Thromboembolic complications and the importance of thrombophilia in pregnancy

Summary

Aim: Overview on pathogenesis, prophylaxis and therapy of thromboembolic complications.

Methods: Literature search in Pubmed.

Results and discussion: In pregnancy, changes in plasma coagulation favour the procoagulant properties to prevent blood loss during delivery. Venous thromboembolism is still one of the leading causes of serious maternal morbidity and mortality in the western world. The risk of developing venous thromboembolism (VTE) is 4–5-fold higher during pregnancy and twenty times higher postnatal. Vascular complications such as deep vein thrombosis (DVT) and pulmonary embolism may occur in pregnancy, especially in patients with acquired or hereditary thrombophilia, as well as recurrent abortion in patients with antiphospholipid syndrome. Recommendations concerning the necessity of prophylactic low molecular weight heparin (LMWH) are made individually, depending on the type of thrombophilia and past medical or family histories of deep vein thrombosis, pulmonary embolism or recurrent abortion, as well as the course of pregnancy. There is no general recommendation for prophylactic heparinisation in patients with asymptomatic thrombophilia. LMWHs are the standard anticoagulants for thromboembolism in pregnancy, as they have few side effects and are not teratogenic. Anticoagulation for acute VTE should usually be given for six weeks after delivery and for a total of at least three months. Additionally, acetylsalicylic acid (75–100 mg/day) is recommended for patients with antiphospholipid syndrome. As DVT in pregnancy often occurs in proximal veins, the risk of post-thrombotic syndrome is high. Prophylaxis appropriate to individual risk and early diagnosis is important to mini-mise short- and long-term complications of thromboembolism in pregnancy.

English version available at: www.phlebologieonline.de

Keywords

Deep vein thrombosis - thromboembolism - thrombophilia - pregnancy

• Literatur

• 1 Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003; 16 (02) 153-168.
• 2 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 (01) 31-36.
• 3 Clark P. et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79 (06) 1166-1170.
• 4 Medcalf RL. The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. Febs J 2005; 272: 4858-4867.
• 5 Stirling Y. et al. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52 (02) 176-182.
• 6 Comp PC. et al. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986; 68 (04) 881-885.
• 7 Toglia MR. Venous thromboembolism during pregnancy. N Engl J Med 1996; 335: 108-114.
• 8 Pabinger I. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood 2002; 100: 1006-1002.
• 9 Langevelde K.v. Increased risk of venous thrombosis in persons with clinically diagnosed superficial vein thrombosis: results from the MEGA study. Blood 2011; 118: 4239-41.
• 10 Heit JA. Trends in the incidence of venous thromboembolism during pregnancy and postpartum: a 30-year population-based study. Ann Intern Med 2005; 143: 697-706.
• 11 Franchini M. Haemostasis and pregnancy. Thromb Haemost 2006; 95 (06) 401-413.
• 12 Pabinger I. et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005; 3 (05) 949-954.
• 13 Brill-Edwards P. 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 (20) 1439-1444.
• 14 Gerhardt A. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and puerperium. N Engl J Med 2000; 342: 374-380.
• 15 Conard J. M.H. Horellou, and M.M. Samama, Inherited thrombophilia and gestational venous thromboembolism. Semin Thromb Hemost 2003; 29 (02) 131-142.
• 16 Kher A, Bauersachs R, Nielsen J.D. The management of thrombosis in pregnancy: role of low-molecular-weight heparin. Thromb Haemost 2007; 97 (04) 505-513.
• 17 James AH. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors and mortality. Am J Obstet Gynecol 2006; 194: 1311-1315.
• 18 Pomp ER. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6: 632-637.
• 19 Bergqvist A, Bergqvist D, Hallbook T. Deep vein thrombosis during pregnancy. A prospective study. Acta Obstet Gynecol Scand 1983; 62 (05) 443-448.
• 20 McColl MD. et al. Prevalence of the post-thrombotic syndrome in young women with previous venous thromboembolism. Br J Haematol 2000; 108 (02) 272-274.
• 21 Greer IA. Prevention of venous thromboembolism in pregnancy. Eur J Med Res 2004; 9 (03) 135-145.
• 22 Conard J. et al. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb Haemost 1990; 63 (02) 319-320.
• 23 Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. GTH Study Group on Natural Inhibitors. Arterioscler Thromb Vasc Biol 1996; 16 (06) 742-748.
• 24 Brenner B. Haemostatic changes in pregnancy. Thromb Res 2004; 114 (05) [phone].
• 25 Robertson L. et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132 (02) 171-196.
• 26 Rosendaal FR. Venous thrombosis: prevalence and interaction of risk factors. Haemostasis 1999; (Suppl. 29) 1: 1-9.
• 27 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344 (16) 1222-1231.
• 28 Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol 2003; 16 (02) 243-259.
• 29 Sucker C. Venöse Thromboembolie und Schwangerschaft. vasomed 2012; 3: 138-145.
• 30 Bates SM. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e691S-736S.
• 31 Zotz RB, Sucker C, Gerhardt A. [Thrombophilia in pregnancy: venous thromboembolism, fetal loss, preeclampsia, intrauterine growth restriction]. Hämostaseologie 2008; 28 (05) 455-464.
• 32 Triplett DA. Antiphospholipid antibodies and recurrent pregnancy loss. Am J Reprod Immunol 1989; 20 (02) 52-67.
• 33 Brenner B, Lanir N, Thaler I. HELLP syndrome associated with factor V R506Q mutation. Br J Haematol 1996; 92 (04) 999-1001.
• 34 van Pampus MG. et al. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 1999; 180 (05) 1146-1150.
• 35 Kosmas IP, Tatsioni A, Ioannidis JP. Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis. J Hypertens 2003; 21 (07) 1221-1228.
• 36 Kosmas IP, Tatsioni A, Ioannidis JP. Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis. J Hypertens 2004; 22 (09) 1655-1662.
• 37 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 (05) 779-785.
• 38 Pabinger I. Thrombophilia and its impact on pregnancy. Hämostaseologie 2008; 28 (03) 130-134.
• 39 Preston FE. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348 9032 913-916.
• 40 Kupferminc M.J. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
• 41 Gris JC. et al. Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. The Nimes Obstetricians and Haematologists Study – NOHA. Thromb Haemost 2000; 84 (02) 228-236.
• 42 Gris JC. et al. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study. Thromb Haemost 1997; 77 (06) 1096-1103.
• 43 Martinelli I. et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343 (14) 1015-1018.
• 44 Pihusch R. et al. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol 2001; 46 (02) 124-131.
• 45 Rasmussen A, Ravn P. High frequency of congenital thrombophilia in women with pathological pregnancies?. Acta Obstet Gynecol Scand 2004; 83 (09) 808-817.
• 46 Grandone E. et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77 (05) 822-824.
• 47 Rai R. et al. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 2001; 16 (05) 961-965.
• 48 Carp H. et al. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Hum Reprod 2002; 17 (06) 1633-1637.
• 49 Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost 2004; 91 (04) 700-711.
• 50 Kovalevsky G. et al. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med 2004; 164 (05) 558-563.
• 51 Hashimoto K. et al. The factor V Leiden mutation in Japanese couples with recurrent spontaneous abortion. Hum Reprod 1999; 14 (07) 1872-1874.
• 52 Lindqvist PG. et al. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost 1999; 81 (04) 532-537.
• 53 Meinardi JR. et al. Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999; 130 (09) 736-739.
• 54 Tormene D. et al. The risk of fetal loss in family members of probands with factor V Leiden mutation. Thromb Haemost 1999; 82 (04) 1237-1239.
• 55 Bauersachs RM. et al. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007; 98 (06) 1237-1245.
• 56 Ginsberg JS, Bates SM. Management of venous thromboembolism during pregnancy. J Thromb Haemost 2003; 1 (07) 1435-1442.
• 57 Samama MM. et al. Pregnancy-associated venous thromboembolism (VTE) in combined heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone. Br J Haematol 2003; 123 (02) 327-334.
• 58 Bates S.M. Management of pregnant women with thrombophilia or a history of venous thromboembolism. Hematology Am Soc Hematol Educ Program 2007; 143-50.
• 59 Bates SM. Pregnancy-associated venous thromboembolism: prevention and treatment. Semin Hematol 2011; 48 (04) 271-284.
• 60 Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106 (02) 401-407.
• 61 Cavazza S. et al. Thromboprophylaxis following cesarean delivery: one site prospective pilot study to evaluate the application of a risk score model. Thromb Res 2012; 129 (01) 28-31.
• 62 Nelson-Piercy C, Peek MJ, Swiet MD. Obstetric physicians: are they needed? The workload of a medical complications in pregnancy clinic. J R Coll Physicians Lond 1996; 30 (02) 150-154.
• 63 Warkentin TE. et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332 (20) 1330-1335.