Risk Factors for Venous Thrombotic Disease

Introduction

Venous thrombosis occurs in about 1 per 1,000 individuals per year.^1,2 It usually affects the deep veins of the leg, but may occur in other sites, such as the upper extremities, cerebral sinus, liver and portal veins, or retinal veins. It also may occur in the superficial veins, usually in the leg. The predilection of thrombosis occurring in the leg is the result of the upright position of man, with the resulting slow antigravitational flow of blood in the veins of the leg. Embolization occurs when parts of the clot dislodge and are transported by the blood flow, usually through the heart to the vasculature of the lungs.³

Thrombosis is a serious disorder. It may be fatal by pulmonary embolism, although this is rare (case fatality rate of venous thrombosis is estimated at 1% to 2%). A common, and often disabling, consequence of deep vein thrombosis is postthrombotic syndrome, with symptoms ranging from discoloration to pain and ulceration.⁴ Because thrombosis is not very rare and often has serious consequences, prophylactic treatment is focussed on preventing first events and recurrences through adequate knowledge about risks and risk factors.⁵

• References

• 1 Nordström M, Lindblad B, Bergqvist D, Kjellström T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992; 232: 155-160.
• 2 Anderson FA, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forrier A, Dalen JE. A population based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT study. Arch Intern Med 1991; 151: 933-938.
• 3 Carter CJ. The natural history and epidemiology of venous thrombosis. Prog Cardiovasc Dis 1994; 36: 423-438.
• 4 Brandjes DP, Büller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, Ten Cate JW. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759-762.
• 5 Rosendaal FR. Risk factors for venous thrombosis: prevalence, risk and interaction. Semin Hematol 1997; 34: 171-187.
• 6 Greenland S. Applications of stratified analysis methods. In: Rothman KJ, Greenland S. eds. Modern Epidemiology. Philadelphia: Lippincott-Raven; 1998: 295-297.
• 7 Virchow R. Phlogose und Thrombose im Gefäßsystem; Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt: Staatsdruckerei. 1856
• 8 White C. An inquiry into the nature and cause of that swelling in one or both of the lower extremities which sometimes happen to in-lying women together with the propriety of drawing the breasts of those who do and also who do not give suck. London: Warrington; 1784
• 9 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-530.
• 10 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: 1453-1457.
• 11 Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977-980.
• 12 Jick H, Derby LE, Wald Myers M, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348: 981-983.
• 13 Trousseau A. Phlegmasia alba dolens. In: Anonymous Clinique Médicale de l’Hôtel-Dieu de Paris. Paris: J.B. Ballière et fils; 1865: 652-695.
• 14 Bick RL. Coagulation abnormalities in malignancy: a review. Semin Thromb Hemost 1992; 18: 353-369.
• 15 Nand S, Messmore H. Hemostasis in malignancy. Am J Hematol 1990; 35: 45-55.
• 16 Donati BM. Cancer and thrombosis: from phlegmasia albans dolens to transgenic mice. Thromb Haemost 1995; 74: 278-281.
• 17 Goldberg RJ, Seneff M, Gore JM, Anderson FA, Greene HL, Wheeler HB, Dalen JE. Occult malignant neoplasms in patients with deep venous thrombosis. Arch Intern Med 1987; 147: 251-253.
• 18 Zurborn KH, Duscha H, Gram J, Bruhn HD. Investigations of coagulation system and fibrinolysis in patients with disseminated adenocarcinomas and non-Hodgkin lymphomas. Oncology 1990; 47: 376-380.
• 19 Monreal M, Fernandez-Llamazares J, Perandreu J, Urrutia A, Sahuquillo JC, Contel E. Occult cancer in patients with venous thromboembolism: which patients, which cancers. Thromb Haemost 1997; 78: 1316-1318.
• 20 Prandoni P, Lensing AWA, Büller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, Ten Cate JW. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992; 327: 1128-1133.
• 21 Nordström M, Lindblad B, Anderson H, Bergqvist D, Kjellström T. Deep venous thrombosis and occult malignancy: an epidemiological study. BMJ 1994; 308: 891-894.
• 22 Coebergh JWW. Incidence and prognosis of cancer in The Netherlands: studies based on cancer registries. (Thesis) Rotterdam: 1991: 191-195.
• 23 Cohen SH, Ehrlich GE, Kaufman MS, Cope C. Thrombophlebitis following knee surgery. J Bone Joint Surg 1973; 55: 106-111.
• 24 Hull RD, Raskob GE. Prophylaxis of venous thromboembolic disease following hip and knee surgery. J Bone Joint Surg 1986; 68: 146-150.
• 25 Bergqvist D. Frequency of thromboembolic complications. In: Bergquist D. ed. Postoperative Thromboembolism. Berlin: Springer-Verlag; 1983: 12-13.
• 26 Mayo M, Halil T, Browse NL. The incidence of deep vein thrombosis after prostatectomy. Br J Urol 1971; 43: 738-742.
• 27 Walsh JJ, Bonnar J, Wright FW. A study of pulmonary embolism and deep vein thrombosis after major gynaecological surgery using labelled fibrinogen, phlebography and lung scanning. J Obstet Gynaecol Br Commonw 1974; 81: 311-316.
• 28 Hjelmstedt A, Bergvall U. Incidence of thrombosis in patients with tibial fractures. Acta Chir Scand 1968; 134: 209-218.
• 29 Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994; 331: 1601-1606.
• 30 Gibbs NM. Venous thrombosis of the lower limbs with particular reference to bed-rest. Br J Surg 1957; 45: 209-235.
• 31 Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legs after stroke. Br Med J 1976; 1: 1178-1181.
• 32 Symington IS, Stack BHR. Pulmonary thromboembolism after travel. Br J Dis Chest 1977; 71: 138-140.
• 33 Cruickshank JM, Gorlin R, Jennett B. Air travel and thrombotic episodes: the economy class syndrome. Lancet 1988; ii 497-498.
• 34 Eschwège V, Robert A. Strikes in French public transport and resistance to activated protein C. Lancet 1996; 347: 206.
• 35 Jordan WM. Pulmonary embolism. Lancet 1961; ii 1146-1147.
• 36 Sartwell PE, Masi AT, Arthes FG, Greene GR, Smith HE. Thromboembolism and oral contraceptives: an epidemiological case-control study. Am J Epidemiol 1969; 90: 365-380.
• 37 Stadel BV. Oral contraceptives and cardiovascular disease (first of two parts). N Engl J Med 1981; 305: 612-618.
• 38 Inman WHW, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J 1968; 193-199.
• 39 Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; i 199-205.
• 40 Boston Collaborative Drug Surveillance Program. Oral contraceptives and venous thromboembolic disease, surgically confirmed gall bladder disease and breast tumours. Lancet 1973; i 1399-1404.
• 41 Porter JB. Oral contraceptives and nonfatal vascular disease–recent experience. Obstet Gynecol 1982; 59: 299-302.
• 42 World Health Organization. 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: 1575-1582.
• 43 Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Transnational Research group on Oral Contraceptives and the Health of Young Women. BMJ 1996; 312: 83-88.
• 44 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995; 346: 1593-1596.
• 45 Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 1991; 133: 32-37.
• 46 Cardiovascular disease and steroid hormone contraception. Report of a WHO Scientific group. WHO Technical Report Series, no. 877. Geneva: World Health Organization; 1998
• 47 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Büller HR, Colly LP, Vandenbroucke JP. The association between oral contraceptives and venous thrombosis: the myth of the diagnostic suspicion- and referral bias. Arch Intern Med 1999; 159: 65-70.
• 48 World Health Organization. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995; 346: 1582-1588.
• 49 Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-1593.
• 50 Andersen BS, Olsen J, Nielsen GL, Steffensen FH, Sørensen HT, Baech J, Gregersen H. Third generation oral contraceptives and heritable thrombophilia as risk factors for non-fatal venous thromboembolism. Thromb Haemost 1998; 79: 28-31.
• 51 Rosing J, Tans G, Nicolaes GA, Thomassen MC, Van Oerle R, Van der Ploeg PM, Heijen P, Hamulyak K, Hemker HC. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97: 233-238.
• 52 Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996; 348: 983-987.
• 53 Grady D, Furberg C. Venous thromboembolic events associated with hormone replacement therapy. JAMA 1997; 278: 477-477.
• 54 Kierkegaard A. Incidence and diagnosis of deep vein thrombosis associated with pregnancy. Acta Obstet Gynecol Scand 1983; 62: 239-243.
• 55 Treffers PE, Huidekoper BL, Weenink GH, Kloosterman GJ. Epidemiological observations of thromboembolic disease during pregnancy and in the puerperium, in 56,022 women. Int J Gynaecol Obstet 1983; 21: 327-331.
• 56 McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, Carty MJ, Greer IA. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78: 1183-1188.
• 57 Love PE, Santoro SE. Antiphospholipid antibodies: anticardiolipin antibodies and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112: 682-698.
• 58 Fijnheer R, Horbach DA, Donders RCJM, Vilé H, van Oort E, Nieuwenhuis HK, Gmelig-Meijling FHJ, de Groot PhG, Derksen RHWM, Factor V Leiden. antiphospholipid antibodies and thrombosis in systemic lupus erythematosus. Thromb Haemost 1996; 76: 514-517.
• 59 Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, Stevens P, Hirsh J. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-3691.
• 60 Simioni P, Prandoni P, Zanon E, Saracino MA, Scudeller A, Villalta S, Scarano L, Girolami B, Benedetti L, Girolami A. Deep venous thrombosis and lupus anticoagulant. Thromb Haemost 1996; 76: 187-189.
• 61 Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. the EMET Group. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism–results of the Spanish multicentric study on thrombophilia (EMET-study). Thromb Haemost 1997; 77: 444-451.
• 62 Halbmayer WM, Haushofer A, Schon R, Mannhalter C, Strohmer E, Baumgarten K, Fischer M. The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors. Thromb Haemost 1994; 71: 68-72.
• 63 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373.
• 64 Broekmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolism: a study of three Dutch families. N Engl J Med 1983; 309: 340-344.
• 65 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briët E. Increased risk of venous thrombosis in carriers of protein C deficiency defect. Lancet 1993; 341: 134-138.
• 66 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. APC-resistance as an additional risk factor for thrombosis in protein C deficient families. Blood 1994; 84: 1031-1035.
• 67 Heijboer 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: 1512-1516.
• 68 Koster T, Rosendaal FR, Briët E, Van der Meer FJM, Colly LP, Trienekens PH, Poort SR, Vandenbroucke JP. 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: 2756-2761.
• 69 Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, Conkie JA, Bertina RM. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 87-93.
• 70 Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300.
• 71 Simmonds RE, Ireland H, Lane DA, Zöller B, García de Frutos P, Dahlbäck B. Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect. Ann Intern Med 1998; 128: 8-14.
• 72 Zöller B, Garcia de Frutos P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995; 85: 3524-3531.
• 73 Simmonds RE, Zöller B, Ireland H, Thompson E, García de Frutos P, Dahlbäck B, Lane DA. Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood 1997; 89: 4364-4370.
• 74 Faioni EM, Valsecchi C, Palla A, Taioli E, Razzari C, Mannucci PM. Free protein S deficiency is a risk factor for venous thrombosis. Thromb Haemost 1997; 78: 1343-1346.
• 75 Koeleman BPC, Van Rumpt D, Hamulyak K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families?. Thromb Haemost 1995; 74: 580-583.
• 76 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: 3518-3523.
• 77 Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism. Clin Haematol 1981; 10: 369-390.
• 78 Demers C, Ginsberg JS, Hirsh J, Henderson P, Blajchman MA. Thrombosis in antithrombin III-deficient persons: report of a large kindred and literature review. Ann Intern Med 1992; 116: 754-761.
• 79 Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency: incidence and clinical features. Am J Med 1989; 87 (Suppl) 34-38.
• 80 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited Thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-662.
• 81 Van Boven HH, Reitsma PH, Rosendaal FR, Bayston TA, Chowdhury V, Bauer KA, Scharrer I, Conard J, Lane DA. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75: 417-421.
• 82 Tait RC, Walker ID, Perry DJ, Islam SI, Daly ME, McCall F, Conkie JA, Carrell RW. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106-112.
• 83 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134.
• 84 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: 1504-1508.
• 85 Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. JAMA 1997; 277: 1305-1307.
• 86 Bertina RM, Koeleman RPC, Koster T, Rosendaal FR, Dirven RJ, De Ronde H, Van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
• 87 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognised 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: 1004-1008.
• 88 Koster T, Rosendaal FR, De Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to a poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506.
• 89 Ridker PM, Hennekens CH, Lindpainter K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-917.
• 90 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in a majority of thrombophilic patients. Blood 1993; 82: 1989-1993.
• 91 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: 3698-3703.
• 92 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol 1997; 98: 353-355.
• 93 Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78: 990-992.
• 94 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.
• 95 Rosendaal FR, Doggen CJM, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-708.
• 96 Souto JC, Coll I, Llobet D, del Río E, Oliver A, Mateo J, Borrell M, Fontcuberta J. The prothrombin 20210A allele is the most present genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 1998; 80: 366-369.
• 97 Jick H, Slone D, Westerholm B, Inman WHW, Vessey MP, Shapiro S, Lewis GP, Worcester J. Venous thromboembolic disease and ABO blood type. Lancet 1969; i 539-542.
• 98 Jick H, Porter J. Thrombophlebitis of the lower extremities and ABO blood type. Arch Intern Med 1978; 138: 1566-1567.
• 99 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
• 100 Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR. The effect of ABO blood groups on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695.
• 101 Weis HJ, Sussman I, Hoyer LW. Stabilization of factor VIII in plasma by the von Willebrand factor. J Clin Invest 1997; 60: 390-404.
• 102 Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb 1994; 14: 1080-1083.
• 103 Den Heijer M, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-762.
• 104 Simioni P, Prandoni P, Burlina A, Tormene D, Sardella C, Ferrari V, Benedetti L, Girolami A. Hyperhomocysteinemia and deep-vein thrombosis: a case-control study. Thromb Haemost 1996; 76: 883-886.
• 105 Den Heijer M, Rosendaal FR, Blom HJ, Gerrits WBJ, Bos GMJ. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998; 80: 874-877.
• 106 D’Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood 1997; 90: 1-11.
• 107 Kang SS, Wong PWK, Norusis M. Homocysteinemia due to folate deficiency. Metabolism 1987; 36: 458-462.
• 108 Rees MM, Rodgers GM. Homocysteinemia: association of a metabolic disorder with vascular disease and thrombosis. Thrombosis Research 1993; 71: 337-359.
• 109 Ubbink JB, Vermaak WJ, Van der Merwe A, Becker PJ. Vitamin B12, vitamin B6, and folate nutritional status in men with hyper-homocysteinemia. Am J Clin Nutr 1993; 57: 47-53.
• 110 Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GH, Bromberg IL, Cerone R. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985; 37: 1-31.
• 111 Engbertsen AMT, Franken DG, Boers GHJ, Stevens EMB, Trijbels FJM, Blom HJ. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 1995; 56: 142-150.
• 112 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GHJ, Den Heijer M, Kluijtmans LAJ, Van den Heuvel LPWJ, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-113.
• 113 Kang SS, Zhou J, Wong PWK, Kowlisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methyl-enetetrahydrofolate reductase. Am J Hum Genet 1988; 48: 536-545.
• 114 Kluijtmans LAJ, Den Heijer 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; 254-258.
• 115 Queré I, Chasse JF, Dupuy E, Bellet E, Molho-Sabatier P, Tobelem G, Janbon C. Homocysteine, 5,10-methylenetetrahydro-folate reductase et thrombose veneuse profonde. Enquête aupres de 120 patients en médécine interne. Rev Med Interne 1998; 19: 29-33.
• 116 Margaglione M, D’Andrea G, d’Addedda M, Giuliani N, Cappucci G, Iannaccone L, Vecchione G, Grandone E, Brancaccio V, Di Minno G. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation. Thromb Haemost 1998; 79: 907-911.
• 117 O’Donnell J, Tuddenham EGD, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated FVIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77: 825-828. (Abstract)
• 118 Kamphuisen PW, Houwing-Duistermaat JJ, van Houwelingen JC, Eikenboom JCJ, Bertina RM, Rosendaal FR. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998; 79: 323-327.
• 119 Zöller B, Svensson PJ, 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: 2521-2524.
• 120 Bertina RM, Reitsma PH, Rosendaal FR, Vandenbroucke JP. Resistance to activated protein C and factor V Leiden as risk factors for venous thrombosis. Thromb Haemost 1995; 74: 449-453.
• 121 de Visser MCH, 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: 1271-1276.
• 122 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.
• 123 Olivieri O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B, Girelli D, Azzini M, Brocco G, Russo C. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91: 465-470.
• 124 Cumming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CR. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90: 725-727.