in human pregnancies complicated by intrauterine growth retardation. J Dev Physiol 1980; 02: 37-46.
• 9 Hellgren M, Blomback M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition. Gynecol Obstet Invest 1981; 12: 141-54.
• 10 Donohoe S. et al. Fluctuations in levels of antiphospholipid antibodies and increased coagulation activation markers in normal and heparin-treated antiphospholipid syndrome pregnancies. Lupus 2002; 11: 11-20.
• 11 Beller FK, Ebert C. The coagulation and fibrinolytic enzyme system in pregnancy and in the puerperium. Eur J Obstet Gynecol Reprod Biol 1982; 13: 177-97.
• 12 Phillips LL. et al. Changes in factor XI (plasma thromboplastin antecedent) levels during pregnancy. Am J Obstet Gynecol 1973; 116: 1114-6.
• 13 Condie RG. A serial study of coagulation factors XII, XI and X in plasma in normal pregnancy and in pregnancy complicated by pre-eclampsia. Br J Obstet Gynaecol 1976; 83: 636-9.
• 14 Clark P. et al. Activated protein C sensitivity, protein C, proteinS and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 1166-70.
• 15 Cadroy Y. et al. Evaluation of six markers of haemostatic system in normal pregnancy and pregnancy complicated by hypertension or pre-eclampsia. Br J Obstet Gynaecol 1993; 100: 416-20.
• 16 Thornton Ca, Bonnar J. Factor VIII-related antigen and factor VIII coagulant activity in normal and preeclamptic pregnancy. Br J Obstet Gynaecol 1977; 84: 919-23.
• 17 Dalaker K, Prydz H. The coagulation factor VII in pregnancy. Br J Haematol 1984; 56: 233-41.
• 18 Bonnar J. et al. Fibrinolytic enzyme system and pregnancy. Br Med J 1969; 03: 387-9.
• 19 Gatti L. et al. Hemostatic parameters and platelet activation by flow-cytometry in normal pregnancy: a longitudinal study. Int J Clin Lab Res 1994; 24: 217-9.
• 20 Kjellberg U. et al. APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb Haemost 1999; 81: 527-31.
• 21 Cerneca F. et al. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur J Obstet Gynecol Reprod Biol 1997; 73: 31-6.
• 22 Faught V. et al. Changes in protein C and protein S levels in normal pregnancy. Am J Obstet Gynecol 1995; 172: 147-50.
• 23 Fernandez JA. et al. Functional and immunologic protein S in normal pregnant women and in full-term newborns. Thromb Haemost 1989; 61: 474-8.
• 24 Weiner CP, Brandt J. Plasma antithrombin III activity in normal pregnancy. Obstet Gynecol 1980; 56: 601-3.
• 25 Clark P, Walker I. The phenomenon known as acquired activated protein C resistance. Br J Haematol 2001; 115: 767-73.
• 26 Biezenski JJ, Moore HC. Fibrinolysis in normal pregnancy. J Clin Pathol 1958; 11: 306-10.
• 27 Shaper AG. et al. Fibrinolysis and plasminogen levels in pregnancy and the puerperium. Lancet 1965; ii: 706-8.
• 28 Menon IS. et al. A comparative study of blood fibrinolytic activity in normal women, pregnant women and women on oral contraceptives. J Obstet Gynaecol Br Commonw 1970; 07: 752-6.
• 29 Ishii A. et al. t-PA activity in peripheral blood obtained from pregnant women. J Perin Med 1994; 22: 113-7.
• 30 Kruithof E. et al. Fibrinolysis in pregnancy:a study of plasminogen activator inhibitors. Blood 1987; 69: 460-6.
• 31 Chabloz P. et al. TAFI antigen and D-dimer levels during normal pregnancy and at delivery. Br J Haematol 2001; 115: 150-2.
• 32 Collen D. et al. Quantitation of thrombin-antithrombin III complexes in human blood. Eur J Clin Invest 1977; 07: 407-11.
• 33 Bellart J. et al. Endothelial cell markers and fibrinopeptide A to D-dimer ratio as a measure of coagulation and fibrinolysis balance in normal pregnancy. Gynecol Obstet Invest 1998; 46: 17-21.
• 34 Lanir N. et al. Haemostatic mechanisms in human placenta. Best Pract Res Clin Haematol 2003; 16: 183-95.
• 35 Dahlamn T. et al. Changes in blood coagulation and fibrinolysis in the normal puerperium. Gynecol Obstet Invest 1985; 20: 37-44.
• 36 Bremme K. et al. Enhanced thrombin generation and fibrinolytic activity in the normal pregnancy and the puerperium. Obstet Gynecol 1992; 80: 132-7.
• 37 Wallenburg HCS, van Kessel PH. Platelet lifespan in normal pregnancy as determined by a non-radioisotopic technique. Br J Obstet Gynaecol 1978; 85: 33-6.
• 38 Fay RA. et al. Platelets in pregnancy - hyperdestruction in pregnancy. Obstet Gynecol 1983; 61: 238-40.
• 39 Douglas JT. et al. Plasma fibrinopeptide A and β-thromboglobulin in pre-eclampsia and pregnancy hypertension. Thromb Haemost 1982; 47: 54-5.
• 40 Fitzgerald DJ. et al. Increased thromboxane biosynthesis in normal pregnancy is mainly derived from platelets. AmJ Obstet Gynecol 1987; 157: 325-30.
• 41 Wilson WA. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-11.
• 42 Wilson WA. Classification criteria for antiphospholipid syndrome. Rheum Dis Clin North Am 2001; 27: 499-505.
• 43 Park KW. The antiphospholipid syndrome. Int Anesthesiol Clin 2004; 42: 45-57.
• 44 Levine JS. et al. The antiphospholipid syndrome. N EnglJ Med 2002; 346: 752-63.
• 45 Greaves M. et al. Guidelines on the investigation and management of the antiphospholipid syndrome. Br J Haematol 2000; 109: 704-15.
• 46 Galli M, Barbui T. Antiphospholipid antibodies and thrombosis: strength of association. HematolJ 2003; 04: 180-6.
• 47 Branch DW, Khamashta MA. Antiphospholipid syndrome: obstetric diagnosis, management, and controversies. Obstet Gynecol 2003; 101: 1333-44.
• 48 Khare M, Nelson-Piercy C. Acquired thrombophilias and pregnancy. Best Pract Res Clin Obstet Gynaecol 2003; 17: 491-507.
• 49 Galli M, Barbui T. Antiphospholipid antibodies and pregnancy. Best Pract Res Clin Obstet Gynaecol 2003; 16: 211-25.
• 50 Lockshin MD. et al. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 1985; 313: 152-6.
• 51 Oshiro BT. et al. Antiphospholipid antibodies and fetal death. Obstet Gynecol 1996; 87: 489-93.
• 52 Yetman DL, Kutteh WH. Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies. Fertil Steril 1996; 66: 540-6.
• 53 Branch DW. et al. Antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin antibodies in women with recurrent pregnancy loss, fertile controls, and antiphospholipid syndrome. Obstet Gynecol 1997; 89: 549-55.
• 54 Branch DW, Silver RM. Criteria for antiphospholipid syndrome: early pregnancy loss, fetal loss, or recurrent pregnancy loss?. Lupus 1996; 05: 409-13.
• 55 Lima F. et al. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 1996; 14: 131-6.
• 56 Kandiah DA, Krillis SA. Beta 2-glycoprotein. Lupus 1994; 03: 207-12.
• 57 Roubey RAS. Tissue factor pathway and the antiphospholipid syndrome. J Autoimmun 2000; 15: 217-20.
• 58 Rand JH. Molecular pathogenesis of the antiphospholipid syndrome. Circ Res 2002; 90: 29-37.
• 59 Rand JH. et al. Pregnancy loss in the antiphospholipid-antibody syndrome - a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154-60.
• 60 Rand JH. et al. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a „lupus procoagulant” phenomenon. Blood 1998; 92: 1652-60.
• 61 Derksen RH. et al. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum 2004; 50: 1028-39.
• 62 Lassere M, Empson M. Treatment of antiphospholipid syndrome in pregnancy - a systematic review of randomized therapeutic trials. Thromb Res 2004; 114: 419-26.
• 63 Rai R. et al. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br Med J 1997; 314: 253-7.
• 64 Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174: 1584-9.
• 65 Clifford K. et al. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994; 09: 1328-32.
• 66 Branch DW. et al. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol 1992; 80: 614-20.
• 67 Triolo G. et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum 2003; 48: 728-31.
• 68 Sanson BJ. et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-72.
• 69 Ginsberg JS. et al. Use of antithrombotic agents during pregnancy. Chest 2001; 119 (Suppl. 01) 122-31S.
• 70 Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1989; 353: 1258-65.
• 71 Branch DW. et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol 2000; 182: 122-7.
• 72 Cowchock FS. et al. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992; 166: 1318-23.
• 73 Silver RK. et al. 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.
• 74 Lockshin MD. et al. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. AmJ Obstet Gynecol 1989; 160: 439-43.
• 75 Laskin CA. et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997; 337: 148-53.
• 76 Zotz RB. et al. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol 2003; 16: 243-59.
• 77 Greer IA. Inherited thrombophilia and venous thromboembolism. Best Pract Res Clin Obstet Gynaecol 2003; 17: 413-25.
• 78 Ginsberg JS, Bates SM. Management of venous thromboembolism during pregnancy. J Thromb Haemost 2003; 01: 1435-42.
• 79 Eldor A. Thrombophilia and its treatment in pregnancy. J Thromb Thrombolysis 2001; 12: 23-30.
• 80 Kierkegaard A. Incidence and diagnosis of deep vein thrombosis associated with pregnancy. Acta Obstet Gynaecol Scand 1983; 62: 239-43.
• 81 Ginsberg JS. et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost 1992; 67: 519-20.
• 82 Gherman RB. et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999; 94: 730-4.
• 83 Gerhardt A. 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: 374-80.
• 84 Hague WM, Dekker GA. Risk factors for thrombosis in pregnancy. Best Pract Res Clin Haematol 2003; 16: 197-210.
• 85 Villarreal C. et al. Congenital thrombophilia associated to obstetric complications. J Thromb Thrombolysis 2002; 14: 163-9.
• 86 Regan L, Rai R. Thrombophilia and pregnancy loss. J Reprod Immunol 2002; 55: 163-80.
• 87 Kujovich JL. Thrombophilia and pregnancy complications. Am J Obstet Gynecol 2004; 191: 412-24.
• 88 Paidas M. et al. Screening and management of inherited thrombophilias in the setting of adverse pregnancy outcome. Clin Perinatol 2004; 31: 783-805.
• 89 Abbate R. et al. Thrombophilias as risk factors for disorders of pregnancy and fetal damage. Pathophysiol Haemost Thromb 2002; 32: 318-21.
• 90 McColl MD. et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78: 1183-8.
• 91 Friederich PW. et al. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis. Ann Intern Med 1996; 125: 955-60.
• 92 Martinelli I. et al. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium. Thromb Haemost 2002; 87: 791-5.
• 93 Harvey D, Lowe GM. Factor V Leiden: association with venous thromboembolism in pregnancy and screening issues. Br J Biomed Sci 2004; 61: 157-64.
• 94 Buchanan GS. et al. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol 2003; 17: 397-411.
• 95 Ginsberg JS. et al. Use of antithrombotic agents during pregnancy. Chest 2001; 119 Suppl 122-31S.
• 96 Greer I, Hunt BJ. Low molecular weight heparin in pregnancy: current issues. Br J Haematol 2004; 128: 593-601.
• 97 Doyle NM, Monga M. Thromboembolic disease in pregnancy. Obstet Gynecol Clin N Am 2004; 31: 319-44.
• 98 Greer IA. Prevention of venous thromboembolism in pregnancy. Best Pract Res Clin Haematol 2003; 16: 261-78.
• 99 Bowles L, Cohen H. Inherited thrombophilias and anticoagulation in pregnancy. Best Pract Res Clin Obstet Gynaecol 2003; 17: 471-89.
• 100 Pettilä V. et al. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractioned heparin or LMW heparin. Thromb Haemost 2002; 87: 182-6.
• 101 Pabinger I, Grafenhofer H. Thrombosis during pregnancy: risk factors, diagnosis and treatment. Pathophysiol Haemost Thromb 2002; 32: 322-4.
• 102 Sanson BJ. et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-72.
• 103 Weitz JL. Low-molecular-weight heparins. N EnglJ Med 1997; 337: 688-98.
• 104 Rey E. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-8.
• 105 Brenner B. et al. Thrombophilia and pregnancy complications. Thromb Haemost 2004; 92: 678-81.
• 106 Porter TF, Scott JR. Evidence-based care of recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol 2005; 19: 85-101.
• 107 Brenner B. Inherited thrombophilia and pregnancy loss. Best Pract Res Clin Haematol 2003; 16: 311-20.
• 108 Hoffman R, Brenner B. Thrombophilia related issues in women and children. Sem Thromb Hemost 2005; 31: 97-103.
• 109 Pabinger I, Vormittag R. Thrombophilia and pregnancy outcomes. J Thromb Haemost 2005; 03: 1603-10.
• 110 Bick RL, Hoppensteadt D. Recurrent miscarriage syndrome and infertility due to blood coagulation protein/platelet defects: a review and update. Clin Appl Thromb Hemost 2005; 11: 1-13.
• 111 Brenner B. et al. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82: 6-9.
• 112 Martinelli I. et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343: 1015-8.
• 113 Preston FE. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-6.
• 114 Vossen CY. et al. Hereditary thrombophilia and fetal loss: a prospective follow-up study. J Thromb Haemost 2004; 02: 592-6.
• 115 Brenner B. et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-7.
• 116 Carp H. et al. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia. J Thromb Haemost 2003; 01: 433-8.
• 117 Brenner B. et al. LIVE-ENOX Investigators. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study. J Thromb Haemost 2005; 03: 227-9.
• 118 Grandone E. et al. Lower birth-weight in neonates of mothers carrying factor V G1691A and factor II A(20210) mutations. Haematologica 2002; 87: 177-81.
• 119 Infante-Rivard C. et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med 2002; 347: 19-25.
• 120 Howley HE. et al. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J Obstet Gynecol 2005; 192: 694-708.
• 121 D’Anna R. et al. Plasma homocysteine in early and late pregnancies complicated with preeclampsia and isolated intrauterine growth restriction. Acta Obstet Gynecol Scand 2004; 83: 155-8.
• 122 Vollset SE. et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr 2000; 71: 962-8.
• 123 Leeda M. et al. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998; 179: 135-9.
• 124 Grandone E, Margaglione M. Inherited thrombophilia and gestational vascular complications. Best Pract Res Clin Haematol 2003; 16: 321-32.
• 125 Said J, Dekker G. Pre-eclampsia and thrombophilia. Best Pract Res Clin Obstet Gynaecol 2003; 17: 441-58.
• 126 Walker JJ. Pre-eclampsia. Lancet 2000; 356: 1260-5.
• 127 Dekker GA. et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995; 173: 1042-8.
• 128 Kupferminc MJ. et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
• 129 van Pampus MG. et al. High prevalence of haemostatic abnormalities in women with a history of severe pre-eclampsia. Ame J Obstet Gynecol 1999; 180: 1146-50.
• 130 Kupferminc MG. et al. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynaecol 2000; 96: 145-9.
• 131 Alfirevic Z. et al. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynaecol 2001; 97: 753-9.
• 132 Lindqvist PG. et al. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost 1999; 81: 532-7.
• 133 Livingston JC. et al. Maternal and fetal inherited thrombophilias are not related to the development of severe pre-eclampsia. Am J Obstet Gynecol 2001; 185: 153-7.
• 134 Kaiser T. et al. Methylenetetrahydrofolate reductase polymorphisms are not a risk factor for preeclampsia/eclampsia among Australian women. Gynaecol Obstet Invest 2000; 50: 100-2.
• 135 Morrison ER. et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost 2002; 87: 779-85.
• 136 O’Shaughnessy KM. et al. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort. Hypertension 1999; 33: 1338-41.
• 137 Alfirevic Z. et al. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet Gynaecol Reprod Biol 2002; 101: 6-14.
• 138 McLintock C. et al. Inherited thrombophilias: implications for pregnancy associated venous thromboembolism and obstetric complications. Curr Probl Obstet Gynaecol Fertil 2001; 24: 115-49.
• 139 Nabhan C, Kwaan HC. Current concepts in the diagnosis and management of thrombotic thrombocytopenic purpura. Hematol Oncol Clin North Am 2003; 17: 177-99.
• 140 Karim R, Sacher RA. Thrombocytopenia in pregnancy. Curr Hematol Rep 2004; 03: 128-33.
• 141 Baxter JK, Weinstein L. HELLP syndrome: the state of the art. Obstet Gynecol Survey 2004; 59: 838-45.
• 142 Reubinoff BE, Schenker JG. HELLP syndrome--a syndrome of hemolysis, elevated liver enzymes and low platelet count--complicating preeclampsiaeclampsia. Int J Gynecol Obstet 1991; 36: 95-102.
• 143 Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?. Am J Obstet Gynecol 1990; 162: 311-6.
• 144 Schiff E. et al. Conservative management of severe preeclampsia remote from term. Obstet Gynecol 1994; 84: 626-30.
• 145 Egerman RS, Sibai BM. HELLP syndrome. Clin Obstet Gynecol 1999; 42: 381-9.
• 146 Eeltink CM. et al. Maternal haemolysis, elevated liver enzymes and low platelets syndrome: specific problems in the newborn. Eur J Pediatr 1993; 152: 160-3.
• 147 Clenney TL, Viera AJ. Corticosteroids for HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome. Br Med J 2004; 329: 270-2.
• 148 Rose CH. et al. Obstetric implications of antepartum corticosteroid therapy for HELLP syndrome. Obstet Gynecol 2004; 104: 1011-4.
• 149 Barrilleaux PS. et al. Postpartum intravenous dexamethasone for severely preeclamptic patients without hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome:a randomized trial. Obstet Gynecol 2005; 105: 843-8.
• 150 van Runnard PJHeimel. et al. Corticosteroids, pregnancy, and HELLP syndrome: a review. Obstet Gynecol Survey 2005; 60: 57-70.
• 151 Maki M. et al. Antithrombin therapy for severe preeclampsia: results of a double-blind, randomized, placebo-controlled trial. BI51.017 Study Group. Thromb Haemost 2000; 84: 583-90.
• 152 Paternoster DM. et al. Efficacy of AT in preeclampsia: a case-control prospective trial. Thrombosis Haemost 2004; 91: 283-9.
• 153 Moake JL. Thrombotic microangiopathies. N EnglJ Med 2002; 347: 589-600.
• 154 Allford Sl. et al., on behalf of the Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003; 120: 556-73.
• 155 Esplin MS, Branch DW. Diagnosis and management of thrombotic microangiopathies during pregnancy. Clin Obstet Gynecol 1999; 42: 360-8.
• 156 Ranzini AC. et al. Thrombotic thrombocytopenic purpura and human immunodeficiency virus complicating pregnancy. Obstet Gynecol 2002; 100: 1133-6.
• 157 Weiner CP. Thrombotic microangiopathy in pregnancy and the postpartum period. Semin Hematol 1987; 24: 119-29.
• 158 Kokame K, Miyata T. Genetic defects leading to hereditary thrombotic thrombocytopenic purpura. Semin Hematol 2004; 41: 34-40.
• 159 Tsai HM. Deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura. Arterioscler Thromb Vasc Biol 2003; 23: 388-96.
• 160 George JN. The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol 2003; 10: 339-44.
• 161 Shamseddine A. et al. Thrombotic thrombocytopenic purpura and pregnancy: report of four cases and literature review. J Clin Apher 2004; 19: 5-10.
• 162 Proia A. et al. Thrombotic thrombocytopenic purpura and pregnancy: a case report and a review of the literature. Ann Hematol 2002; 81: 210-4.
• 163 Castella M. et al. Thrombotic thrombocytopenic purpura and pregnancy: a review of ten cases. Vox Sang 2004; 87: 287-90.
• 164 Vesely SK. et al. Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpurahemolytic uremic syndrome. Transfusion 2004; 44: 1149-58.
• 165 British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. BrJ Haematol 2003; 120: 574-96.
• 166 George JN. et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88: 3-40.
• 167 Burrows RF, Kelton JG. Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med 1993; 329: 1463-6.
• 168 Kessler I. et al. The obstetrical management of patients with immunologic thrombocytopenic purpura. Int J Gynaecol Obstet 1982; 20: 23-8.
• 169 George JN, Raskob GE. Idiopathic thrombocytopenic purpura: diagnosis and management. Am J Med Sci 1998; 316: 87-93.
• 170 McCrae KR. et al. Platelets: an update on diagnosis and management of thrombocytopenic disorders. Hematology (Am Soc Hematol Educ Program) 2001; 01: 282-305.
• 171 Sacher RA. ITP in pregnancy and the newborn: introduction. Blut 1989; 59: 124-7.
• 172 Gill KK, Kelton JG. Management of idiopathic thrombocytopenic purpura in pregnancy. Sem Hematol 2000; 37: 275-89.
• 173 Greaves M, Letsky EA. Guidelines on the investigation and management of thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia. Br J Obstet Gynaecol 1997; 104: 1108.
• 174 Letsky EA, Greaves M. Guidelines on the investigation and management of thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia. Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task Force of the British Society for Haematology. Br J Haematol 1996; 95: 21-6.
• 175 Webert KE. et al. A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood 2003; 102: 4306-11.
• 176 Seremetis S, Afshani V. Management of bleeding disorders in pregnancy. In: Consultative Hemostasis and Thrombosis. W.B. Saunders; 2002: 437-448.
• 177 Lee CA, Kadir RA. von Willebrand disease and women’s health. Sem Hematol 2005; 42: 42-8.
• 178 Kadir RA. et al. Pregnancy in women with von Willebrand’s disease or factor XI deficiency. Br J Obstet Gynaecol 1998; 105: 314-21.
• 179 Ramsahoye BH. et al. Obstetric management in von Willebrand’s disease: a report of 24 pregnancies and a review of the literature. Haemophilia 1995; 01: 140-4.
• 180 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: 2515-21.
• 181 Chediak JR. et al. von Willebrand’s disease and pregnancy: management during delivery and outcome of offspring. Am J Obstet Gynaecol 1986; 155: 618-24.
• 182 Mannucci PM. How I treat patients with von Willebrand disease. Blood 2001; 97: 1915-9.
• 183 Charles K. et al. Successful use of desmopressin (DDAVP) in pregnant women with inherited storage pool disease. (abstract) Haemophilia 2000; 06: 241.
• 184 Lak M. et al. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br J Haematol 2000; 111: 1236-9.
• 185 Greer IA. et al. Haemorrhagic problems in obstetrics and gynaecology in patients with congenital coagulopathies. Br J Obstet Gynaecol 1991; 98: 909-18.
• 186 Kadir RA. et al. The obstetric experience of carriers of haemophilia. BrJ Obstet Gynaecol 1997; 104: 803-10.
• 187 Ljung R. et al. Normal vaginal delivery is to be recommended for haemophilia carrier gravidae. Acta Paediatrica 1994; 83: 609-11.
• 188 Yang MY, Ragni MV. Clinical manifestations and management of labor and delivery in women with factor IX deficiency. Haemophilia 2004; 10: 483-90.
• 189 Kadir RA. et al. Factor XI deficiency in women. Am J Hematol 1999; 60: 48-54.
• 190 Bolton-Maggs PHB. Bleeding problems in factor XI deficient women. Haemophilia 1999; 05: 155-9.
• 191 Bolton-Maggs PHB. et al. Inheritance and bleeding in factor XI deficiency. Br J Haematol 1988; 69: 521-8.
• 192 Lusher J. Systemic causes of excessive uterine bleeding. Sem Hematol 1999; 36: 10-20.
• 193 Leticee N. et al. Pregnancy in mother with Glanzmann’s thrombasthenia and isoantibody against GPIIb-IIIa: is there a foetal risk?. Eur J Obstet Gynecol Reprod Biol 2005; 121: 139-42.
• 194 Eskandari N. et al. Factor VII deficiency in pregnancy treated with recombinant factor VIIa. Obstet Gynecol 2002; 99: 935-7.
• 195 Pehlivanov B. et al. Factor VII deficiency and its treatment in delivery with recombinant factor VII. Eur J Obstet Gynecol Reprod Biol 2004; 116: 237-8.
• 196 Frenkel E. et al. Congenital hypofibrinogenemia in pregnancy: report of two cases and review of the literature. Obstet Gynecol Survey 2004; 59: 775-9.
• 197 Cohen AJ, Kessler CM. Acquired inhibitors. Bailleres Clin Haematol 1996; 09: 331-54.
• 198 Bouvry P, Recloux P. Acquired hemophilia. Haematologica 1994; 79: 550-6.
• 199 Morrison AE. Acquired haemophilia and its management. BrJ Haematol 1995; 89: 231-6.
• 200 Hay CRM. Acquired haemophilia. Bailleres Clin Haematol 1998; 11: 287-303.
• 201 Franchini M. et al. Acquired hemophilia A: a concise review. AmJ Hematol 2005; 80: 55-63.
• 202 Hay CRM. et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors’ Organization (UKHCDO). BrJ Haematol 2000; 111: 78-90.
• 203 Feinstein DI. et al. Diagnosis and management of patients with spontaneously acquired inhibitors of coagulation. Hematology 1999; 192-208.
• 204 Delgado J. et al. Acquired hemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121: 21-35.
• 205 Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981; 45: 200-3.
• 206 Bossi P. et al. Acquired haemophilia due to factor VIII inhibitors in 34 patients. Am J Med 1998; 105: 400-8.
• 207 Yee TT. et al. Factor VIII inhibitors in haemophiliacs: a single-centre experience over 34 years, 1964-97. Br J Haematol 1999; 104: 909-14.
• 208 Yee TT. et al. A survey of patients with acquired hemophilia in a hemophilia centre over a 28-year period. Clin Lab Haem 2000; 22: 275-8.
• 209 Rosenthal N. et al. Acquired haemophilia in a female patient. In: Anniversary Volume for Robert Tilden Frank; by his colleagues, collaborators, associates, and friends. St Louis: CV Mosby; 1937
• 210 Madison FW, Quick AJ. Hemophilia-like disease in the female. Am J Med Sci 1945; 209: 443-7.
• 211 Fantl P, Nance MH. An acquired haemorrhagic disease ina female due to an inhibitor of blood coagulation. Med J Austr 1946; 02: 125-8.
• 212 Chargaff E, West R. The biological significance of the thromboplastic protein of blood. J Biol Chem 1946; 166: 189-97.
• 213 Dreskin OH, Rosenthal N. A hemophilia-like disease with prolonged coagulation time and a circulating anticoagulant. Report of a case in a female. Blood 1950; 05: 46-60.
• 214 Frick PG. Hemophilia-like disease following pregnancy, with transplacental transfer of an acquired circulating anticoagulant. Blood 1953; 08: 598-608.
• 215 O’Brien JR. An acquired coagulation defect in a woman. J Clin Pathol 1953; 06: 22-5.
• 216 Bruno MS, Brody HS. Hypothromboplastinemia associated with a circulating anticoagulant and hemorrhagic diathesis. Am J Med 1954; 16: 756-63.
• 217 Nilson IM. et al. Circulating anticoagulant after pregnancy and its response to ACTH. Acta Haematol 1958; 19: 40-50.
• 218 Magrolius A. et al. Circulating anticoagulants: a study of 40 cases and a review of literature. Medicine 1961; 40: 145-202.
• 219 Bloom Al. et al. A clinical and laboratory study of a patient with an unusual factor VIII inhibitor. Thromb Diath Haemorrh 1966; 15: 15-28.
• 220 Greenwood RJ, Robin SC. Hemophilia-like postpartum bleeding. Obstet Gynecol 1967; 30: 362-6.
• 221 Sherman LA. et al. Circulating anticoagulant (antifactor VIII) treated with immunosuppressive drugs. Thromb Diath Haemorrh 1969; 21: 249-58.
• 222 Marengo-Rowe AJ. et al. Hemophilia-like disease associated with pregnancy. Obstet Gynecol 1972; 40: 56-64.
• 223 Piana L. et al. An unusual case of postpartum hemorrhage: the antihemophilic A factor inhibitor. Rev Fr Gynecol Obstet 1972; 67: 621-4.
• 224 Voke J, Letsky E. Pregnancy and antibody to factor VIII. J Clin Pathol 1977; 30: 928.
• 225 Michiels JJ. et al. Factor VIII inhibitor postpartum. Scand J Haematol 1978; 20: 97-107.
• 226 Erskine JG. et al. Plasma exchange in nonhemophiliac patients with inhibitors to factor VIII C. Br Med J 1981; 283: 760.
• 227 Files JC. et al. Postpartum treatment of a patient with a FVIII inhibitor. N Engl J Med 1981; 305: 1650.
• 228 Coller BS. et al. Normal pregnancy in a patient with a prior postpartum factor VIII inhibitor: with observations on pathogenesis and prognosis. Blood 1981; 58: 619-24.
• 229 Spero JA. et al. Corticosteroid therapy for acquired FVIII:C inhibitors. Br J Haematol 1981; 48: 635-42.
• 230 Shitamoto BS. et al. Postpartum hemophilia. AmJ Pathol 1982; 78: 789-91.
• 231 Reece EA. et al. Factor VIII inhibitor. A cause of severe postpartum hemorrhage. Am J Obstet Gynecol 1982; 144: 985-7.
• 232 Vicente V. et al. Normal pregnancy in a patient with a postpartum FVIII inhibitor. Am J Hematol 1987; 24: 107-9.
• 233 O’Sullivan JL. et al. Spontaneous postpartum factor VIII inhibitor development with bleeding into the face and neck. J Oral Maxillofac Surg 1988; 84: 802-5.
• 234 Lian ECY. et al. Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor. Ann Intern Med 1989; 110: 774-8.
• 235 Haedicke G. et al. Tracheal obstruction after emergency tracheostomy in a patient with a postpartum VIII inhibitor. Crit Care Med 1990; 18: 449-50.
• 236 Schwertfeger R. et al. Successful treatment of a patient with postpartum factor VIII inhibitor with recombinant human interferona 2a. Am J Hematol 1991; 37: 190-3.
• 237 Hultin MB. Acquired inhibitors in malignant and nonmalignant disease states. Am J Med 1991; 5A Suppl 9-13.
• 238 Marwaha N. et al. Simultaneous occurrence of factor VIII C inhibitor and antinuclear antibody in postpartum period. Am J Hematol 1991; 37: 49-50.
• 239 Hauser I. et al. Postpartum factor VIII inhibitors. Wien Klin Wochenschr 1993; 105: 355-8.
• 240 Hudak C. et al. Pregnancy associated factor VIII inhibitor: treatment with intravenous high-dose immunoglobulin. Am J Hematol 1993; 43: 158.
• 241 Hauser I. et al. Postpartum factor VIII inhibitors. A review of the literature with special reference to the value of steroid and immunosuppressive treatment. Thromb Haemost 1995; 73: 1-5.
• 242 Ries M. et al. Severe intracranial hemorrhage in a newborn infant with transplacental transfer of an acquired factor VIII:C inhibitor. J Pediatr 1995; 127: 649-50.
• 243 Kadir RA. et al. Acquired haemophilia, an unusual cause of severe postpartum haemorrhage. Br J Obstet Gynaecol 1997; 104: 854-6.
• 244 Michiels JJ. et al. Acquired haemophilia A in women postpartum: management of bleeding episodes and natural history of the factor VIII inhibitor. Eur J Haematol 1997; 59: 105-9.
• 245 Solymoss S. Postpartum acquired factor VIII inhibitors: results of a survey. Am J Hematol 1998; 59: 1-4.
• 246 Brox AG. et al. Successful treatment of acquired factor VIII inhibitors with cyclosporin. AmJ Hematol 1998; 57: 87-8.
• 247 Santagostino E. et al. Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: the advantages of early intervention. Br J Haematol 1999; 104: 22-6.
• 248 Shobeiri SA. et al. Postpartum acquired hemophilia (factor VIII inhibitors): a case report and review of the literature. Obstet Gynecol Surv 2000; 55: 729-37.
• 249 Michiels JJ. Acquired hemophilia in women postpartum: clinical manifestations, diagnosis and treatment. Clin Appl Thromb Hemost 2000; 06: 82-6.
• 250 Ehrenfort S. et al. Clinical characteristics and treatment modalities of acquired hemophilia. Report of 30 cases and comprehensive review of the literature. (abstract) Haemophilia 2000; 06: 292.
• 251 Saxena R. et al. Acquired haemophilia -a study of ten cases. Haemophilia 2000; 06: 78-83.
• 252 Mazzucconi MG. et al. Postpartum inhibitor to factor VIII: treatment with high-dose immunoglobulin and dexamethasone. Haemophilia 2001; 07: 422-7.
• 253 Kashyap R. et al. Postpartum acquired haemophilia: clinical recognition and management. Haemophilia 2001; 07: 327-30.
• 254 Jansen M. et al. Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb). Br J Haematol 2001; 112: 91-7.
• 255 Lian EC. et al. Acquired factor VIII inhibitor treated with cyclophosphamide, vincristine, and prednisone. Am J Hematol 2002; 69: 294-5.
• 256 Delgado J. et al. Acquired hemophilia: a singlecenter survey with emphasis on immunotherapy and treatment-related side-effects. Eur J Haematol 2002; 69: 158-64.
• 257 Howland EJ. et al. Acquired factor VIII inhibitors as a cause of primary post-partum haemorrhage. Eur J Obstet Gynecol Reprod Biol 2002; 103: 97-8.
• 258 Baudo F, de Cataldo F. Italian Association of Haemophilia Centres (AICE): Register of acquired factor VIII inhibitors (RIIA). Acquired factor VIII inhibitors in pregnancy: data from the Italian Haemophilia Register relevant to clinical practice. Br J Obstet Gynaecol 2003; 110: 311-4.
• 259 Pejsa V. et al. Rapid decrease in high titer of factor VIII inhibitors upon immunosuppressive treatment in severe postpartum acquired hemophilia A. Croat Med J 2004; 45: 213-6.
• 260 Stasi R. et al. Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia. Blood 2004; 103: 4424-8.
• 261 Sallah S. Treatment of acquired haemophilia with factor eight inhibitor bypassing activity. Haemophilia 2004; 10: 169-73.
• 262 Huang YW. et al. Acquired factor VIII inhibitors in non-haemophilic patients: clinical experience of 15 cases. Haemophilia 2004; 10: 713-21.
• 263 Zeitler H. et al. Treatment of acquired hemophilia by the Bonn-Malmö Protocol: documentation of an in vivo imunomodulating concept. Blood 2005; 105: 2287-93.
• 264 Porteous AO. et al. Acquired haemophilia and postpartum haemorrhage treated with internal pudendal embolisation. Br J Obstet Gynaecol 2005; 112: 678-9.
• 265 Prescott R. et al. The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Recombinate and Kogenate Study Groups. Blood 1997; 89: 3663-71.
• 266 Mudad R, Kane WH. DDAVP in acquired haemophilia A: case report and review of the literature. Am J Haematol 1993; 43: 295-9.
• 267 Morrison AE. et al. Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood 1993; 81: 1520-31.