Inherited Thrombophilia: Implications for Prevention and Treatment of Venous Thromboembolism

 

 Buy Article Permissions and Reprints

ABSTRACT

Inherited thrombophilia, defined as a genetically determined tendency to develop venous thromboembolism (VTE), contributes to the pathogenesis of ~40% of VTE episodes. About 50% of carriers of inherited thrombophilic traits develop VTE, but the impact of the different abnormalities is variable in terms of clinical penetrance. Some rare abnormalities (natural anticoagulant deficiencies, homozygous factor V Leiden, and combined defects) result in more severe thrombophilic phenotypes, characterized by early-onset events, more frequent recurrence, and positive family history, whereas the common polymorphisms (heterozygous factor V Leiden and prothrombin G20210A) are associated with lower VTE risk, often in association with triggering risk factors. Therefore, clinical implications of inherited thrombophilia should be assessed in the framework of coexisting and/or circumstantial risk factors involved in the multifactorial pathogenesis of VTE. These considerations should be taken into account when assessing the need and modalities of primary and secondary thromboprophylaxis in patients carrying inherited thrombophilic traits.

REFERENCES

• 1 Heit J A. Venous thromboembolism: disease burden, outcomes and risk factors.  J Thromb Haemost. 2005;  3(8) 1611-1617
  CrossrefPubMedGoogle Scholar
• 2 Naess I A, Christiansen S C, Romundstad P, Cannegieter S C, Rosendaal F R, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study.  J Thromb Haemost. 2007;  5(4) 692-699
  CrossrefPubMedGoogle Scholar
• 3 Silverstein M D, Heit J A, Mohr D N, Petterson T M, O'Fallon W M, Melton III L J. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.  Arch Intern Med. 1998;  158(6) 585-593
  CrossrefPubMedGoogle Scholar
• 4 Geerts W. Prevention of venous thromboembolism: a key patient safety priority.  J Thromb Haemost. 2009;  7(Suppl 1) 1-8
  PubMedGoogle Scholar
• 5 Goldhaber S Z. Venous thromboembolism prophylaxis: quality, location (hospital vs. home), and duration.  Thromb Haemost. 2009;  102(1) 1-2
  PubMedGoogle Scholar
• 6 Jordan F LJ, Nandorff A. The familial tendency in thrombo-embolic disease.  Acta Med Scand. 1956;  156(4) 267-275
  CrossrefPubMedGoogle Scholar
• 7 Egeberg O. Inherited antithrombin deficiency causing thrombophilia.  Thromb Diath Haemorrh. 1965;  13 516-530
  PubMedGoogle Scholar
• 8 Griffin J H, Evatt B, Zimmerman T S, Kleiss A J, Wideman C. Deficiency of protein C in congenital thrombotic disease.  J Clin Invest. 1981;  68 1370-1373
  CrossrefPubMedGoogle Scholar
• 9 Comp P C, Esmon C T. Recurrent venous thromboembolism in patients with a partial deficiency of protein S.  N Engl J Med. 1984;  311(24) 1525-1528
  CrossrefPubMedGoogle Scholar
• 10 Dahlbäck B, Carlsson M, Svensson P J. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.  Proc Natl Acad Sci U S A. 1993;  90(3) 1004-1008
  CrossrefPubMedGoogle Scholar
• 11 Bertina R M, Koeleman B PC, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369(6475) 64-67
  CrossrefPubMedGoogle Scholar
• 12 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. 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(10) 3698-3703
  CrossrefPubMedGoogle Scholar
• 13 Rosendaal F R. Venous thrombosis: a multicausal disease.  Lancet. 1999;  353(9159) 1167-1173
  CrossrefPubMedGoogle Scholar
• 14 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over.  Semin Thromb Hemost. 2008;  34(8) 747-761
  Article in Thieme ConnectPubMedGoogle Scholar
• 15 Heit J A, Silverstein M D, Mohr D N, Petterson T M, O'Fallon W M, Melton III L J. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study.  Arch Intern Med. 2000;  160(6) 809-815
  CrossrefPubMedGoogle Scholar
• 16 Samama M M, Dahl O E, Quinlan D J, Mismetti P, Rosencher N. Quantification of risk factors for venous thromboembolism: a preliminary study for the development of a risk assessment tool.  Haematologica. 2003;  88(12) 1410-1421
  PubMedGoogle Scholar
• 17 Lane D A, Mannucci P M, Bauer K A et al.. Inherited thrombophilia: Part 1.  Thromb Haemost. 1996;  76(5) 651-662
  PubMedGoogle Scholar
• 18 Martinelli I, Cattaneo M, Taioli E, De Stefano V, Chiusolo P, Mannucci P M. Genetic risk factors for superficial vein thrombosis.  Thromb Haemost. 1999;  82(4) 1215-1217
  PubMedGoogle Scholar
• 19 Margaglione M, Brancaccio V, Ciampa A, Papa M L, Grandone E, Di Minno G. Inherited thrombophilic risk factors in a large cohort of individuals referred to Italian thrombophilia centers: distinct roles in different clinical settings.  Haematologica. 2001;  86(6) 634-639
  PubMedGoogle Scholar
• 20 Martinelli I. Unusual forms of venous thrombosis and thrombophilia.  Pathophysiol Haemost Thromb. 2002;  32(5-6) 343-345
  CrossrefPubMedGoogle Scholar
• 21 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis.  N Engl J Med. 2001;  344(16) 1222-1231
  CrossrefPubMedGoogle Scholar
• 22 Middeldorp S, Levi M. Thrombophilia: an update.  Semin Thromb Hemost. 2007;  33(6) 563-572
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Rosendaal F R, Reitsma P H. Genetics of venous thrombosis.  J Thromb Haemost. 2009;  7(Suppl 1) 301-304
  CrossrefPubMedGoogle Scholar
• 24 Robertson L, Wu O, Langhorne P Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study et al. Thrombophilia in pregnancy: a systematic review.  Br J Haematol. 2006;  132(2) 171-196
  CrossrefPubMedGoogle Scholar
• 25 van der Meer F JM, Koster T, Vandenbroucke J P, Briët E, Rosendaal F R. The Leiden Thrombophilia Study (LETS).  Thromb Haemost. 1997;  78(1) 631-635
  PubMedGoogle Scholar
• 26 Martinelli I, Mannucci P M, 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(7) 2353-2358
  PubMedGoogle Scholar
• 27 Sanson B-J, Simioni P, Tormene D et al.. The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study.  Blood. 1999;  94(11) 3702-3706
  PubMedGoogle Scholar
• 28 Simioni P, Sanson B-J, Prandoni P et al.. Incidence of venous thromboembolism in families with inherited thrombophilia.  Thromb Haemost. 1999;  81(2) 198-202
  PubMedGoogle Scholar
• 29 Middeldorp S, Henkens C M, Koopman M M 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(1) 15-20
  CrossrefPubMedGoogle Scholar
• 30 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).  Blood. 1995;  85(6) 1504-1508
  PubMedGoogle Scholar
• 31 Martinelli I, Bucciarelli P, Margaglione M, De Stefano V, Castaman G, Mannucci P M. The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both.  Br J Haematol. 2000;  111(4) 1223-1229
  CrossrefPubMedGoogle Scholar
• 32 Meinardi J R, Middeldorp S, de Kam P J et al.. Risk of venous thromboembolism in carriers of factor V Leiden with a concomitant inherited thrombophilic defect: a retrospective analysis.  Blood Coagul Fibrinolysis. 2001;  12(8) 713-720
  CrossrefPubMedGoogle Scholar
• 33 van Boven H H, Reitsma P H, Rosendaal F R et al.. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency.  Thromb Haemost. 1996;  75(3) 417-421
  PubMedGoogle Scholar
• 34 Margaglione M, D'Andrea G, Colaizzo D et al.. Coexistence of factor V Leiden and Factor II A20210 mutations and recurrent venous thromboembolism.  Thromb Haemost. 1999;  82(6) 1583-1587
  PubMedGoogle Scholar
• 35 Vossen C Y, Conard J, Fontcuberta J et al.. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT).  J Thromb Haemost. 2005;  3(3) 459-464
  CrossrefPubMedGoogle Scholar
• 36 de Moerloose P, Neerman-Arbez M. Congenital fibrinogen disorders.  Semin Thromb Hemost. 2009;  35(4) 356-366
  Article in Thieme ConnectPubMedGoogle Scholar
• 37 Bezemer I D, Doggen C J, Vos H L, Rosendaal F R. No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study.  Arch Intern Med. 2007;  167(5) 497-501
  CrossrefPubMedGoogle Scholar
• 38 Eekhoff E M, Rosendaal F R, Vandenbroucke J P. Minor events and the risk of deep venous thrombosis.  Thromb Haemost. 2000;  83(3) 408-411
  PubMedGoogle Scholar
• 39 Castoldi E, Simioni P, Kalafatis M et al.. Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family.  Blood. 2000;  96(4) 1443-1448
  PubMedGoogle Scholar
• 40 Palareti G, Leali N, Coccheri S Italian Study on Complications of Oral Anticoagulant Therapy et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT).  Lancet. 1996;  348(9025) 423-428
  CrossrefPubMedGoogle Scholar
• 41 Vandenbroucke J P, van der Meer F J, Helmerhorst F M, Rosendaal F R, Factor V. Factor V Leiden: should we screen oral contraceptive users and pregnant women?.  BMJ. 1996;  313(7065) 1127-1130
  CrossrefPubMedGoogle Scholar
• 42 Cosmi B, Legnani C, Bernardi F, Coccheri S, Palareti G. Value of family history in identifying women at risk of venous thromboembolism during oral contraception: observational study.  BMJ. 2001;  322 1024-1025
  CrossrefPubMedGoogle Scholar
• 43 Varga E A, Kerlin B A, Wurster M W. Social and ethical controversies in thrombophilia testing and update on genetic risk factors for venous thromboembolism.  Semin Thromb Hemost. 2008;  34(6) 549-561
  Article in Thieme ConnectPubMedGoogle Scholar
• 44 Geerts W H, Bergqvist D, Pineo G F American College of Chest Physicians et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133(6, Suppl) 381S-453S
  CrossrefPubMedGoogle Scholar
• 45 Patnaik M M, Moll S. Inherited antithrombin deficiency: a review.  Haemophilia. 2008;  14(6) 1229-1239
  CrossrefPubMedGoogle Scholar
• 46 Rodgers G M. Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency. An update.  Thromb Haemost. 2009;  101(5) 806-812
  PubMedGoogle Scholar
• 47 Finazzi G, Caccia R, Barbui T. Different prevalence of thromboembolism in the subtypes of congenital antithrombin III deficiency: review of 404 cases.  Thromb Haemost. 1987;  58(4) 1094
  PubMedGoogle Scholar
• 48 Goldenberg N A, Manco-Johnson M J. Protein C deficiency.  Haemophilia. 2008;  14(6) 1214-1221
  CrossrefPubMedGoogle Scholar
• 49 McColl M D, Ramsay J E, Tait R C et al.. Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost. 1997;  78(4) 1183-1188
  PubMedGoogle Scholar
• 50 Gerhardt A, Scharf R E, Beckmann M W 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(6) 374-380
  CrossrefPubMedGoogle Scholar
• 51 Bates S M, Greer I A, Pabinger I, Sofaer S, Hirsh J. 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(6, Suppl) 844S-886S
  CrossrefPubMedGoogle Scholar
• 52 Screening di trombofilia e indicazioni alla profilassi in gravidanza [in Italian]. Linee Guida della Società Italiana per lo Studio dell'Emostasi e della Trombosi (SISET); last update May 2008. Available at: http://www.siset.org/lineeguida/LG5.pdf
  Google Scholar
• 53 Martinelli I, De Stefano V, Taioli E, Paciaroni K, Rossi E, Mannucci P M. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium.  Thromb Haemost. 2002;  87(5) 791-795
  PubMedGoogle Scholar
• 54 Vandenbroucke J P, Rosing J, Bloemenkamp K WM et al.. Oral contraceptives and the risk of venous thrombosis.  N Engl J Med. 2001;  344 1527-1535
  CrossrefPubMedGoogle Scholar
• 55 Bloemenkamp K WM, Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects.  Arch Intern Med. 2000;  160 49-52
  CrossrefPubMedGoogle Scholar
• 56 Pabinger I, Schneider B. The GTH Study Group on Natural Inhibitors . Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication.  Thromb Haemost. 1994;  71(5) 548-552
  PubMedGoogle Scholar
• 57 Mohllajee A P, Curtis K M, Martins S L, Peterson H B. Does use of hormonal contraceptives among women with thrombogenic mutations increase their risk of venous thromboembolism? A systematic review.  Contraception. 2006;  73(2) 166-178
  CrossrefPubMedGoogle Scholar
• 58 Wu O, Robertson L, Langhorne P et al.. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.  Thromb Haemost. 2005;  94(1) 17-25
  PubMedGoogle Scholar
• 59 Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci P M. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.  N Engl J Med. 1998;  338(25) 1793-1797
  CrossrefPubMedGoogle Scholar
• 60 van Vlijmen E F, Brouwer J L, Veeger N J, Eskes T K, de Graeff P A, van der Meer J. Oral contraceptives and the absolute risk of venous thromboembolism in women with single or multiple thrombophilic defects: results from a retrospective family cohort study.  Arch Intern Med. 2007;  167(3) 282-289
  CrossrefPubMedGoogle Scholar
• 61 Schulman S, Tengborn L. Treatment of venous thromboembolism in patients with congenital deficiency of antithrombin III.  Thromb Haemost. 1992;  68(6) 634-636
  PubMedGoogle Scholar
• 62 Chan Y C, Valenti D, Mansfield A O, Stansby G. Warfarin induced skin necrosis.  Br J Surg. 2000;  87(3) 266-272
  CrossrefPubMedGoogle Scholar
• 63 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. American College of Chest Physicians . Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133(6, Suppl) 160S-198S
  CrossrefPubMedGoogle Scholar
• 64 Prandoni P, Lensing A WA, Cogo A et al.. The long-term clinical course of acute deep venous thrombosis.  Ann Intern Med. 1996;  125(1) 1-7
  CrossrefPubMedGoogle Scholar
• 65 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(2) 199-205
  CrossrefPubMedGoogle Scholar
• 66 Heit J A, Mohr D N, Silverstein M D, Petterson T M, O'Fallon W M, Melton III L J. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.  Arch Intern Med. 2000;  160(6) 761-768
  CrossrefPubMedGoogle Scholar
• 67 Kearon C, Kahn S, Agnelli G et al.. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133 454S-545S
  CrossrefPubMedGoogle Scholar
• 68 Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study.  Lancet. 2003;  362(9383) 523-526
  CrossrefPubMedGoogle Scholar
• 69 Ho W K, Hankey G J, Quinlan D J, Eikelboom J W. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review.  Arch Intern Med. 2006;  166(7) 729-736
  CrossrefPubMedGoogle Scholar
• 70 Dalen J E. Should patients with venous thromboembolism be screened for thrombophilia?.  Am J Med. 2008;  121(6) 458-463
  CrossrefPubMedGoogle Scholar
• 71 Kearon C, Julian J A, Kovacs M J ELATE Investigators et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial.  Blood. 2008;  112(12) 4432-4436
  CrossrefPubMedGoogle Scholar
• 72 Marchiori A, Mosena L, Prins M H, Prandoni P. 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(8) 1107-1114
  CrossrefPubMedGoogle Scholar
• 73 Christiansen S C, Cannegieter S C, Koster T, Vandenbroucke J P, Rosendaal F R. Thrombophilia, clinical factors, and recurrent venous thrombotic events.  JAMA. 2005;  293(19) 2352-2361
  CrossrefPubMedGoogle Scholar
• 74 De Stefano V, Martinelli I, Mannucci P M et al.. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.  N Engl J Med. 1999;  341(11) 801-806
  CrossrefPubMedGoogle Scholar
• 75 Brouwer J L, Lijfering L M, ten Kate M I et al.. High long term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C, or antithrombin.  Thromb Haemost. 2009;  101 703-710
  PubMedGoogle Scholar
• 76 Kyrle P A, Minar E, Hirschl M et al.. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism.  N Engl J Med. 2000;  343(7) 457-462
  CrossrefPubMedGoogle Scholar
• 77 Schulman S, Svenungsson E, Granqvist S. Duration of Anticoagulation Study Group . Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy.  Am J Med. 1998;  104(4) 332-338
  CrossrefPubMedGoogle Scholar
• 78 Palareti G, Cosmi B, Legnani C et al.. D-dimer testing to determine the duration of anticoagulant therapy.  N Engl J Med. 2006;  355 1780-1789
  CrossrefPubMedGoogle Scholar
• 79 Prandoni P, Lensing A W, Prins M H et al.. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism.  Ann Intern Med. 2002;  137(12) 955-960
  CrossrefPubMedGoogle Scholar
• 80 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(5) 515-522
  PubMedGoogle Scholar
• 81 Young L, Ockelford P, Milne D et al.. Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality.  J Thromb Haemost. 2006;  4 1919-1924
  CrossrefPubMedGoogle Scholar
• 82 Spiezia L, Tormene D, Pesavento R, Salmaso L, Simioni P, Prandoni P. Thrombophilia as a predictor of persistent residual vein thrombosis.  Haematologica. 2008;  93(3) 479-480
  CrossrefPubMedGoogle Scholar
• 83 Eichinger S, Kyrle P A. Duration of anticoagulation after initial idiopathic venous thrombosis—the swinging pendulum: risk assessment to predict recurrence.  J Thromb Haemost. 2009;  7(Suppl 1) 291-295
  CrossrefPubMedGoogle Scholar
• 84 De Stefano V, Rossi E, Za T, Leone G. Prophylaxis and treatment of venous thromboembolism in individuals with inherited thrombophilia.  Semin Thromb Hemost. 2006;  32(8) 767-780
  Article in Thieme ConnectPubMedGoogle Scholar

Antonio CoppolaM.D. 

Regional Reference Centre for Coagulation Disorders, Federico II University

Via S. Pansini, 5 - 80131 Naples, Italy

Email: antocopp@unina.it