Inherited Thrombophilia and Venous Thromboembolism

ABSTRACT

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.

Inherited thrombophilia - genetic defects - acquired risk factors - recurrent venous thromboembolism (VTE) - laboratory screening - prophylaxis of VTE

REFERENCES

• 1 Egeberg O. Inherited antithrombin deficiency causing thrombophilia.  Thromb Diath Haemorrh. 1965;  13 516-530
• 2 Prandoni P, Bilora F, Marchiori A et al.. An association between atherosclerosis and venous thrombosis.  N Engl J Med. 2003;  348 1435-1441
• 3 Koeleman B P, Reitsma P H, Allaart C F, Bertina R M. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families.  Blood. 1994;  84 1031-1035
• 4 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;  75 417-421
• 5 Zoller B, Berntsdotter A, Garcia de Frutos P, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S.  Blood. 1995;  85 3518-3523
• 6 Ridker P M, Miletich J P, Stampfer M J, Goldhaber S Z, Lindpaintner K, Hennekens C H. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism.  Circulation. 1995;  92 2800-2802
• 7 Simioni P, Prandoni P, Lensing A W 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 Engl J Med. 1997;  336 399-403
• 8 Simioni P, Prandoni P, Lensing A W et al.. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis.  Blood. 2000;  96 3329-3333
• 9 Miles J S, Miletich J P, Goldhaber S Z, Hennekens C H, Ridker P M. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism.  J Am Coll Cardiol. 2001;  37 215-218
• 10 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;  341 801-806
• 11 Eichinger S, Pabinger I, Stumpflen A et al.. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden.  Thromb Haemost. 1997;  77 624-628
• 12 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
• 13 Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. 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
• 14 Kearon C, Gent M, Hirsh J et al.. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.  N Engl J Med. 1999;  340 901-907
• 15 Margaglione M, D'Andrea G, Colaiazzo D et al.. Coexistence of factor V Leiden and factor II A20210 mutations and recurrent venous thromboembolism.  Thromb Haemost. 1999;  82 1583-1587
• 16 De Stefano V, Martinelli I, Mannucci P M et al.. The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation.  Br J Haematol. 2001;  113 630-635
• 17 Simioni P. Risk of recurrent venous thromboembolism and thrombophilia: does discrepancy make complexity or vice versa?.  J Thromb Haemost. 2003;  1 16-18
• 18 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 2352-2361
• 19 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;  362 523-526
• 20 Simioni P, Sanson B J, Prandoni P et al.. Incidence of venous thromboembolism in families with inherited thrombophilia.  Thromb Haemost. 1999;  81 198-202
• 21 Lane D A, Olds R J, Boisclair M et al.. Antithrombin III mutation database: first update.  Thromb Haemost. 1993;  70 361-369
• 22 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 2353-2358
• 23 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 1094 (letter)
• 24 Vasse M, Borg J Y, Monconduit M. Protein C: Rouen, a new hereditary protein C abnormality with low anticoagulant but normal amidolytic activities.  Thromb Res. 1989;  56 387-398
• 25 Mimuro J, Muramatsu S, Kaneko M et al.. An abnormal protein C (protein C Yonago) with an amino acid substitution of Gly for Arg-15 caused by a single base mutation of C to G in codon 57 (CGG→GGG). Deteriorated calcium-dependent conformation of the gamma-carboxyglutamic acid domain relevant to a thrombotic tendency.  Int J Hematol. 1993;  57 9-14
• 26 Girolami A, Simioni P, Girolami B et al.. A novel dysfunctional protein C (protein C Padua 2) associated with a thrombotic tendency: substitution of Cys for Arg-1 results in a strongly reduced affinity for binding of Ca ++ .  Br J Haematol. 1993;  85 521-527
• 27 Gandrille S, Alhenc-Gelas M, Gaussem P et al.. Five novel mutations located in exons III and IX of the protein C gene in patients presenting with defective protein C anticoagulant activity.  Blood. 1993;  82 159-168
• 28 Wojcik E G, Simioni P, van den Berg M, Girolami A, Bertina R M. Mutations which introduce free cysteine residues in the Gla-domain of vitamin K dependent proteins result in the formation of complexes with alpha 1-microglobulin.  Thromb Haemost. 1996;  75 70-75
• 29 Comp P C, Esmon C T. Recurrent venous thromboembolism in patients with a partial deficiency of protein S.  N Engl J Med. 1984;  311 1525-1528
• 30 Schwarz H P, Fischer M, Hopmeier P, Batard M A, Griffin J H. Plasma protein S deficiency in familial thrombotic disease.  Blood. 1984;  64 1297-1300
• 31 Gandrille S, Borgel D, Ireland H et al.. Protein S deficiency: a database of mutations. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.  Thromb Haemost. 1997;  77 1201-1214
• 32 Faioni E M, Boyer-Neumann C, Franchi F, Wolf M, Meyer D, Mannucci P M. Another protein S functional assay is sensitive to resistance to activated protein C.  Thromb Haemost. 1994;  72 648 (letter)
• 33 Simioni P, Gavasso S, Luni S, Invidiato S, Girolami A. A protein S functional assay yields unsatisfactory results in patients with activated protein C resistance.  Blood Coagul Fibrinolysis. 1995;  6 286-287
• 34 Faioni E M, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci P M. Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay.  Thromb Haemost. 1993;  70 1067-1071
• 35 Rees D C, Cox M, Clegg J B. World distribution of factor V Leiden.  Lancet. 1995;  346 1133-1134
• 36 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden.  Blood. 1995;  85 1504-1508
• 37 Bertina R M, Koeleman B P, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 64-67
• 38 Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C.  Blood. 1998;  91 1140-1144
• 39 Simioni P, Kalafatis M, Manfrin D, Tormene D, Girolami A. Factor V variants, activated protein C resistance and venous thromboembolism.  Blood Coagul Fibrinolysis. 1998;  9 661-662
• 40 Bernardi F, Faioni E M, Castoldi E et al.. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype.  Blood. 1997;  90 1552-1557
• 41 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 1135-1139
• 42 de Visser M C, Rosendaal F R, Bertina R M. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis.  Blood. 1999;  93 1271-1276
• 43 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 3698-3703
• 44 Makris M, Preston F E, Beauchamp N J et al.. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia.  Thromb Haemost. 1997;  78 1426-1429
• 45 Rosendaal F R, Doggen C J, Zivelin A et al.. Geographic distribution of the 20210 G to A prothrombin variant.  Thromb Haemost. 1998;  79 706-708
• 46 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis.  Thromb Haemost. 1999;  81 165-176
• 47 Guba S C, Fonseca V, Fink L M. Hyperhomocysteinemia and thrombosis.  Semin Thromb Hemost. 1999;  25 291-309
• 48 Koster T, Blann A D, Briet 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;  345 152-155
• 49 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 79-84
• 50 van der Meer F J, Koster T, Vandenbroucke J P, Briet E, Rosendaal F R. The Leiden Thrombophilia Study (LETS).  Thromb Haemost. 1997;  78 631-635
• 51 Cushman M, Tsai A W, White R H et al.. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.  Am J Med. 2004;  117 19-25
• 52 Tsai A W, Cushman M, Rosamond W D et al.. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE).  Am J Med. 2002;  113 636-642
• 53 Vandenbroucke J P, Koster T, Briet E, Reitsma P H, Bertina R M, Rosendaal F R. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.  Lancet. 1994;  344 1453-1457
• 54 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 1414-1420
• 55 van't Veer C, Golden N J, Kalafatis M, Simioni P, Bertina R M, Mann K G. An in vitro analysis of the combination of hemophilia A and factor V (Leiden).  Blood. 1997;  90 3067-3072
• 56 van Dijk K, van der Bom J G, Fischer K, Grobbee D E, van den Berg H M. Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature.  Thromb Haemost. 2004;  92 305-310
• 57 Dargaud Y, Meunier S, Negrier C. Haemophilia and thrombophilia: an unexpected association!.  Haemophilia. 2004;  10 319-326
• 58 Simioni P, Castoldi E, Lunghi B, Tormene D, Rosing J, Bernardi F. An underestimated combination of opposites resulting in enhanced thrombotic tendency.  Blood. 2005;  106 2363-2365
• 59 Geerts W H, Pineo G F, Heit J A et al.. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 338S-400S
• 60 Büller 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
• 61 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 3702-3706
• 62 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;  160 761-768
• 63 Kyrle P A, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of recurrent venous thromboembolism in men and women.  N Engl J Med. 2004;  350 2558-2563
• 64 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;  137 955-960
• 65 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
• 66 Tormene D, Simioni P, Prandoni P et al.. The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study.  Blood. 2002;  100 2403-2405
• 67 Tripodi A. A review of the clinical and diagnostic utility of laboratory tests for the detection of congenital thrombophilia.  Semin Thromb Hemost. 2005;  31 25-32
• 68 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
• 69 Sere K M, Rosing J, Hackeng T M. Inhibition of thrombin generation by protein S at low procoagulant stimuli: implications for maintenance of the hemostatic balance.  Blood. 2004;  104 3624-3630
• 70 Curvers J, Thomassen M C, Rimmer J et al.. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test.  Thromb Haemost. 2002;  88 5-11
• 71 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;  135 322-327
• 72 Simioni P, Prandoni P, Girolami A. Low rate of venous thromboembolism in asymptomatic relatives of probands with factor V Leiden mutation.  Ann Intern Med. 1999;  130 538 (letter)
• 73 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;  72 352-358
• 74 Tormene D, Simioni P, Pagnan A, Prandoni P. The G20210A prothrombin gene mutation: is there room for screening families?.  J Thromb Haemost. 2004;  2 1487-1488