Genetic Approach to Thrombophilia

Summary

Venous thrombosis is a multifactorial disease. Multiple interactions between genetic and environmental factors contribute to the development of the disease. Presently, we know of six or seven genetic risk factors for venous thrombosis. However, together these defects can explain the clustering of thrombotic events in only a small subset of families with thrombophilia. As to the identification of new genetic risk factors for thrombosis, we seem to have arrived at the end of a practicable road with the classical approach of thrombophilia, which usually starts with the study of the association of hemostatic phenotypes and thrombotic risk. At the same time we have undertaken various genetic approaches aiming at identifying polymorphisms/ mutations causing thrombotic risk. This review summarizes what we have learnt so far, what to do and what not to do. The odds for finding remaining common genetic risk factors for venous thrombosis during the next ten years may be predicted to be fairly high.

Key words

Thrombophilia - venous thrombosis - genetic risk factors - polymorphisms

• References

• 1 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V. et al. Inherited thrombophilia: part I. Thromb Heamost 1996; 76: 651-2.
• 2 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-73.
• 3 Bertina RM. Molecular risk factors for thrombosis. Thromb Haemost 1999; 82: 601-9.
• 4 Heyboer H, Brandjes DPM, Büller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990; 323: 1512-6.
• 5 Egeberg O. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-30.
• 6 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic desease. J Clin Invest 1981; 68: 1370-3.
• 7 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-8.
• 8 Egeberg O. Inherited fibrinogen abnormality causing thrombophilia. Thromb Diathes Haemorrh 1967; 17: 176-87.
• 9 Dahlbäck B, Carlsson M, Svensson PJ. 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 USA 1993; 90: 1004-8.
• 10 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 11 Jick H, Slone D, Westerholm B. Venous thromboembolic disease and ABO blood type. Lancet 1969; i: 539-42.
• 12 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. 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: 3698-703.
• 13 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell 1993; 72: 477-80.
• 14 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families. Blood 1994; 84: 1031-5.
• 15 Zöller 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: 3518-23.
• 16 van Boven HH, Reitsma PH, Rosendaal FR, Bayston TA, Chowdhury V, Bauer KA. et al. Factor V Leiden (F V R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75: 417-21.
• 17 Koeleman BPC, van Rumpt D, Hamulyák K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families. Thromb Haemost 1995; 74: 580-3.
• 18 Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78: 297-301.
• 19 Koeleman BPC, Reitsma PH, Bertina RM. Familial thrombophilia: a complex genetic disorder. Sem Hematol 1997; 34: 256-64.
• 20 Bertina RM. Prevalence of heriditary thrombophilia and the identification of genetic risk factors. Fibrinolysis 1988; 2 S2 7-13.
• 21 Thaler E, Lechner K. Antitrombin III deficiency and thromboembolism. Clin Haematol 1981; 10: 369-90.
• 22 Van Boven HH, Lane DA. Antithrombin and its inherited deficiency states. Sem Hematol 1997; 34: 188-204.
• 23 Broekmans AW, Conard J. Hereditary protein C deficiency. In: Bertina RM. ed. Protein C and Related Proteins. Edinburgh: Churchill Livingstone; 1998: 160-81.
• 24 Reitsma PH, Poort SR, Allaart CF, Briët E, Bertina RM. The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects. Blood 1991; 890-4.
• 25 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briët E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-8.
• 26 Engesser L, Broekmans AW, Briët E, Brommer EJ, Bertina RM. Hereditary protein S deficiency: clinical manifestations. Ann Intern Med 1987; 106: 677-82.
• 27 Reitsma PH, Ploos van Amstel HK, Bertina RM. Three novel mutations in five unrelated subjects with hereditary protein S deficiency type I. J Clin Invest 1994; 93: 486-92.
• 28 Bernardi F, Faioni EM, Castoldi E, Lunghi B, Castaman G, Sacchi E. et al. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997; 90: 1552-7.
• 29 Le W, Yu JD, Lu L, Tao R, You B, Cai X. et al. Association of the R 455 K polymorphism of the factor V gene with poor response to activated protein C and increased risk of coronary artery disease in the Chinese population. Clin Genet 2000; 57: 296-303.
• 30 De Visser MHC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden, increases the risk of venous thrombosis. Blood 1999; 93: 1271-6.
• 31 den Heyer M, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH. et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Eng J Med 1996; 334: 759-62.
• 32 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effects of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
• 33 Meijers JCM, Tekelenburg WLH, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696-701.
• 34 van Hylckama Vlieg A, van der Linden IK, Bertina RM, Rosendaal FR. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95: 3678-82.
• 35 Van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-9.
• 36 Holzman NA, Marteau TM. Will genetics revolutionize Medicine. N Engl J Med 2000; 343: 141-4.
• 37 Schulman S. Duration of anticoagulants in acute or recurrent venous thromboembolism. Curr Opin Pulm Med 2000; 6: 321-5.
• 38 van den Belt AGM, Hutten BA, Prins MH, Bossny PMM. Duration of oral anticoagulant treatment in patients with venous thromboembolism and a deficiency of antithrombin, protein C or protein S – A decision analysis. Thromb Haemost 2000; 84: 758-63.
• 39 De Moerloose P, Bounameaux HR, Mannucci PM. Screening tests for thrombophilic patients. Which test for which patient, by whom, when and why? Sem Thromb Haemost 1998; 24: 321-6.
• 40 Rettie AE, Wienkers LC, Gonzales FJ, Trager WF, Korzekwa KR. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 4: 39-42.
• 41 Steward DJ, Haining RL, Henne KR, Davids G, Rushmore TH, Trager WF. et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997; 7: 361-7.
• 42 Aithal GP, Day CP, Kesteven PJL, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and riks of bleeding complications. Lancet 1998; 353: 717-9.
• 43 Chu K, Sheue-Mei W, Stanley T, Stafford DW, High KA. A mutation in the propeptide of factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 1996; 98: 1619-25.
• 44 Oldenburg J, Quenzel EM, Harbrecht K, Fregin A, Kress W, Muller CR. et al. Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haemat 1997; 98: 240-4.
• 45 Zöller B, Svensson PH, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-4.
• 46 Lane DA, Olds RJ, Boisclair M, Chowdhury V, Thein SL, Cooper DN. et al. Antithrombin mutation database: first update. Thromb Haemost 1993; 70: 361-9.
• 47 Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H. et al. Protein C deficiency a database of mutations, 1995 update. Thromb Haemost 1995; 73: 876-89.
• 48 Gandrille S, Borgel D, Sala N, Espinosa-Parilla Y, Simmonds R, Rezende S. et al. Protein S deficiency: a database of mutations – summary of the first update. Thromb Haemost 2000; 84: 918.
• 49 Zöller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343: 1536-8.
• 50 Lensen RPM, Rosendaal FR, Koster T, Allaart CF, de Ronde H, Vandenbroucke JP. et al. Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection in patients. Blood 1996; 88: 4205-8.
• 51 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK. 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: 1426-9.
• 52 de Stefano V, Martinelli I, Mannucci PM, Paciaroni K, Chiusolo P, Casorelli I. 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: 801-6.
• 53 Miletich J, Sherman L, Broze Jr G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-6.
• 54 Tait RC, Walker ID, Reitsma PH, Islam SIAM, McCall F, Poort SR. et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 87-93.
• 55 Brenner B, Zivelin A, Lanir N, Greengard JS, Griffin JH, Seligsohn U. Venous thromboembolism associated wth double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis. Blood 1996; 88: 877-80.
• 56 Bertina RM. The prothrombin 20210 G to A variation and thrombosis. Curr Op Hematol 1998; 5: 339-42.
• 57 Bovill EG, Hasstedt SJ, Callas PW, Valliere JE, Scott BT, Bauer KA. et al. The G20210A prothrombin polymorphism is not associated with increased thromboembolic risk in a large protein C deficient kindred. Thomb Haemost 2000; 83: 366-70.
• 58 Bertina RM. Protein C deficiency and venous thrombosis – the search for the second genetic defect. Thromb Haemost 2000; 83: 360-1.
• 59 Faioni EM, Franchi F, Bucciarelli P, Margaglione M, de Stefano V, Castaman G. 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. Blood 1999; 94: 3062-6.
• 60 Greengard JS, Alhenc-Gelas M, Gandrille S, Emmerich J, Aiach M, Griffin JH. Pseudo-homozygous activated protein C resistance due to coinheritance of heterozygous factor V-R506Q and type I factor V deficiency associated with thrombosis. Thromb Haemost 1995; 73: 1361.
• 61 Simioni P, Scudeller A, Radossi P, Gavasso S, Girolami B, Tormene D. et al. “Pseudohomozygous” activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kinreds. Thromb Haemost 1996; 75: 422-6.
• 62 Zehnder JL, Jain M. Recurrent thrombosis due to compound heterozygosity for factor V Leiden and factor V deficiency. Blood Coag Fibrinol 1996; 7: 361-2.
• 63 Guasch JF, Lensen RPM, Bertina RM. Molecular characterization of a type I quantitative factor V deficiency in a thrombosis patient that is “Pseudo homozygous” for activated protein C resistance. Thromb Haemost 1997; 77: 252-7.
• 64 Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genetics 1999; 22: 231-8.
• 65 Cambien F, Poirier O, Nicaud V, Herrmann SM, Mallet C, Ricard S. et al. Sequence diversity in 36 candadate genes for cardiovascular disorders. Am J Hum Genet 1999; 65: 183-91.
• 66 Gambaro G, Anglani F, D’Angelo A. Association studies of genetic polymorphisms and complex disease. Lancet 2000; 355: 308-11.
• 67 Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994; 265: 2037-45.
• 68 Risch N. Searching for genes in complex diseases: lessons from systemic lupus erythematosus. J Clin Invest 2000; 105: 1503-6.
• 69 Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996; 273: 1516-7.
• 70 Öhlin AK, Marlar RA. The first mutation identified in the thrombomodulin gene in a 45-year old man presenting with thromboembolic disease. Blood 1995; 85: 330-6.
• 71 Öhlin AK, Marlar RA. Thrombomodulin gene defects in families with thromboembolic disease – a report on four families. Thromb Haemost 1999; 81: 338-44.
• 72 Faioni EM, Merati G, Peyvandi F, Bettini PM, Mannucci PM. The G1456 to T mutation in the thrombomodulin gene is not frequent in patients with venous thrombosis. Blood 1997; 89: 1467.
• 73 Doggen CJ, Kunz G, Rosendaal FR, Lane DA, Vos HL, Stubbs PJ. et al. A mutation in the thrombomodulin gene, 127 G to A, coding for Ala 25 Thr and the risk of myocardial infarction in men. Thromb Haemost 1998; 743-8.
• 74 Ireland H, Kunz G, Kyriakoulis K, Stubbs PJ, Lane DA. Thrombomodulin gene mutations associated with myocardial infarction. Circulation 1997; 96: 15-8.
• 75 Girolami A, Simioni P, Scarano L, Carraro G. Prothrombin and the prothrombin 20210G to A polymorphism: their relationship with hypercoagulability and thrombosis. Blood Rev 1999; 13: 205-10.
• 76 Vicente V, Gonzalez-Conejero R, Rivera J, Corral J. The prothrombin gene variant 20210A in venous and atherial thromboembolism. Haematologica 1999; 84: 356-62.
• 77 Ridker PM, Hennekens CH, Miletich JP. G2010A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation 1999; 99: 999-1004.
• 78 Zivelin A, Rosenberg N, Faier S, Kornbrot N, Peretz H, Mannhalter C. et al. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood 1998; 92: 119-24.
• 79 Ceelie H, Bertina RM, van Hylckama Vlieg A, Rosendaal FR, Vos HL. Polymorphisms in the prothrombin gene and their association with plasma prothrombin levels. Thromb Haemost. 2001 in press.
• 80 Rosendaal FR, Doggen CJM, Zivelin A, Arruda V, Aiach M, Siskovick D. et al. Geographical distribution of the prothrombin 20210A G to A prothrombin variant. Thromb Haemost 1998; 79: 706-8.
• 81 Merati G, Biguzzi E, Oganesyan N, Fetiveau R, Qu DF, Buciarelli P. et al. A 23 bp insertion in the endothelial protein C recepter (EPCR) gene in patients with myocardial infarction and deep vein thrombosis. Thromb Haemost. (Suppl Aug 1999): 507a (abstr.).
• 82 Esmon CT. The endothelial cell protein C receptor. Thromb Haemost 2000; 83: 639-43.
• 83 Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genetics 1999; 22: 139-44.
• 84 Marchetti G, Paracchini P, Paparacchini M, Ferrati M, Bernardi F. A polymorphism in the 5′ region of coagulation factor VII gene (F7) caused by an inserted decanucleotide. Hum Genet 1993; 90: 575-6.
• 85 Pollak ES, Hung HL, Godin W, Overton GC, High KA. Functional characterization of the human factor VII 5′ flanking region. J Biol Chem 1996; 271: 1736-47.
• 86 Van ’t Hooft FM, Silveira A, Tornvall P, Iliadou A, Ehrenborg E, Eriksson P. Two common functional polymorphisms in the promoter region of the coagulation factor VII gene determining plasma factor VII activity and mass concentration. Blood 1999; 93: 3432-41.
• 87 Green F, Kelleher C, Wilkes H, Temple A, Meade TW, Humphries S. A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Artherioscler Thromb 1991; 11: 540-6.
• 88 Hunault M, Arbini AA, Lopacink S, Carew JA, Bauer KA. The Arg 353 Gln polymorphism reduces the level of coagulation factor VII; in vivo and in vitro studies. Artherioscler Thromb Vasc Biol 1997; 17: 2825-9.
• 89 Pinotti M, Toso R, Girelli D, Bindini D, Ferraresi P, Papa ML. et al. Modulation of factor VII levels by intron 7 polymorphisms: population and in vitro studies. Blood 2000; 95: 3423-8.
• 90 Bernardi F, Marchetti G, Pinotti M, Archieri P, Baroncini C, Papacchini M. et al. Factor VII gene polymorphisms contribute about one third of of the factor VII level variation in plasma. Arterioscler Thromb Vasc Biol 1996; 16: 72-6.
• 91 Collins A, Lonjon C, Morton NE. Genetic epidemiology of single-nucleotide polymorphisms. Proc Natl Acad Sci USA 1999; 96: 15173-7.
• 92 Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombosis. Blood 2000; 95: 1517-32.
• 93 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81: 165-76.
• 94 Kluijtmans LA, den Heyer M, Reitsma PH, Heil SG, Blom HJ, Rosendaal FR. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost 1998; 79: 254-8.
• 95 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-8.
• 96 Martinelli I, Landi G, Merati G, Cella R, Tosetto A, Mannucci PM. Factor V gene mutation is a risk factor for cerebral vein thrombosis. Thromb Haemost 1996; 75: 393-4.
• 97 Martinelli I, Cattaneo M, Taioli E, De Stefano V, Chiusolo P, Mannucci PM. Genetic risk factors for superficial vein thrombosis. Thromb Haemost 1999; 82: 1215-7.
• 98 Amitrano L, Brancaccio V, Guardascione MA, Margaglione M, Iannaccone L, D’Andrea G, Marmo R. et al. Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis. Hepatology 2001; 31: 345-8.
• 99 Martinelli I, Cattaneo M, Pauzeri D, Mannucci PM. Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism. Thromb Haemost 1997; 77: 440-3.
• 100 Ma AD, Abrams CS. Activated protein C resistance, factor V Leiden and retinal vessel occlusion. Retina 1998; 18: 297-300.
• 101 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.
• 102 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci PM. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol 1999; 19: 700-3.
• 103 Svensson PJ, Benoni G, Fredin H, Björgell O, Nilsson P, Hedlund U. et al. Female gender and resistance to activated protein C (FV:Q506) as potential risk factors for thrombosis after elective hip arthroplasty. Thromb Haemost 1997; 78: 993-6.
• 104 Philipp CS, Dilley A, Saidi P, Evatt B, Austin H, Zawadsky J. et al. Deletion polymorphism in the angiotensin-converting enzyme gene as a thombophilic risk factor after hip arthroplasty. Thromb Haemost 1998; 80: 869-73.
• 105 Dilley A, Austin H, Hooper WC, Latty C, Ribeiro M, Wenger NK. et al. Relation of three genetic traits to venous thrombosis in a African-american population. Am J Epidemiol 1998; 147: 1-6.
• 106 Nichols WC, Amano K, Cacheris PM, Figueiredo MS, Michaelides Schwaab R. et al. Moderation of Hemophilia A phenotype by the factor V R506Q mutation. Blood 1996; 88: 1183-7.
• 107 Lee DH, Walker IR, Teitel J, Poon MC, Ritchie B, Akabutu J. et al. Effect of factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 2000; 83: 387-91.
• 108 Koeleman BPC, Reitsma PH, Bakker E, Bertina RM. Location on the human genetic linkage map of 26 genes involved in blood coagulation. Thromb Haemost 1997; 77: 873-8.
• 109 Scott BT, Bovill EG, Callas PW, Hasstedt SJ, Leppert MF, Valliere JE. et al. Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large kindred. Thromb Haemost 2001; 85: 82-7.
• 110 Souto JC, Almasy L, Borrell M, Gari M, Martinez E, Mateo J. et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101: 1546-51.
• 111 de Lange M, Snieder H, Ariens RAS, Spector TD, Grant PJ. The genetics of haemostasis: a twin study. Lancet 2001; 357: 101-5.
• 112 Kamphuisen PW, Lensen R, Houwing-Duistermaat JJ, Eikenboom JC, Harvey M, Bertina RM. et al. Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia. Br J Haematol 2000; 109: 519-22.
• 113 Kamphuisen PW, Houwing-Duistermaat JJ, van Houwelingen HC, Eikenboom JCJ, Bertina RM, Rosendaal FR. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998; 79: 323-6.
• 114 Tosetto A, Castaman G, Cappellari A, Rodeghiero F. The VITA project: heritability of resistance to activated protein C. Thromb Haemost 2000; 84: 811-4.
• 115 Soria JM, Almasy L, Souto JC, Tirado I, Borrell M, Mateo J. et al. Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis. Blood 2000; 95: 2780-5.
• 116 Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998; 62: 1198-211.
• 117 Williams JT, Van Eerdewegh P, Almasy L, Blangero J. Joint multipoint linkage. Analysis of multivariate qualitative and quantitative traints I. Likehood formulation and simulation results. Am J Hum Genet 1999; 65: 1134-47.
• 118 Souto JC, Almasy L, Muñiz-Diaz E, Soria JM, Borrell M, Bayén L. et al. Functional effects of the ABO locus polymorphism on plasma levels of von Willebrand factor, factor VIII and activated partial thromboplastin time. Artherioscler Thromb Vasc Biol 2000; 20: 2024-8.
• 119 Souto JC, Almasy L, Borrell M, Blanco-Vaca F, Mateo J, Soria JM. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: The GAIT study. Am J Hum Genet 2000; 67: 1452-9.
• 120 Bovill EG, Bauer KA, Dickermann JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712-7.
• 121 Tomczak JA, Ando RA, Sobel HG, Bovill EG, Long G. Genetic analysis of a large kindred exhibiting type I protein C deficiency and associated thrombosis. Thromb Res 1994; 74: 243-54.
• 122 Hasstedt SJ, Bovill EG, Callas PW, Long GL. An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency. Am J Hum Genet 1998; 63: 569-76.
• 123 Spielman RS, Ewens WJ. De TDT and other family based tests for linkage disequilibrium and association. Am J Hum Genet 1996; 59: 983-9.
• 124 Koeleman BPC. Genetic analysis of inherited thrombophilia. PhD Thesis. Leiden University 1997.
• 125 Guasch JF, Reitsma PH, Bertina RM. Linkage studies in familial thrombosis point to the interleukin-1 locus as a candidate susceptibility marker. Thromb Haemost. 1997 (suppl): 391-2a (abstr.).
• 126 Castaman G, Tosetto A, Capellari A, Ruggeri M, Rodeghiero F. The A20210 allele in the prothrombin gene enhances the risk of venous thrombosis in carriers of inherited protein S deficiency. Blood Coagul Fibrinol 2000; 11: 321-6.
• 127 Ehrenforth S, von Depka Prondsinski M, Aygoren-Pursun E, NowakGottl U, Scharrer I, Ganser A. Study of the prothrombin gene 20210 GA variant in FV:Q506 carriers in relationship to the presence or absence of juvenile venous thromboembolism. Arterioscler Thromb Vasc Biol 1999; 19: 276-80.
• 128 Koster T, Rosendaal FR, Briët E, Van der Meer FJM, Colly LP, Trienekens PH. 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: 2756-61.
• 129 Bertina RM. Factor V Leiden and other coagulation risk factor mutations affecting thrombotic risk. Clin Chem 1997; 43: 1678-83.
• 130 Arnaud E, Barbalat V, Nicaud V, Cambien F, Evans A, Morrison C. et al. Polymorphisms in the 5′ regulatory region of the tissue factor gene and the risk of myocardial infarction and venous thromboembolism: the ECTIM and PATHROS studies. Arterioscler Thromb Vasc Biol 2000; 20: 892-8.
• 131 Humphries SE, Lane A, Green FR, Cooper J, Miller GJ. Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration. Arterioscler Thromb 1994; 14: 193-8.
• 132 Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briët E, Vandenbroucke JP. 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: 719-22.
• 133 de Visser MHC, Poort SR, Vos HL, Rosendaal FR, Bertina RM. Factor X levels, polymorphisms in the promoter region of factor X, and the risk of venous thrombosis. Submitted for publication.
• 134 Schüttrumpf J, Jiminez-Boj E, Graf S, Huber K, Watzke HH. A genetic variant in the promoter of coagulation factor X increases the risk of acute coronary syndromes. Thromb Haemost 1999; (suppl) 509a (abstr.).
• 135 Kanaji T, Okamura T, Osaki K, Kuroiwa M, Shimoda K, Hamasaki N. et al. A common genetic polymorphism (46C to T subsitution) in the 5′-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998; 91: 2010-4.
• 136 Helley D, Besmond C, Ducrocq R, da Silva F, Guillin MC, Bezeaud A. et al. Polymorphism in exon 10 of the human coagulation factor V gene in a population at risk for sickle cell disease. Hum Genet 1997; 100: 245-8.
• 137 Hiyoski M, Arnutti P, Prajoonwiwat W, Nathalang O, Suwanasophon C, Kokaseam R. et al. A polymorphism nt 1628 G→A (R485K) in exon 10 of the coagulation factor V gene may be a risk factor for thrombosis in the indigenous Thai population. Thromb Haemost 1998; 80: 705-6.
• 138 Luddington R, Jackson A, Pannerselvam S, Brown K, Baglin T. The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost 2000; 83: 204-8.
• 139 Alhenc-Gelas M, Nicaud V, Gandrille S, van Dreden P, Amiral J, Aubry ML. et al. The factor V gene A4070G mutation and the risk of venous thrombosis. Thromb Haemost 1999; 81: 193-7.
• 140 Lunghi B, Iacoviello L, Gemmati D, Dilasio MG, Castoldi E, Pinotti M. et al. Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma. Thromb Haemost 1996; 75: 45-8.
• 141 Castoldi E, Rosing J, Girelli D, Hoekema L, Lunghi B, Mingozzi F. et al. Mutation in the R2 FV gene affect the ratio between the two FV isoforms in plasma. Thromb Haemost 2000; 83: 362-5.
• 142 Keightley AM, Lam YM, Brady JN, Cameron CL, Lillicrap D. Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF:Ag levels: identification of three novel single nucleotide polymorphisms in the vWF gene promoter. Blood 1999; 12: 4277-83.
• 143 Kamphuisen PW, Eikenboom JCJ, Rosendaal FR, Koster T, Blann AD, Vos HL. et al. High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. Submitted for publication.
• 144 Carter AM, Catto AJ, Kohler HP, Ariens RA, Stickland MH, Grant PJ. Alpha-fibrinogen Thr 312 Ala polymorphism and venous thromboembolism. Blood 2000; 96: 1177-9.
• 145 Baumann RE, Henschen AH. Human fibrinogen polymorphic site analysis by restriction endonuclease digestion and allele-specific polymerase chain reaction amplification: identification of polymorphisms at position A312 and B448. Blood 1993; 82: 2117-24.
• 146 Thomas AE, Green FR, Humphries SE. Association of genetic variation at the β-fibrinogen gene locus and plasma fibrinogen levels: Interaction between allele frequency of the G/A^–455 polymorphism, age and smoking. Clin Genet 1996; 50: 184-90.
• 147 Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G. et al. β-fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction (the ECTIM study). Circulation 1996; 93: 440-9.
• 148 Zito F, Di Castelnuova A, Amore C, D’Orazio A, Donati MB, Iacoviello L. Bcl I polymorphism in the fibrinogen beta-chain gene is associated with the risk of familial myocardial infarction by increasing plasma fibrinogen levels. A case-control study in a sample of Gissi-2 patients. Arterioscler Thromb Vasc Biol 1997; 17: 3489-94.
• 149 Corral J, Gonzalez-Gonejero P, Iniesta JA, Rivera J, Martinez C, Vicente V. The FXIII Val 34 Leu polymorphism in venous and arterial thrombosis. Haematologica 2000; 85: 293-7.
• 150 Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood 1999; 93: 906-8.
• 151 Renner W, Koppel H, Hoffmann C, Schallmoser K, Stanger O, Toplak H. et al. Prothrombin G20210A, factor V Leiden and factor XIII Val 34 Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria. Thromb Res 2000; 99: 35-9.
• 152 Mikkola H, Syrjala M, Rasi V, Vahtera E, Hamalainen E, Peltonen L. et al. Deficiency in the A subunit of coagulation factor XIII: two novel point mutations demonstrate different effects on transcript levels. Blood 1994; 84: 517-25.
• 153 Margaglione M, Bossone A, Brancaccio V, Giampa A, Di Minno G. Factor XIII Val 34 Leu polymorphism and risk of deep venous thrombosis. Thromb Haemost 2000; 84: 1118-9.
• 154 Franco RF, Reitsma PH, Lourenco D, Maffei FH, Morrelli V, Tavella MH. et al. Factor XIII Val 34 Leu is a genetic factor involved in the etiology of venous thrombosis. Thromb Haemost 1999; 81: 676-99.
• 155 Alhenc-Gelas M, Reny J, Aubry M, Aiach M, Emmerich J. The Val 34 Leu mutation and the risk of venous thrombosis. Thromb Haemost 2000; 84: 1117-8.
• 156 Balogh I, Szôke G, Kárpáti L, Wartiovaara U, Katona É, Komáromi I. et al. Val 34 Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia. Blood 2000; 96: 2479-86.
• 157 Ariëns RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII Val 34 Leu polymorphism accelerates thrombin activation of factor XIII and effects crosslinked fibrin structure. Blood 2000; 96: 988-95.
• 158 Wartiovaara U, Mikkola H, Szôke G, Haramura G, Kárpáti L, Balogh I. et al. Effect of Val 34 Leu polymorphism on the activation of the coagulation factor XIII. Thromb Haemost 2000; 84: 595-600.
• 159 Kohler HP, Ariëns RA, Whitaker P, Grant PJ. A common polymorphism in the FXIIIA subunit gene (FXIII Val 34 Leu) affects cross-linking activity. Thromb Haemost; 1998; 704.
• 160 van Hylckama Vlieg A, Komanasin N, Ariëns RAS, Poort SR, Grant PJ, Bertina RM. et al. Factor XIII Val 34 Leu, factor XIII antigen levels and activity and the risk of deep venous thrombosis. Submitted for publication.
• 161 Franco RF, Fagundes MG, Meijers JCM, Reitsma PH, Lourenço DM, Silva WA, Maffei FH, Carlos E. Identification of polymorphisms in the TAFI gene promoter: relationship with plasma TAFI levels and risk of venous thrombosis. Blood 2000; 96: 565a (abstr.).
• 162 Spek CA, Koster T, Rosendaal FR, Bertina RM, Reitsma PH. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arteriocler Thromb Vasc Biol 1995; 15: 214-8.
• 163 Aiach M, Nicaud V, Alhenc-Gelas M, Gandrille S, Arnaud E, Amiral J. et al. Complex association of protein C gene promoter polymorphism with circulating protein C levels and thrombotic risk. Arterioscler Throm Vasc Biol 1999; 19: 1573-6.
• 164 Scopes D, Berg LP, Krawczak M, Kakkar VV, Cooper DN. Polymorphic variation in the human protein C (PROC C) gene promoter can influence transcriptional efficiency in vitro. Blood Coag Fibrinol 1995; 6: 317-21.
• 165 Diepstraten CM, Ploos van Amstel JK, Reitsma PH, Bertina RM. A CCA/CCG neutral polymorphism in the codon for Pro 626 in the human protein S gene PS alpha (PROS1). Nucl Acid Res 1991; 19: 5091.
• 166 Matheron-Leroy C, Duchemin J, Levent M, Gouault-Heilman M. Influence of the nt 2148 A to G substitution (Pro 626 dimorphism) in the PROS1 gene on circulating free PS levels in healthy volunteers – reappraisal of protein S normal ranges. Thromb Haemost 2000; 83: 798-9.
• 167 Matheron-Leroy C, Duchemin L, Levent M, Gouault-Heilmann M. Genetic modulation of plasma protein S levels by two frequent dimorphisms in the PROS1 gene. Thromb Haemost 1999; 82: 1088-92.
• 168 Mustafa S, Pabinger I, Mannhalter C. Two new frequent dimorphisms in the protein S (PROS1) gene. Thromb Haemost 1996; 65: 511-3.
• 169 van der Velden PA, Krommenhoek-van Es T, Allaart CF, Bertina RM. A frequent thrombomodulin amino acid dimorphism is not associated with thrombophilia. Thromb Haemost 1991; 65: 511-3.
• 170 Kleesiek K, Schmidt M, Gotting G, Schwerz B, Lange S, Muller-Berghaus G. et al. The 536 CT transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk of venous thrombosis. Thromb Haemost 1999; 82: 1-5.
• 171 Miyata T, Sakata T, Kumeda K, Uchida K, Tsushima M, Fujimura H, Kawasaki T, Kato H. C-399T polymorphism in the pomoter region of human tissue factor pathway inhibitor (TFPI) gene does not change the plasma TFPI antigen level and does not cause venous thrombosis. Thromb Haemost 1998; 80: 345-6.
• 172 Arnaud E, Moatti D, Emmerich J, Aiach M, de Prost D. No link between the TFPI V264M mutation and venous thromboembolic disease. Thromb Haemost 1999; 82: 159-60.
• 173 Hessner MJ, Luhm RA. The C536T transition in the tissue factor pathway inhibitor (TFPI) gene does not contribute to risk of venous thrombosis among carriers of factor V Leiden. Thromb Haemost 2000; 94: 724-5.
• 174 Moatti D, Haidar B, Fumeron F, Gauci L, Boudvillain O, Seknadji P. et al. A new T-278C polymorphism in the 5′ regulatory region of the tissue factor pathway inhibitor gene association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels. Thromb Haemost 2000; 84: 244-9.
• 175 Moatti D, Seknadji P, Galand C, Poirier O, Fumeron F, Desprez S. et al. Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subsject: Impact of the V264M substitution on plasma levels of TFPI. Artherioscler Thromb Vasc Biol 1994; 19: 862-9.
• 176 Gonzales-Conejero R, Lozano ML, Corral J, Martinez C, Vicente V. The TFPI 536CT mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost 2000; 83: 787-8.
• 177 Evans GD, Langdown J, Brown K, Baglin TP. The C536T transition in the tissue factor pathway inhibitor gene is not a common cause of venus thromboembolic disease in the UK population. Thromb Haemost 2000; 83: 511.
• 178 Ludwig M, Wohn KD, Schleunig WD, Olek K. Allelic dimorphism in the human tissue-type plasminogen activator (TPA) gene as a result of an Alu isertion/deletion event. Hum Genet 1992; 88: 388-92.
• 179 Jern C, Ladenvall P, Wall U, Jern S. Gene polymorphism of t-PA is associated with forearm vascular release rate of t-PA. Artherioscler Thromb Vasc Biol 1999; 19: 454-9.
• 180 Ladenvall P, Wall U, Jern S, Jern C. Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PAI) locus: asssociation with vascular t-PA release in vivo. Thromb Haemost 2000; 84: 150-5.
• 181 van den Eijnden-Schauwen Y, Lakenberg N, Emeis JJ, de Knijff P. Alu-repeat polymorphism in the tissue-type plasminogen activator gene does not effect basal endothelial tPA synthesis. Thromb Haemost 1995; 74: 1202a (abstr.).
• 182 Burzotta F, Di Castelnuovo A, Amore C, D’Orazio A, Di Bitondo R, Donati MB. et al. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in Italians: a model of gene environment interaction. Thromb Haemost 1998; 79: 354-8.
• 183 Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in hepG2 cells. J Biol Chem 1993; 268: 10739-45.
• 184 Morange PE, Henry M, Tregonet D, Granet B, Aillaud MF, Alessi MC. et al. The A-844G polymorphism in the PAI-1 gene is associated with a higher risk of venous thrombosis in factor V Leiden carriers. Atherioscler Thromb Vasc Biol 2000; 20: 1387-91.
• 185 Akar N, Yilmaz E, Akar E, Avcu F, Yalcin A, Cin S. Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thrombotic patients with and without FV 1691 G-A. Thromb Res 2000; 97: 227-30.
• 186 Hong Y, Pederson NL, Egberg N, de Faire U. Moderate genetic influences on plasma levels of plasminogen activator inhibitor-1 and evidence of genetic and environmental influences shared by plasminogen activator-1, triglycerides, and body mass index. Arterioscler Thromb Vasc Biol 1997; 17: 2776-82.
• 187 Dawson S, Hamsten A, Wiman B, Henney A, Humphries S. Genetic variation in the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1991; 11: 183-90.
• 188 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ. et al. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 1995; 74: 837-41.
• 189 Eriksson P, Kallin B, van ’t Hooft FM, Bävenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor-1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
• 190 Ridker PM, Hennekens CH, Lindpainter K, Stampfer MJ, Miletich JP. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohost of US men. Circulation 1997; 95: 59-62.
• 191 Henry M, Chomiki N, Scarabin PY, Alessi MC, Peiretti F, Arveiller D. et al. Five frequent polymorphisms of the PAI-1 gene. Lack of association between genotype, PAI-1 activity, and trigly ceride levels in a healty population. Artherioscler Thromb Vasc Biol 1997; 17: 851-8.
• 192 Grobic N, Stegnar M, Peternel P, Kaider A, Binder BR. A novel G/A and the 4G/5G polymorphisms within the promoter of the plaminogen activator inhibitor-1 gene in patients with deep vein thrombosis. Thromb Res 1996; 84: 431-43.
• 193 Stegnar M, Uhrin P, Peternel P, Mavri A, Salobir-Pajnic B, Stare J. et al. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thromboembolism. Thromb Haemost 1998; 79: 975-9.
• 194 Zöller B, Garcia de Frutos P, Dahlbäck B. A common 4G allele in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene as a risk factor for pulmonary embolism and arterial thrombosis in hereditary protein S deficiency. Thromb Haemost 1998; 79: 802-7.
• 195 Arnaud E, Nicaud V, Poirier O, Rendu F, Alhenc-Gelas M, Fiessinger JN. et al. Protective effect of a thrombin receptor (protease-activated receptor 1) gene polymorphism toward venous thromboembolism. Arterioscler Thromb Vasc Biol 2000; 20: 585-92.
• 196 Rigat N, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343-6.
• 197 De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Sem Thromb Hemost 1998; 24: 367-79.
• 198 de Visser MC, Guasch JF, Kamphuisen PW, Vos HL, Rosendaal FR, Bertina RM. The HR2 haplotype of factor V: effects on factor V levels, normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost 2000; 83: 577-82.