Thrombophilia and Venous Thromboembolism: Implications for Testing

ABSTRACT

In the last decades, the knowledge on the etiology of venous thromboembolism (VTE) has increased tremendously. In approximately half of patients presenting with VTE, one or more thrombophilic defects can be identified. This has led to widespread testing for thrombophilia, despite the fact that, at present, it is unclear whether this should have therapeutic consequences. Here we review the currently established hereditary and acquired thrombophilic defects, and focus on the pros and cons of testing in the setting of VTE.

Thrombophilia is defined as a disorder associated with an increased tendency to venous thromboembolism (VTE). Thrombophilia can be acquired, such as in patients with cancer, or congenital, in which case a defect in the coagulation system is hereditary. Egeberg was the first to use the term thrombophilia in 1965, when he described a Norwegian family that had a remarkable tendency to VTE, based on a deficiency of antithrombin.[1] Since then, various laboratory abnormalities, both hereditary and acquired, have been discovered that increase the risk of VTE. This article reviews the currently established thrombophilic abnormalities and discusses the potential usefulness and implications of testing for thrombophilia.

Thrombophilia - venous thromboembolism - testing

REFERENCES

• 1 Egeberg O. Inherited antithrombin deficiency causing thrombophilia.  Thromb Diath Haemorrh. 1965;  13 516-530
• 2 Heijboer H, Brandjes D P, Büller H R, Sturk A, ten Cate J W. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis.  N Engl J Med. 1990;  323(22) 1512-1516
• 3 Koster T, Rosendaal F R, Briet E et al.. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study).  Blood. 1995;  85(10) 2756-2761
• 4 Reitsma P H. Protein C deficiency: summary of the 1995 database update.  Nucleic Acids Res. 1996;  24(1) 157-159
• 5 Marlar R A, Neumann A. Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies.  Semin Thromb Hemost. 1990;  16(4) 299-309
• 6 Bick R L. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects.  Hematol Oncol Clin North Am. 2003;  17(1) 9-36
• 7 Monagle P, Andrew M, Halton J et al.. Homozygous protein C deficiency: description of a new mutation and successful treatment with low molecular weight heparin.  Thromb Haemost. 1998;  79(4) 756-761
• 8 Dykes A C, Walker I D, McMahon A D, Islam S I, Tait R C. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state.  Br J Haematol. 2001;  113(3) 636-641
• 9 Pabinger I, Brücker S, Kyrle P A 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(5) 547-553
• 10 Hackeng T M, Van't Veer C, Meijers J, Bouma B. Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa.  J Biol Chem. 1994;  269(33) 21051-21058
• 11 Anderson D R, Brill-Edwards P, Walker I. Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy.  Haemostasis. 1992;  22(3) 124-128
• 12 Tait R C, Walker I D, Perry D J et al.. Prevalence of antithrombin deficiency in the healthy population.  Br J Haematol. 1994;  87(1) 106-112
• 13 Rees D C, Cox M, Clegg J B. World distribution of factor V Leiden.  Lancet. 1995;  346(8983) 1133-1134
• 14 Williamson D, Brown K, Luddington R, Baglin C, Baglin T, Factor V. Cambridge: a new mutation (Arg306right-arrowThr) associated with resistance to activated protein C.  Blood. 1998;  91(4) 1140-1144
• 15 Chan W P, Lee C K, Kwong Y L, Lam C K, Liang R. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese.  Blood. 1998;  91(4) 1135-1139
• 16 Griffin J H, Heeb M J, Kojima Y et al.. Activated protein C resistance: molecular mechanisms.  Thromb Haemost. 1995;  74(1) 444-448
• 17 van der Neut Kolfschoten M, Dirven R J, Vos H L, Tans G, Rosing J, Bertina R M. Factor Va is inactivated by activated protein C in the absence of cleavage sites at Arg-306, Arg-506, and Arg-679.  J Biol Chem. 2004;  279(8) 6567-6575
• 18 Roelse J C, Koopman M MW, Buller H R et al.. Absence of mutations at the activated protein C cleavage sites of factor VIII in 125 patients with venous thrombosis.  Br J Haematol. 1996;  92(3) 740-743
• 19 Soria J M, Almasy L, Souto J C et al.. A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility.  Blood. 2003;  101 163-167
• 20 Tosetto A, Simioni M, Madeo D, Rodeghiero F. Intraindividual consistency of the activated protein C resistance phenotype.  Br J Haematol. 2004;  126(3) 405-409
• 21 Rosing J, Hoekema L, Nicolaes G A et al.. Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C.  J Biol Chem. 1995;  270(46) 27852-27858
• 22 Rosendaal F R, Doggen C J, Zivelin A et al.. Geographic distribution of the 20210 G to A prothrombin variant.  Thromb Haemost. 1998;  79(4) 706-708
• 23 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
• 24 Folsom A R, Cushman M, Tsai M Y et al.. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors.  Blood. 2002;  99(8) 2720-2725
• 25 Koster T, Blann A D, Briët E, Vandenbroucke J P, Rosendaal F R. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis.  Lancet. 1995;  345(8943) 152-155
• 26 van Hylckama Vlieg A, van der Linden I K, Bertina R M, Rosendaal F R. High levels of factor IX increase the risk of venous thrombosis.  Blood. 2000;  95(12) 3678-3682
• 27 Meijers J CM, Tekelenburg W, Bouma B N, Bertina R M, Rosendaal F R. High levels of coagulation factor XI as a risk factor for venous thrombosis.  N Engl J Med. 2000;  342 696-701
• 28 Koster T, Rosendaal F R, Reitsma P H, van der Velden P A, Briët E, Vandenbroucke J P. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms-the Leiden Thrombophilia Study (LETS).  Thromb Haemost. 1994;  71(6) 719-722
• 29 O'Donnell J, Mumford A D, Manning R A, Laffan M. Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response.  Thromb Haemost. 2000;  83(1) 10-13
• 30 Kraaijenhagen R A, in't Anker P, Koopman M M et al.. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism.  Thromb Haemost. 2000;  83(1) 5-9
• 31 Kamphuisen P W, Eikenboom J C, Vos H L et al.. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions.  Thromb Haemost. 1999;  81(5) 680-683
• 32 Kamphuisen P W, Houwing-Duistermaat J J, van Houwelingen H C, Eikenboom J C, Bertina R M, Rosendaal F R. Familial clustering of factor VIII and von Willebrand factor levels.  Thromb Haemost. 1998;  79(2) 323-327
• 33 Libourel E J, Balje-Volkers Degrees C P, Hamulyak K et al.. High factor VIII plasma levels as a risk factor for venous thrombosis: no evidence of inheritance from a family cohort study.  Haematologica. 2004;  89(1) 118-120
• 34 von dem Borne P A, Bajzar L, Meijers J CM, Nesheim M E, Bouma B N. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis.  J Clin Invest. 1997;  99(10) 2323-2327
• 35 Kamphuisen P W, Rosendaal F R, Eikenboom J CJ, Bos R, Bertina R M, Factor V. Antigen levels and venous thrombosis: risk profile, interaction with factor V Leiden, and relation with factor VIII antigen levels.  Arterioscler Thromb Vasc Biol. 2000;  20(5) 1382-1386
• 36 de Visser M C, Poort S R, Vos H L, Rosendaal F R, Bertina R M. Factor X levels, polymorphisms in the promoter region of factor X, and the risk of venous thrombosis.  Thromb Haemost. 2001;  85(6) 1011-1017
• 37 Mudd S H, Skovby F, Levy H L et al.. The natural history of homocystinuria due to cystathionine beta-synthase deficiency.  Am J Hum Genet. 1985;  37(1) 1-31
• 38 Kraus J P, Janosik M, Kozich V et al.. Cystathionine beta-synthase mutations in homocystinuria.  Hum Mutat. 1999;  13(5) 362-375
• 39 Frosst P, Blom H J, Milos R et al.. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet. 1995;  10(1) 111-113
• 40 den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies.  J Thromb Haemost. 2005;  3(2) 292-299
• 41 Dahm A, van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina R M, Sandset P M. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis.  Blood. 2003;  101(11) 4387-4392
• 42 Meltzer M E, Doggen C J, de Groot P G, Rosendaal F R, Lisman T. Fibrinolysis and the risk of venous and arterial thrombosis.  Curr Opin Hematol. 2007;  14(3) 242-248
• 43 van Tilburg N H, Rosendaal F R, Bertina R M. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis.  Blood. 2000;  95(9) 2855-2859
• 44 Eichinger S, Schonauer V, Weltermann A et al.. Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism.  Blood. 2004;  103(10) 3773-3776
• 45 Martini C H, Brandts A, de Bruijne E L et al.. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis.  Br J Haematol. 2006;  134(1) 92-94
• 46 Koster T, Rosendaal F R, Briët E, Vandenbroucke J P. John Hageman's factor and deep-vein thrombosis: Leiden Thrombophilia Study.  Br J Haematol. 1994;  87(2) 422-424
• 47 Zeerleder S, Schloesser M, Redondo M et al.. Reevaluation of the incidence of thromboembolic complications in congenital factor XII deficiency-a study on 73 subjects from 14 Swiss families.  Thromb Haemost. 1999;  82(4) 1240-1246
• 48 Miyakis S, Lockshin M D, Atsumi T et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4(2) 295-306
• 49 Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature.  Blood. 2003;  101(5) 1827-1832
• 50 Martinelli I. Pros and cons of thrombophilia testing: pros.  J Thromb Haemost. 2003;  1(3) 410-411
• 51 Machin S J. Pros and cons of thrombophilia testing: cons.  J Thromb Haemost. 2003;  1(3) 412-413
• 52 Prandoni P, Bernardi E, Marchiori A et al.. The long term clinical course of acute deep vein thrombosis of the arm: prospective cohort study.  BMJ. 2004;  329(7464) 484-485
• 53 van Dongen C J, Vink R, Hutten B A, Büller H R, Prins M H. The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event: a meta-analysis.  Arch Intern Med. 2003;  163(11) 1285-1293
• 54 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
• 55 Buller H R, Agnelli G, Hull R D, Hyers T M, Prins M H, Raskob G E. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 401S-428S
• 56 Van der Meer F J, Rosendaal F R, Vandenbroucke J P, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors.  Arch Intern Med. 1993;  153(13) 1557-1562
• 57 Palareti G, Leali N, Coccheri S et al.. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy.  Lancet. 1996;  348(9025) 423-428
• 58 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
• 59 van den Belt A G, Sanson B J, Simioni P et al.. Recurrence of venous thromboembolism in patients with familial thrombophilia.  Arch Intern Med. 1997;  157(19) 2227-2232
• 60 De Stefano V, Leone G, Mastrangelo S et al.. Clinical manifestations and management of inherited thrombophilia: retrospective analysis and follow-up after diagnosis of 238 patients with congenital deficiency of antithrombin III, protein C, protein S.  Thromb Haemost. 1994;  72(3) 352-358
• 61 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
• 62 Vink R, Kraaijenhagen R A, Levi M, Büller H R. Individualized duration of oral anticoagulant therapy for deep vein thrombosis based on a decision model.  J Thromb Haemost. 2003;  1(12) 2523-2530
• 63 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
• 64 Legnani C, Cosmi B, Cini M, Frascaro M, Guazzaloca G, Palareti G. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism.  Br J Haematol. 2004;  124(4) 504-510
• 65 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
• 66 Eichinger S, Stumpflen A, Hirschl M et al.. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism.  Thromb Haemost. 1998;  80(4) 566-569
• 67 Keijzer M B, Blom H J, Bos G M, Willems H P, Gerrits W B, Rosendaal F R. Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis.  Thromb Haemost. 2002;  88(5) 723-728
• 68 den Heijer M, Blom H J, Gerrits W B et al.. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?.  Lancet. 1995;  345(8954) 882-885
• 69 Prandoni P, Simioni P, Girolami A. Antiphospholipid antibodies, recurrent thromboembolism, and intensity of warfarin anticoagulation.  Thromb Haemost. 1996;  75(5) 859
• 70 Rance A, Emmerich J, Fiessinger J N. Anticardiolipin antibodies and recurrent thromboembolism.  Thromb Haemost. 1997;  77(1) 221-222
• 71 de Godoy J M, de Godoy M F, Braile D M. Recurrent thrombosis in patients with deep vein thrombosis and/or venous thromboembolism associated with anticardiolipin antibodies.  Angiology. 2006;  57(1) 79-83
• 72 Schulman S, Svenungsson E, Granqvist 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(4) 332-338
• 73 Kearon C, Ginsberg J S, Kovacs M J et al.. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.  N Engl J Med. 2003;  349(7) 631-639
• 74 Hull R, Hirsh J, Jay R et al.. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.  N Engl J Med. 1982;  307(27) 1676-1681
• 75 Crowther M A, Ginsberg J S, Julian J et al.. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome.  N Engl J Med. 2003;  349(12) 1133-1138
• 76 Finazzi G, Marchioli R, Brancaccio V et al.. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS)1.  J Thromb Haemost. 2005;  3(5) 848-853
• 77 Hutten B A, Prins M H. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism.  Cochrane Database Syst Rev. 2006;  (1) CD001367
• 78 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
• 79 De Stefano V, Rossi E, Paciaroni K, Leone G. Screening for inherited thrombophilia: indications and therapeutic implications.  Haematologica. 2002;  87(10) 1095-1108
• 80 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
• 81 Middeldorp S, Meinardi J R, Koopman M M et al.. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism.  Ann Intern Med. 2001;  135(5) 322-327
• 82 Marchetti M, Quaglini S, Barosi G. Cost-effectiveness of screening and extended anticoagulation for carriers of both factor V Leiden and prothrombin G20210A.  QJM. 2001;  94(7) 365-372
• 83 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(11) 1-110
• 84 Korlaar I M, Vossen C Y, Rosendaal F R et al.. Attitudes toward genetic testing for thrombophilia in asymptomatic members of a large family with heritable protein C deficiency.  J Thromb Haemost. 2005;  3(11) 2437-2444
• 85 Legnani C, Razzaboni E, Gremigni P, Ricci Bitti P E, Favaretto E, Palareti G. Psychological impact of testing for thrombophilic alterations.  Thromb Haemost. 2006;  96(3) 348-355
• 86 Bank I, Scavenius M P, Büller H R, Middeldorp S. Social aspects of genetic testing for factor V Leiden mutation in healthy individuals and their importance for daily practice.  Thromb Res. 2004;  113(1) 7-12
• 87 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
• 88 Bucciarelli P, Rosendaal F R, Tripodi A et al.. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.  Arterioscler Thromb Vasc Biol. 1999;  19(4) 1026-1033
• 89 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
• 90 Faioni E M, Franchi F, Bucciarelli P et al.. Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden).  Blood. 1999;  94(9) 3062-3066
• 91 Tormene D, Fortuna S, Tognin G et al.. The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study.  J Thromb Haemost. 2005;  3(7) 1414-1420
• 92 Heit J A, Sobell J L, Li H, Sommer S S. The incidence of venous thromboembolism among factor V Leiden carriers: a community-based cohort study.  J Thromb Haemost. 2005;  3(2) 305-311
• 93 Simioni P, Tormene D, Prandoni P et al.. Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study.  Blood. 2002;  99(6) 1938-1942
• 94 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
• 95 Bank I, Libourel E J, Middeldorp S et al.. Prothrombin 20210A mutation: a mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study.  Arch Intern Med. 2004;  164(17) 1932-1937
• 96 Coppens M, Van de Poel M H, Bank I et al.. A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation.  Blood. 2006;  108(8) 2604-2607
• 97 Bank I, Libourel E J, Middeldorp S et al.. Elevated levels of FVIII:C within families are associated with an increased risk for venous and arterial thrombosis.  J Thromb Haemost. 2005;  3(1) 79-84
• 98 Van de Poel M H, Coppens M, Middeldorp S et al.. Absolute risk of venous and arterial thromboembolism associated with mild hyperhomocysteinemia. Results from a retrospective family cohort study.  J Thromb Haemost. 2005;  3(suppl 1) P0481