Thrombophilia: An Update

This issue of Seminars in Thrombosis and Hemostasis is dedicated to inherited thrombophilia. The various clinical manifestations and implications for testing are discussed in different articles. Furthermore, animal models that are being used to study thrombophilia are discussed. Thrombophilia is defined as a disorder associated with an increased tendency to venous thromboembolism (VTE).[1] Thrombophilia can be acquired (such as in patients with cancer) or congenital, in which case a defect in the coagulation system is inherited. The term thrombophilia was introduced as a MeSH (Medical Subject Headings) term in 1998, and using this as a search term in the PubMed database at present yields more than 16,500 publications, of which the vast majority is related to inherited forms of this condition. This introduction provides a short overview of thrombophilia, with an emphasis on topics that will not be covered in the reviews in this issue.

The first case of inherited thrombophilia was described in 1965 by Egeberg[2] in a publication on a Norwegian family with a remarkable tendency to develop venous thrombosis, which was shown to be due to a deficiency of the physiologic anticoagulant antithrombin. Since then, various forms of inherited thrombophilia have been identified and in a large number of clinical studies, the relative and absolute risk for VTE of each of these thrombophilic conditions has been studied.

It is important to emphasize that thrombophilia is diagnosed on clinical grounds.[1] [3] Major criteria are listed in Table [1]. The most common features are recurrent VTE, a family history of thrombosis, thrombosis at an unusual location, and thrombosis at young age, but it should be realized that the majority of patients with thrombophilia will have their first manifestation of thrombosis at a later age. In most patients with inherited thrombophilia, the tendency to VTE is mild to moderate and can be controlled easily with antithrombotic agents. Defects leading to inherited thrombophilia may also cause clinical manifestations other than thrombosis, such as skin necrosis in patients with a protein C deficiency who are treated with vitamin K antagonists, or neonatal purpura fulminans in homozygous protein C deficiency (Fig. [1]). In addition, many thrombophilic disorders are associated with an increased risk of pregnancy loss, preeclampsia, and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome of pregnancy.

Table 1 Most Common Features of Thrombophilia Recurrent venous thromboembolism Thrombosis in an unusual site (cerebral sinuses, mesenteric, portal) Venous thromboembolism at a young age Family history of venous thromboembolism Recurrent fetal loss Preeclampsia, HELLP syndrome HELLP, hemolysis, elevated liver enzymes, and low platelets.

Figure 1 Purpura fulminans in a baby with homozygous protein C deficiency.

REFERENCES

• 1 Levi M, Middeldorp S. Inherited thrombophilia. In: Young NS, Gerson SL, High KA Clinical Hematology. Philadelphia, PA; Elsevier 2006: 867-878
• 2 Egeberg O. Inherited antithrombin III deficiency causing thrombophilia.  Thromb Diath Haemorrh. 1965;  13 516-530
• 3 Middeldorp S, Buller H R, Prins M H, Hirsh J. Approach to the thrombophilic patient. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia, PA; Lippincott Williams & Wilkins 2001: 1085-1100
• 4 Halbmayer W M, Mannhalter C, Feichtinger C, Rubi K, Fischer M. The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thromboembolism.  Thromb Haemost. 1992;  68(3) 285-290
• 5 Koster T, Rosendaal F R, Briet E, Vandenbroucke J P. John Hagemann's factor and deep-vein thrombosis: Leiden Thrombophilia Study.  Br J Haematol. 1994;  87(2) 422-424
• 6 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
• 7 Ohlin A K, Marlar R A. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease.  Blood. 1995;  85(2) 330-336
• 8 Heit J A, Petterson T M, Owen W G, Burke J P, DE Andrade M, Melton III L J. Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: a population-based case-control study.  J Thromb Haemost. 2005;  3(4) 710-717
• 9 Sugiyama S, Hirota H, Kimura R et al.. Haplotype of thrombomodulin gene associated with plasma thrombomodulin level and deep vein thrombosis in the Japanese population.  Thromb Res. 2007;  119(1) 35-43
• 10 Dahlback 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
• 11 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(6475) 64-67
• 12 Voorberg J, Roelse J, Koopman R et al.. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V.  Lancet. 1994;  343(8912) 1535-1536
• 13 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
• 14 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
• 15 Ray J G, Shmorgun D, Chan W S. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: meta-analysis of 31 studies.  Pathophysiol Haemost Thromb. 2002;  32(2) 51-58
• 16 Miletich J, Sherman L, Broze Jr G. Absence of thrombosis in subjects with heterozygous protein C deficiency.  N Engl J Med. 1987;  317(16) 991-996
• 17 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
• 18 Tait R C, Walker I D, Reitsma P H et al.. Prevalence of protein C deficiency in the healthy population.  Thromb Haemost. 1995;  73(1) 87-93
• 19 Rees D C, Cox M, Clegg J B. World distribution of factor V Leiden.  Lancet. 1995;  346(8983) 1133-1134
• 20 Ridker P M, Miletich J P, Hennekens C H, Buring J E. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening.  JAMA. 1997;  277(16) 1305-1307
• 21 Dilley A, Austin H, Hooper W C et al.. Prevalence of the prothrombin 20210 G-to-A variant in blacks: infants, patients with venous thrombosis, patients with myocardial infarction, and control subjects.  J Lab Clin Med. 1998;  132(6) 452-455
• 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 Bauer K A, Weiss L M, Sparrow D, Vokonas P S, Rosenberg R D. Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative Aging Study.  J Clin Invest. 1987;  80(6) 1527-1534
• 24 Boisclair M D, Lane D A, Wilde J T, Ireland H, Preston F E, Ofosu F A. A comparative evaluation of assays for markers of activated coagulation and/or fibrinolysis: thrombin-antithrombin complex, D-dimer and fibrinogen/fibrin fragment E antigen.  Br J Haematol. 1990;  74(4) 471-479
• 25 Dewerchin M, Herault J P, Wallays G et al.. Life-threatening thrombosis in mice with targeted Arg48-to-Cys mutation of the heparin-binding domain of antithrombin.  Circ Res. 2003;  93(11) 1120-1126
• 26 Levi M, Dorffler-Melly J, Reitsma P et al.. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice.  Blood. 2003;  101(12) 4823-4827
• 27 Sanson B J, Simioni P, Prins M H. on behalf of the TACT-study group. The incidence of venous thromboembolism in asymptomatic carriers of a marker of thrombophilia.  Blood. 1999;  94 3702-3706
• 28 Middeldorp S, Henkens C MA, Koopman M MW 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
• 29 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
• 30 Friederich P W, Sanson B J, Simioni P et al.. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis.  Ann Intern Med. 1996;  125 955-960
• 31 Pabinger I, Kyrle P A, Heistinger M et al.. The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study.  Thromb Haemost. 1994;  71(4) 441-445
• 32 Middeldorp S, Meinardi J R, Koopman M MW 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
• 33 Coppens M, van der 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 2604-2607
• 34 Rosendaal F R. Venous thrombosis: a multicausal disease.  Lancet. 1999;  353 1167-1173
• 35 Boekholdt S M, Bijsterveld N R, Moons A H, Levi M, Buller H R, Peters R J. Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review.  Circulation. 2001;  104 3063-3068
• 36 Kim R J, Becker R C. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies.  Am Heart J. 2003;  146 948-957
• 37 Sanson B J, Friederich P W, Simioni P et al.. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women.  Thromb Haemost. 1996;  75(3) 387-388
• 38 Preston F E, Rosendaal F R, Walker I D et al.. Increased fetal loss in women with heritable thrombophilia.  Lancet. 1996;  348 913-916
• 39 Meinardi J R, Middeldorp S, de Kam P J et al.. Increased risk for fetal loss in carriers of the factor V Leiden mutation.  Ann Intern Med. 1999;  130(9) 736-739
• 40 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis.  Lancet. 2003;  361 901-908
• 41 Dizon-Townson D S, Nelson L M, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia.  Am J Obstet Gynecol. 1996;  175(4 Pt 1) 902-905
• 42 van Pampus M G, Dekker G A, Wolf H et al.. High prevalence of haemostatic abnormalities in women with severe pre-eclampsia.  Am J Obstet Gynecol. 1999;  180 1146-1150
• 43 Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review.  Eur J Obstet Gynecol Reprod Biol. 2002;  101 6-14
• 44 Middeldorp S. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications-No.  J Thromb Haemost. 2003;  1 2073-2074
• 45 Middeldorp S. Low-molecular-weight heparin to prevent pre-eclampsia: there is no evidence and potential harm.  Neth J Med. 2004;  62(3) 69-70
• 46 Brenner B. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications-Yes.  J Thromb Haemost. 2003;  1(10) 2070-2072
• 47 Di Nisio M, Peters L W, Middeldorp S. Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome.  Cochrane Database Syst Rev. 2005;  (2) , CD004734
• 48 Branson H E, Katz J, Marble R, Griffin J H. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant.  Lancet. 1983;  2 1165-1168
• 49 Broekmans A W, Bertina R M, Loeliger E A, Hofmann V, Klingemann H G. Protein C and the development of skin necrosis during anticoagulant therapy.  Thromb Haemost. 1983;  49 251
• 50 Vink R, Kraaijenhagen R A, Levi M, Buller H R. Individualised duration of oral anticoagulant therapy for deep vein thrombosis based on a decision model.  J Thromb Haemost. 2003;  1(12) 2523-2530
• 51 Cohn D M, Roshani S, Middeldorp S. Thrombophilia and venous thromboembolism: implications for testing.  Semin Thromb Hemost. 2007;  33 573-581
• 52 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
• 53 Greengard J S, Eichinger S, Griffin J H, Bauer K A. Brief report: variability of thrombosis among homozygous siblings with resistance to activated protein C due to an Arg- > Gln mutation in the gene for factor V.  N Engl J Med. 1994;  331(23) 1559-1562
• 54 Emmerich J, Alhenc-Gelas M, Aillaud M F et al.. Clinical features in 36 patients homozygous for the ARG 506- > GLN factor V mutation.  Thromb Haemost. 1997;  77(4) 620-623
• 55 Meinardi J R, Pelsma P, Koning H et al.. Double-homozygosity for factor V Leiden and the prothrombin gene 20210A variant in a young patient with idiopathic venous thrombosis.  Blood. 1999;  94 1828-1829
• 56 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(4) 1031-1035
• 57 Koeleman B P, van Rumpt D, Hamulyak K, Reitsma P H, Bertina R M. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families?.  Thromb Haemost. 1995;  74(2) 580-583
• 58 Zoller B, Berntsdotter A, Garcia de Frutos P, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S.  Blood. 1995;  85(12) 3518-3523
• 59 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.  Blood Coagul Fibrinolysis. 2001;  12(8) 713-720
• 60 Meinardi J R, Middeldorp S, de Kam P J et al.. The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders.  Br J Haematol. 2002;  116(3) 625-631
• 61 Libourel E J, Bank I, Meinardi J R et al.. Co-segregation of thrombophilic disorders in factor V Leiden carriers; the contributions of factor VIII, factor XI, thrombin activatable fibrinolysis inhibitor and lipoprotein(a) to the absolute risk of venous thromboembolism.  Haematologica. 2002;  87 1068-1073
• 62 Anonymous. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.  Lancet. 1995;  346(8990) 1575-1582
• 63 Daly E, Vessey M P, Painter R, Hawkins M M. Case-control study of venous thromboembolism risk in users of hormone replacement therapy.  Lancet. 1996;  348(9033) 1027
• 64 Jick H, Derby L E, Myers M W, Vasilakis C, Newton K M. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens.  Lancet. 1996;  348(9033) 981-983
• 65 Kemmeren J M, Algra A, Grobbee D E. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis.  BMJ. 2001;  323 131-134
• 66 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(8935) 1453-1457
• 67 Bloemenkamp K WM, Rosendaal F R, Helmerhorst F M, Buller H R, Vandenbroucke J P. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen.  Lancet. 1995;  346(8990) 1593-1596
• 68 Kierkegaard A. Incidence and diagnosis of deep vein thrombosis associated with pregnancy.  Acta Obstet Gynecol Scand. 1983;  62(3) 239-243
• 69 Greer I A. Thrombosis in pregnancy: maternal and fetal issues.  Lancet. 1999;  353(9160) 1258-1265
• 70 Conard J, Horellou M H, van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women.  Thromb Haemost. 1990;  63(2) 319-320
• 71 De Stefano V, Leone G, Mastrangelo S et al.. Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C, protein S.  Thromb Haemost. 1994;  71(6) 799-800
• 72 Simioni P, Sanson B J, Prandoni P et al.. The incidence of venous thromboembolism in families with inherited thrombophilia.  Thromb Haemost. 1999;  81(2) 198-202
• 73 Middeldorp S, Libourel E J, Hamulyak K, van der M J, Buller H R. The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden.  Br J Haematol. 2001;  113(2) 553-555
• 74 Kearon C. Natural history of venous thromboembolism.  Circulation. 2003;  107(23suppl 1) I22-I30
• 75 Prandoni P, Lensing A W, Cogo A et al.. The long-term clinical course of acute deep venous thrombosis.  Ann Intern Med. 1996;  125(1) 1-7
• 76 Van Dongen C JJ, Vink R, Hutten B A, Buller 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 1285-1293
• 77 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
• 78 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
• 79 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
• 80 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
• 81 Kraaijenhagen R A, in 't Anker P S, Koopman M MW, Reitsma P H, Prins M H, Buller H R. High plasma concentration of factor VIIIc: a major risk factor for venous thromboembolism.  Thromb Haemost. 2000;  83(1) 5-9
• 82 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
• 83 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
• 84 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(3 suppl) 338S-400S
• 85 Nurmohamed M T, Rosendaal F R, Buller H R et al.. Low molecular weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis.  Lancet. 1992;  340 152-156
• 86 Warkentin T E, Levine M N, Hirsh J 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
• 87 Bates S M, Greer I A, Hirsh J, Ginsberg J S. Use of antithrombotic agents during pregnancy. The seventh ACCP conference on antithrombotic and thrombolytic therapy.  Chest. 2004;  126(suppl) 627S-644S
• 88 Sanson B J, Lensing A WA, Prins M H et al.. Safety of low-molecular-weight heparin in pregnancy: a systematic review.  Thromb Haemost. 1999;  81 668-672
• 89 Pabinger I, Grafenhofer H, Kaider A et al.. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis.  J Thromb Haemost. 2005;  3(5) 949-954
• 90 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
• 91 Koster T, Small R A, Rosendaal F R, Helmerhorst F M. Oral contraceptives and venous thromboembolism: a quantitative discussion of the uncertainties.  J Intern Med. 1995;  238(1) 31-37
• 92 Anonymous. Cardiovascular disease and use of oral and injectable progestagen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.  Contraception. 1998;  57(5) 315-324
• 93 Gladson C L, Scharrer I, Hach V, Beck K H, Griffin J H. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis.  Thromb Haemost. 1988;  59(1) 18-22
• 94 Ben-Tal O, Zivelin A, Seligsohn U. The relative frequency of hereditary thrombotic disorders among 107 patients with thrombophilia in Israel.  Thromb Haemost. 1989;  61(1) 50-54
• 95 Schattner A, Kasher I, Berrebi A. Causes and outcome of deep-vein thrombosis in otherwise-healthy patients under 50 years.  QJM. 1997;  90(4) 283-287
• 96 O'Donnell J, Tuddenham E G, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction.  Thromb Haemost. 1997;  77(5) 825-828
• 97 Heijboer H, Brandjes D P, Buller 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
• 98 Pabinger I, Brucker 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
• 99 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
• 100 Koster T, Rosendaal F R, de Ronde H, Briet E, Vandenbroucke J P, Bertina R M. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study.  Lancet. 1993;  342(8886-8887) 1503-1506
• 101 Cumming A M, Keeney S, Salden A, Bhavnani M, Shwe K H, Hay C R. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population.  Br J Haematol. 1997;  98(2) 353-355
• 102 Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3′-untranslated region of the prothrombin gene.  Br J Haematol. 1997;  98 907-909