Thrombophilic states: their relevance in prevention and treatment of venous thromboembolism

Česká verzia

Authors: H. Poul; P. Kessler
Authors place of work: Oddělení hematologie a transfuziologie nemocnice Pelhřimov, přednosta prim. MUDr. Petr Kessler
Published in the journal: Vnitř Lék 2009; 55(3): 242-252
Category: 15th Parizek's Days

Summary

Thrombophilic states are congenital or acquired haemostasis disorders with pathophysiological and statistical association to increased risk of thrombosis. Venous thromboembolism is their most important clinical manifestation. More than 50% of patients with unprovoked thrombosis have one of the known thrombophilias. Patients with congenital thrombophilias have, in comparison to those without thrombophilia, increased risk of the first thromboembolic event, while the impact of genetically defined thrombophilic states on recurrence is less evident. The risk of recurrence in patients with idiopathic thrombosis is 7–10% per year even in the absence of a known thrombophilia. The risk of recurrent event is affected by a range of other factors (persisting or undiagnosed precipitating factor, proximal thrombosis and pulmonary embolism, incomplete recanalization, vessel thrombosis, presence of some thrombophilias, high D-dimmer levels after anticoagulant therapy discontinuation). Identification and subsequent monitoring of these factors is crucial for optimal selection of the treatment to be used as a secondary prevention of venous thromboembolism and its duration. Primary prevention of venous thromboembolism requires good knowledge of general precipitating factors as well as the specific risks in each patient and thus also means an early investigation of thrombophilic states in patients who will benefit from their identification and in whom there is at least medium probability of their identification. Universal long‑term prevention in so far asymptomatic carriers of congenital thrombophilias is not indicated considering the potential complications of anticoagulant treatment. Women with thrombophilic disorders have an increased risk of thromboembolic event if using hormonal contraception and during pregnancy. They also have an increased risk of pregnancy complications related to placental circulation blood flow disorders.

Key words:
thrombophilia – venous thromboembolism – thrombosis prophylaxis – recurrent thrombosis – gravidity

Zdroje

1. Ageno W, Squizzato A, Garcia D et al. Epidemiology and risk factors of venous thromboembolism. Semin Thromb Hemost 2006; 32: 651–658.

2. Kearon C, Julian JA, Kovacs MJ et al. ELATE Investigators. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood 2008; 112: 4432–4436.

3. Zöller B, García de Frutos P, Hillarp A et al. Thrombophilia as a multigenic disease. Haematologica 1999; 84: 59–70.

4. Bertina RM, Koeleman BP, Koster T et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64–67.

5. den HeijerM, Koster T, Blom HJ et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759–762.

6. Heijboer H, Brandjes DP, Büller HR et al. Deficiencies of coagulation‑inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990; 323: 1512–1516.

7. Koster T, Rosendaal FR, de Ronde H et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Trombophilia Study. Lancet 1993; 342: 1503–1506.

8. Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991–996.

9. Pabinger I, Brücker S, Kyrle PA et al. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagul Fibrinolysis 1992; 3: 547–553.

10. Tait RC, Walker ID, Perry DJ et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106–112.

11. Tait RC, Walker ID, Reitsma PH et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 87–93.

12. Nordström M, Lindblad B, Bergqvist D et al. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992; 232: 155–160.

13. Martinelli I, Mannucci PM, De Stefano V et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92: 2353–2358.

14. Simioni P, Sanson BJ, Prandoni P et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81: 198–202.

15. Middeldorp S, Henkens CM, Koopman MM et al. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med 1998; 128: 15–20.

16. 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.

17. Blom JW, Doggen CJ, Osanto S et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715–722.

18. Koster T, Blann AD, Briët E et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152–155.

19. Kraaijenhagen RA, in’t Anker PS, Koopman MM et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5–9.

20. van Hylckama Vlieg A, van der Linden IK, Bertina RM et al. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95: 3678–3682.

21. Meijers JCM. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Eng J Med 2000; 342: 696–701.

22. den Heijer M, Rosendaal FR, Blom HJ et al. Hyperhomocysteinemia and venous thrombosis: a meta‑analysis. Thromb Haemost 1998; 80: 874–877.

23. Wahl DG, Guillemin F, de Maistre E et al. Meta‑analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7: 15–22.

24. Christiaens L. Idiopathic venous thromboembolic disease. Risk factors for recurrence in 2006. Arch Mal Coeur Vaiss 2007; 100: 133–138.

25. Linnemann B, Zgouras D, Schindewolf M et al. Impact of sex and traditional cardiovascular risk factors on the risk of recurrent venous thromboembolism: results from the German MAISTHRO Registry. Blood Coagul Fibrinolysis 2008; 19: 159–165.

26. Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med 2008; 121: 458–463.

27. Stevenson MD, Rawdin A, Papaioannou D. Thrombophilia testing in people with venous thromboembolism: systematic review and cost‑effectiveness analysis. Health Technol Assess 2009; 13: 1–91.

28. Sternitzky R, Hochauf S, Schellong SM. Secondary prophylaxis of venous thromboembolism. Hamostaseologie 2007; 27: 32–40.

29. Prandoni P, Noventa F, Ghirarduzzi A et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92: 199–205.

30. Baglin T, Luddington R, Brown K et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523–526.

31. Palareti G, Legnani C, Cosmi B et al. Predictive value of D‑dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation 2003; 108: 313–318.

32. Lindmarker P, Schulman S, Sten-Linder M et al. The risk of recurrent venous thromboembolism in carriers and non‑carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost 1999; 81: 684–689.

33. Simioni P, Prandoni P, Lensing AW et al. The risk of recurrent venous thromboembolism in patients with an Arg506→Gln mutation in the gene for factor V (factor V Leiden). N Eng J Med 1997; 336: 399–403.

34. Ridker PM. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 1995; 92: 2800–2802.

35. Eichinger S, Weltermann A, Mannhalter C et al. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism. Arch Intern Med 2002; 162: 2357–2360.

36. Kovac M, Mikovic D, Antonijevic N et al. FV Leiden mutation and risk of recurrent venous thromboembolism in Serbian population. J Thromb Thrombolysis 2008; 25: 284–287.

37. Marchiori A, Mosena L, Prins MH et al. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007; 92: 1107–1114.

38. Eichinger S, Minar E, Hirschl M et al. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost 1999; 81: 14–17.

39. De Stefano V, Martinelli I, Mannucci PM et al. The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation. Br J Haematol 2001; 113: 630–635.

40. Miles JS, Miletich JP, Goldhaber SZ et al. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. J Am Coll Cardiol 2001; 37: 215–218.

41. Eichinger S, Stümpflen A, Hirschl M et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80: 566–569.

42. den Heijer M, Blom HJ, Gerrits WB et al. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet 1995; 345: 882–885.

43. Kyrle PA, Minar E, Hirschl M et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Eng J Med 2000; 343: 457–462.

44. Legnani C, Cini M, Cosmi B et al. Risk of deep vein thrombosis: interaction between oral contraceptives and high factor VIII levels. Haematologica 2004; 89: 1347–1351.

45. Eischer L, Gartner V, Schulman S et al. For the AUREC-FVIII investigators (as listed in acknowledgements). 6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII. Ann Hematol 2008. [Epub ahead of print].

46. Prandoni P, Simioni P, Girolami A. Antiphospholipid antibodies, recurrent thromboembolism, and intensity of warfarin anticoagulation. Thromb Haemost 1996; 75: 859.

47. Rance A, Emmerich J, Fiessinger JN. Anticardiolipin antibodies and recurrent thromboembolism. Thromb Haemost 1997; 77: 221–222.

48. Schulman S, Svenungsson E, Grangvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998; 104: 332–338.

49. Bounameaux H, Perrier A. Duration of anticoagulation therapy for venous thromboembolism. Hematology Am Soc Hematol Educ Program 2008; 2008: 252–258.

50. Cosmi B, Legnani C, Cini M et al. D‑dimer and factor VIII are independent risk factors for recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis. Thromb Res 2008; 122: 610–617.

51. Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl 3): 338S–400S.

52. White RH, Zhou H, Romano PS. Incidence of symptomatic venous tromboembolism after different elective or urgent surgical procedures. Thromb Haemost 2003; 90: 446–455.

53. Bates SM, Greer IA, Pabinger I et al. American College of Chest Physicians. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl 6): 844S–886S.

54. Heit JA, Melton LJ 3rd, Lohse CM et al. Incidence of venous tromboembolism in hospitalized patients vs community residents. Mayo Clin Proc 2001; 76: 1102–1110.

55. Heit JA, O’Fallon WM, Petterson TM et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population‑based study. Arch Intern Med 2002; 162: 1245–1248.

56. Alikhan R, Cohen AT, Combe S et al. Risk factors for venous tromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164: 963–968.

57. Heit JA, Silverstein MD, Mohr DN et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population‑based case control study. Arch Intern Med 2000; 160: 809–815.

58. Heit JA, Petterson TM, Bailey KR et al. The influence of tumor site on venous tromboembolism risk among cancer patients: a population‑based study (Abstract 2596). Blood 2004; 104: 711a.

59. Levitan N, Dowlati A, Remick SC. Rates of initial and recurrent tromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999; 78: 285–291.

60. Palareti G, Cosmi B. Predicting the risk of recurrence of venous thromboembolism. Curr Opin Hematol 2004; 11: 192–197.

61. Kearon C, Gent M, Hirsh J et al. A comparsion of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous tromboembolism. N Engl J Med 1999; 340: 901–907.

62. Agnelli G, Prandoni P, Santamaria MG et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Eng J Med 2001; 345: 165–169.

63. Baglin T, Luddington R, Brown K et al. Incidence of recurrent venous tromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523–526.

64. Hansson PO, Sörbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160: 769–774.

65. Cushman M, Tsai AW, White RH et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117: 19–25.

66. Heit JA, Mohr DN, Silverstein MD et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population‑based cohort study. Arch Intern Med 2000; 160: 761–768.

67. Prandoni P, Lensing AW, Piccioli A et al. Recurrent venous tromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484–3488.

68. Prandoni P, Lensing AW, Cogo A et al. The long‑term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1–7.

69. Agnelli G, Becattini C. Treatment of DVT: how long is enough and how do you predict recurrence. J Thromb Thrombolysis 2008; 25: 37–44.

70. Piovella F, Crippa L, Barone M et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002; 87: 515–522.

71. Prandoni P, Lensing AW, Prins MH et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 955–960.

72. Eichinger S, Minar E, Bialonczyk C et al. D‑dimer levels and risk of recurrent venous thromboembolism. JAMA 2003; 290: 1071–1074.

73. Verhovsek M, Douketis JD, Yi Q et al. Systematic review: D‑dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 2008; 149: 481–490.

74. Palareti G, Cosmi B, Legnani C et al. PROLONG Investigators. D‑dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355: 1780–1789.

75. Rey E, Kahn SR, David M et al. Thrombophilic disorders and fetal loss: a meta‑analysis. Lancet 2003; 361: 901–908.

76. Gris JC, Mercier E, Quéré I et al. Low-molecular-weight heparin versus low‑dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103: 3695–3699.

77. Clark P, Brennand J, Conkie JA et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 1166–1170.

78. Stirling Y, Woolf L, North WR et al. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52: 176–182.

79. Bonnar J, McNicol GP, Douglas AS. Fibrinolytic enzyme system and pregnancy. Br Med J 1969; 3: 387–389.

80. Beller FK, Ebert C. The coagulation and fibrinolytic enzyme system in pregnancy and in the puerperium. Eur J Obstet Gynecol Reprod Biol 1982; 13: 177–197.

81. McColl MD, Ramsay JE, Tait RC et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78: 1183–1188.

82. Lindqvist P, Dahlbäck B, Marsˆál K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999; 94: 595–599.

83. Eldor A. Thrombophilia, thrombosis and pregnancy. Thromb Haemost 2001; 86: 104–111.

84. Martinelli I, Legnani C, Bucciarelli P et al. Risk of pregnancy‑related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 2001; 86: 800–803.

85. 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.

86. Bokarewa MI, Bremme K, Blombäck M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 1996; 92: 473–478.

87. Pomp ER, Lenselink AM, Rosendaal FR et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6: 632–637.

88. Martinelli I, De Stefano V, Taioli E et al. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium. Thromb Haemost 2002; 87: 791–795.

89. Blanco-Molina A, Trujillo-Santos J, Criado J et al. RIETE Investigators. Venous thromboembolism during pregnancy or postpartum: findings from the RIETE Registry. Thromb Haemost 2007; 97: 186–190.

90. Wu O, Robertson L, Twaddle S et al. Screening for thrombophilia in high‑risk situations: systematic review and cost‑effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess 2006; 10: 1–110.

91. 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 Eng J Med 2000; 342: 374–380.

92. Gerhardt A, Scharf RE, Zotz RB. Effect of hemostatic risk factors on the individual probability of thrombosis during pregnancy and the puerperium. Thromb Haemost 2003; 90: 77–85.

93. Hallak M, Senderowicz J, Cassel A et al. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. Am J Obstet Gynec 1997; 176: 889–893.

94. Hirsch DR, Mikkola KM, Marks PW et al. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J 1996; 131: 1145–1148.

95. Lensen RP, Bertina RM, de Ronde H et al. Venous thrombotic risk in family members of unselected individuals with factor V Leiden. Thromb Haemost 2000; 83: 817–821.

96. Meglic L, Stegnar M, Milanez T et al. Factor V Leiden, prothrombin 20210G-A, methylentetrahydrofolate reductase 677C-T and plasminogen activator inhibitor 4G/5G polymorphism in women with pregnancy‑related venous tromboembolism. Eur J Obstet Gynecol Reprod Biol 2003; 111: 157–163.

97. Ogunyemi D, Cuellar F, Ku W et al. Association between inherited trombophilias, antiphospholipid antibodies, and lipoprotein A levels and venous tromboembolism in pregnancy. Am J Perinatol 2003; 20: 17–24.

98. Nelen WL, Blom HJ, Steegers EA et al. Hyperhomocysteinaemia and recurrent early pregnancy loss: a meta analysis. Fertil Steril 2000; 74: 1196–1199.

99. Lindqvist PG, Svensson PJ, Marsaál K et al. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost 1999; 81: 532–537.

100. Sarasin FP, Bounameaux H. Decision analysis model of prolonged oral anticoagulant treatment in factor V Leiden carriers with first episode of deep vein thrombosis. BMJ 1998; 316: 95–99.

101. Robertson L, Wu O, Langhorne P et al. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171–196.

102. Bauersachs RM, Dudenhausen J, Faridi A et al. EThIG Investigators. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007; 98: 1237–1245.

103. Lindhoff-Last E, Luxembourg B. Evidence‑based indications for thrombophilia screening. Vasa 2008; 37: 19–30.

104. Simioni P. Who should be tested for thrombophilia? Curr Opin Hematol 2006; 13: 337–343.

105. Marchetti M, Pistorio A, Barosi G. Extended anticoagulation for prevention of recurrent venous thromboembolism in carriers of factor V Leiden: cost‑effectiveness analysis. Thromb Haemost 2000; 84: 752–757.

106. DiNisio M, Peters LW, Middeldorp S. Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome. Protocol for a Cochrane Review. The Cochrane Library 2004.

107. Middeldorp S. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications – No. J Thromb Haemost 2003; 1: 2073–2074.