Prophylaxis and Treatment of Venous Thromboembolism in Individuals with Inherited Thrombophilia

ABSTRACT

Venous thromboembolism (VTE) susceptibility genes are widely diffuse in the general population, but clinical penetrance of genotypes is incomplete and has variable expressivity. Therefore, the indiscriminate search for carriers is of doubtful utility and potentially detrimental for screened individuals. A targeted screening in kindreds in which VTE already occurred can be more fruitful in identifying individuals sharing with the proband one or more known susceptibility genes (possibly cosegregating with other ones still unknown). Clinical penetrance is variable, and is higher in the relatively rare deficiencies of antithrombin (AT), protein C (PC), or protein S (PS), and lower in the presence of the common polymorphisms factor V Leiden and prothrombin G20210A. Women with inherited thrombophilia should be warned about the thrombotic risk associated with the use of oral contraceptives or hormonal replacement treatment. Moreover, prophylaxis during puerperium and surgery or after trauma is warranted. The absolute risk associated with such situations is low but not negligible in the presence of deficiencies of AT, PC, or PS, homozygous conditions, and carriership of multiple defects. In such cases primary prophylaxis should be applied also during pregnancy and in general should be more stringent; moreover, in these patients the option for indefinite duration of secondary anticoagulant prophylaxis after VTE should be considered because of the relevant risk of recurrent VTE. In all cases, a careful balance of benefits and risks associated with prophylactic measures should be achieved, and patient preferences should be considered.

KEYWORDS

Inherited thrombophilia - antithrombotic prophylaxis - pregnancy and puerperium - surgery - hormonal treatment

REFERENCES

• 1 Jordan FLJ, Nandorff A. The familial tendency in thromboembolic disease.  Acta Med Scand. 1956;  156 267-275
• 2 Egeberg O. Inherited antithrombin deficiency causing thrombophilia.  Thromb Diath Haemorrh. 1965;  13 516-530
• 3 Griffin J, Evatt B, Zimmerman T, Kleiss A, Wideman C. Deficiency of protein C in congenital thrombotic disease.  J Clin Invest. 1981;  68 1370-1373
• 4 Comp P, Esmon C. Recurrent venous thromboembolism in patients with a partial deficiency of protein S.  N Engl J Med. 1984;  311 1525-1528
• 5 Schwarz H P, Fischer M, Hopmeier P, Batard M, Griffin J. Plasma protein S deficiency in familial thrombotic disease.  Blood. 1984;  64 1297-1300
• 6 Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2132 consecutive unselected patients with venous thromboembolism: results of the Spanish multicentric study on thrombophilia.  Thromb Haemost. 1997;  77 444-451
• 7 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis.  N Engl J Med. 2001;  344 1222-1231
• 8 De Stefano V, Rossi E, Paciaroni K, Leone G. Screening for inherited thrombophilia: indications and therapeutic implications.  Haematologica. 2002;  87 1095-1108
• 9 Tait R C, Walker I D, Perry D J et al.. Prevalence of antithrombin deficiency in the healthy population.  Br J Haematol. 1994;  87 106-112
• 10 Beauchamp N J, Dykes A C, Parikh N, Tait R C, Daly M E. The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population.  Br J Haematol. 2004;  125 647-654
• 11 Dahlbäck 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 1004-1008
• 12 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 1503-1506
• 13 Svensson P J, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis.  N Engl J Med. 1994;  330 517-522
• 14 Bertina R M, Koeleman BPC, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 64-67
• 15 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
• 16 De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications.  Semin Thromb Hemost. 1998;  24 367-379
• 17 Rosendaal F R, Doggen CJM, Zivelin A et al.. Geographic distribution of the 20210 G to A prothrombin variant.  Thromb Haemost. 1998;  79 706-708
• 18 Emmerich J, Rosendaal F R, Cattaneo M et al.. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism: pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism.  Thromb Haemost. 2001;  86 809-816
• 19 den Heijer M, Rosendaal F R, Blom H J, Gerrits WBJ, Bos GMJ. Hyperhomocysteinemia and venous thrombosis: a meta-analysis.  Thromb Haemost. 1998;  80 874-877
• 20 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis.  Thromb Haemost. 1999;  81 165-176
• 21 De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G. Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism.  Semin Thromb Hemost. 2000;  26 305-311
• 22 Bauer K A, Rosendaal F R, Heit J A. Hypercoagulability: too many tests, too much conflicting data.  Hematology (Am Soc Hematol Educ Program). 2002;  353-368
• 23 Humphries S E, Ridker P M, Talmud P J. Genetic testing for cardiovascular disease susceptibility: a useful clinical management tool or possible misinformation?.  Arterioscler Thromb Vasc Biol. 2004;  24 628-636
• 24 Rosendaal F R. Venous thrombosis: a multicausal disease.  Lancet. 1999;  353 1167-1173
• 25 Botto L D, Khoury M J. Commentary: facing the challenge of gene-environment interaction: the two-by-four table and beyond.  Am J Epidemiol. 2001;  153 1016-1020
• 26 Yang Q, Khoury M J, Botto L, Friedman J M, Flanders W D. Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes.  Am J Hum Genet. 2003;  72 636-649
• 27 Khoury M J. Genetics and genomics in practice: the continuum from genetic disease to genetic information in health and disease.  Genet Med. 2003;  5 261-268
• 28 Kelada S N, Eaton D L, Wang S S, Rothman N R, Khoury M J. The role of genetic polymorphisms in environmental health.  Environ Health Perspect. 2003;  111 1055-1064
• 29 Khoury M J, Yang Q, Gwinn M, Little J, Dana Flanders W. An epidemiologic assessment of genomic profiling for measuring susceptibility to common diseases and targeting interventions.  Genet Med. 2004;  6 38-47
• 30 Thornton-Wells T A, Moore J H, Haines J L. Genetics, statistics and human disease: analytical retooling for complexity.  Trends Genet. 2004;  20 640-647
• 31 Vandenbroucke J P, van der Meer FJM, Helmerhorst F M, Rosendaal F R. Factor V Leiden: should we screen oral contraceptive users and pregnant women?.  BMJ. 1996;  313 1127-1130
• 32 Clark P, Twaddle S, Walker I D, Scott L, Greer I A. Cost-effectiveness of screening for the factor V Leiden mutation in pregnant women.  Lancet. 2002;  359 1919-1920
• 33 Grody W W, Griffin J H, Taylor A K, Korf B R, Heit J A. ACMG Factor V Leiden Working Group . . American College of Medical Genetics consensus statement on factor V Leiden mutation testing.  Genet Med. 2001;  3 139-148
• 34 Recommendations of the European Society of Human Genetics . Provision of genetic services in Europe: current practices and issues.  Eur J Hum Genet. 2003;  11(suppl 2) S2-S4
• 35 Recommendations of the European Society of Human Genetics . Population genetic screening programmes: technical, social and ethical issues.  Eur J Hum Genet. 2003;  11(suppl 2) S5-S7
• 36 Tosetto A, Frezzato M, Rodeghiero F. Prevalence and risk factors of non-fatal venous thromboembolism in the active population of the VITA Project.  J Thromb Haemost. 2003;  1 1724-1729
• 37 Tosetto A, Missiaglia E, Frezzato M, Rodeghiero F. The VITA project: prothrombin G20210A mutation and venous thromboembolism in the general population.  Thromb Haemost. 1999;  82 1395-1398
• 38 Lane D A, Mannucci P M, Bauer K A et al.. Inherited thrombophilia: part 2.  Thromb Haemost. 1996;  76 824-834
• 39 Walker I D, Greaves M, Preston F E. Guideline. Investigation and management of heritable thrombophilia.  Br J Haematol. 2001;  114 512-528
• 40 Mannucci P M. Genetic hypercoagulability: prevention suggests testing family members.  Blood. 2001;  98 21-22
• 41 Martinelli I. Pros and cons of thrombophilia testing: pros.  J Thromb Haemost. 2003;  1 410-411
• 42 Langlois N J, Wells P S. Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review.  Thromb Haemost. 2003;  90 17-26
• 43 De Stefano V. Inherited thrombophilia and life-time risk of venous thromboembolism: is the burden reducible?.  J Thromb Haemost. 2004;  2 1522-1525
• 44 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;  71 441-445
• 45 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
• 46 Vossen C Y, Conard J, Fontcuberta J et al.. Risk of first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT).  J Thromb Haemost. 2005;  3 459-464
• 47 Middeldorp S, Henkens C M, Koopman M M et al.. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.  Ann Intern Med. 1998;  128 15-20
• 48 Simioni P, Tormene D, Prandoni P et al.. Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study.  Blood. 2002;  99 1938-1942
• 49 Tirado I, Mateo J, Soria J M et al.. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.  Haematologica. 2001;  86 1200-1208
• 50 Martinelli I, Bucciarelli P, Margaglione M et al.. 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 1223-1229
• 51 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
• 52 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 1932-1937
• 53 Martinelli I, Bucciarelli P, Zighetti M L, Cafro A, Mannucci P M. Low risk of thrombosis in family members of patients with hyperhomocysteinaemia.  Br J Haematol. 2002;  117 709-711
• 54 Green D. Genetic hypercoagulability: screening should be an informed choice.  Blood. 2001;  98 20
• 55 Machin S J. Pros and cons of thrombophilia testing: cons.  J Thromb Haemost. 2003;  1 412-413
• 56 Baglin T. Management of thrombophilia: who to screen?.  Pathophysiol Haemost Thromb. 2003/2004;  33 401-404
• 57 De Stefano V, Rossi E, Paciaroni K et al.. Different circumstances of the first venous thromboembolism among younger or older heterozygous carriers of the G20210A polymorphism in the prothrombin gene.  Haematologica. 2003;  88 61-66
• 58 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
• 59 Spencer F A, Goldberg R J. Asymptomatic thrombophilia-a family affair.  J Thromb Haemost. 2005;  3 457-458
• 60 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
• 61 Robertson L, Wu O, Langhorne P et al.. Thrombophilia in pregnancy: a systematic review.  Br J Haematol. 2006;  132 171-196
• 62 McColl M D, Ramsay J E, Tait R C et al.. Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost. 1997;  78 1183-1188
• 63 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 3) 627S-644S
• 64 Guideline . Investigation and management of heritable thrombophilia.  Br J Haematol. 2001;  114 512-528
• 65 Conard J, Horellou M H, Samama M M. Inherited thrombophilia and gestational venous thromboembolism.  Semin Thromb Hemost. 2003;  29 131-142
• 66 Greer I A, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy.  Blood. 2005;  106 401-407
• 67 Ginsberg J S, Bates S M. Management of venous thromboembolism during pregnancy.  J Thromb Haemost. 2003;  1 1435-1442
• 68 Greer I A. Thrombosis in pregnancy: maternal and fetal issues.  Lancet. 1999;  353 1258-1265
• 69 Ray J G, Chan W S. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation.  Obstet Gynecol Surv. 1999;  54 265-271
• 70 Martinelli I, De Stefano V, Taioli E et al.. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium.  Thromb Haemost. 2002;  87 791-795
• 71 De Stefano V, Finazzi G, Mannucci P M. Inherited thrombophilia: pathogenesis, clinical syndromes, and management.  Blood. 1996;  87 3531-3544
• 72 Abildgaard U, Viskjold F, Majak P. Hereditary antithrombin deficiency and pregnancy: venous thromboembolism despite prophylaxis with LMW heparin.  Thromb Haemost. 2001;  (suppl) , (abst P1470)
• 73 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin.  Gynecol Obstet Invest. 1982;  14 127-141
• 74 De Stefano V, Leone G, De Carolis S et al.. Management of pregnancy in women with antithrombin III congenital defect: report of four cases.  Thromb Haemost. 1988;  59 193-196
• 75 Menache D, O'Malley J P, Schorr J B, Wagner B, Williams C. Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group.  Blood. 1990;  75 33-39
• 76 Wu O, Clark P, Lowe GDO, Walker I D, Greer I A. Thrombophilia and venous thromboembolism after total hip or knee replacement surgery: a systematic review.  J Thromb Haemost. 2005;  3 811-813
• 77 Lindahl T L, Lundahl T H, Nilsson L, Andersson C A. APC-resistance is a risk factor for postoperative thromboembolism in elective replacement of the hip or knee-a prospective study.  Thromb Haemost. 1999;  81 18-21
• 78 Wahlander K, Larson G, Lindahl T L et al.. Factor V Leiden (G1691A) and prothrombin G20210A mutations as potential risk factors for venous thromboembolism after total hip or total knee replacement surgery.  Thromb Haemost. 2002;  87 580-585
• 79 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;  71 799-800
• 80 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(suppl 3) 338S-400S
• 81 Tengborn L, Bergqvist D. Surgery in patients with congenital antithrombin III deficiency.  Acta Chir Scand. 1988;  154 179-183
• 82 Mannucci P M, Boyer C, Wolf M, Tripodi A, Larrieu M J. Treatment of congenital antithrombin III deficiency with concentrates.  Br J Haematol. 1982;  50 531-535
• 83 Konkle B A, Bauer K A, Weinstein R et al.. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures.  Transfusion. 2003;  43 390-394
• 84 Wuthrich R P. Factor V Leiden mutation: potential thrombogenic role in renal vein, dialysis graft and transplant vascular thrombosis.  Curr Opin Nephrol Hypertens. 2001;  10 409-414
• 85 Irish A. Hypercoagulability in renal transplant recipients. Identifying patients at risk of renal allograft thrombosis and evaluating strategies for prevention.  Am J Cardiovasc Drugs. 2004;  4 139-149
• 86 Wuthrich R P, Cicvara-Muzar S, Booy C, Maly F E. Heterozygosity for the factor V Leiden (G1691A) mutation predisposes renal transplant recipients to thrombotic complications and graft loss.  Transplantation. 2001;  72 549-550
• 87 Heidenreich S, Junker R, Wolters H et al.. Outcome of kidney transplantation in patients with inherited thrombophilia: data of a prospective study.  J Am Soc Nephrol. 2003;  14 234-239
• 88 Ekberg H, Svensson P J, Simanaitis M, Dahlbäck B. Factor V R506Q mutation (activated protein C resistance) is an additional risk factor for early renal graft loss associated with acute vascular rejection.  Transplantation. 2000;  69 1577-1581
• 89 Fischereder M, Gohring P, Schneeberger H et al.. Early loss of renal transplants in patients with thrombophilia.  Transplantation. 1998;  65 936-939
• 90 Friedman G S, Meier-Kriesche H U, Kaplan B et al.. Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of renal allograft thrombosis.  Transplantation. 2001;  72 1073-1078
• 91 Martinelli I, Taioli E, Battaglioli T et al.. Risk of venous thromboembolism after air travel. Interaction with thrombophilia and oral contraceptives.  Arch Intern Med. 2003;  163 2771-2774
• 92 Lapostolle F, Surget V, Borron S W et al.. Severe pulmonary embolism associated with air travel.  N Engl J Med. 2001;  345 779-783
• 93 Pérez-Rodriguez E, Jiménez D, Diàz G et al.. Incidence of air travel-related pulmonary embolism at the Madrid-Barajas airport.  Arch Intern Med. 2003;  163 2766-2770
• 94 Otterson G A, Monahan B P, Harold N et al.. Clinical significance of the FV:Q506 mutation in unselected oncology patients.  Am J Med. 1996;  101 406-412
• 95 Pihusch R, Danzl G, Scholz M et al.. Impact of thrombophilic gene mutations on thrombosis risk in patients with gastrointestinal carcinoma.  Cancer. 2002;  94 3120-3126
• 96 Nowak-Gottl U, Wermes C, Junker R et al.. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors.  Blood. 1999;  93 1595-1599
• 97 Ruggeri M, Gisslinger H, Tosetto A et al.. Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia.  Am J Hematol. 2002;  71 1-6
• 98 Blom J W, Doggen CJM, Osanto S, Rosendaal F R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.  JAMA. 2005;  293 715-722
• 99 Vandenbroucke J P, Rosing J, Bloemenkamp KWM et al.. Medical progress: oral contraceptives and the risk of venous thrombosis.  N Engl J Med. 2001;  344 1527-1535
• 100 Gomes MPV, Deitcher S R. Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy. A clinical review.  Arch Intern Med. 2004;  164 1965-1976
• 101 Heinemann L A, Dinger J. Safety of a new oral contraceptive containing drospirenone.  Drug Saf. 2004;  27 1001-1018
• 102 Pabinger I, Schneider B. Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natural Inhibitors.  Thromb Haemost. 1994;  71 548-552
• 103 Wu O, Robertson L, Langhorne P et al.. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review.  Thromb Haemost. 2005;  94 17-25
• 104 Vandenbroucke J P, Koster T, Briet E et al.. Increased risk of venous thrombosis in oral contraceptives users who are carriers of factor V Leiden mutation.  Lancet. 1994;  344 1453-1457
• 105 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M, Büller 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 1593-1596
• 106 Andersen B S, Olsen J, Nielsen G L et al.. Third generation oral contraceptives and heritable thrombophilia as risk factors of non-fatal venous thromboembolism.  Thromb Haemost. 1998;  79 28-31
• 107 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci P M. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis.  Arterioscler Thromb Vasc Biol. 1999;  19 700-703
• 108 Spannagl M, Heinemann L A, Schramm W. Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism?.  Eur J Contracept Reprod Health Care. 2000;  5 105-112
• 109 Santamaria A, Mateo J, Oliver A et al.. Risk of thrombosis associated with oral contraceptives in women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene.  Haematologica. 2001;  86 965-971
• 110 Ehrenforth S, Nemes L, Mannhalter C et al.. Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691A.  J Thromb Haemost. 2004;  2 430-436
• 111 Rosing J, Tans G, Nicolaes G A et al.. 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
• 112 Martinelli I, Sacchi E, Landi G et al.. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.  N Engl J Med. 1998;  338 1793-1797
• 113 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting factors.  Arch Intern Med. 2000;  160 49-52
• 114 Rosendaal F R, Vessey M, Rumley A et al.. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis.  Br J Haematol. 2002;  116 851-854
• 115 Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population.  J Intern Med. 1992;  232 155-160
• 116 Büller H R, Agnelli G, Hull R D et al.. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(suppl 3) 401S-428S
• 117 Schulman S, Tengborn L. Treatment of venous thromboembolism in patients with congenital deficiency of antithrombin III.  Thromb Haemost. 1992;  68 634-636
• 118 De Stefano V, Paciaroni K, Chiusolo P et al.. Treatment of acute thrombosis in patients with congenital antithrombin III deficiency.  Thromb Haemost. 1997;  (suppl) 433 , (abst)
• 119 Schwartz R S, Bauer K A, Rosenberg R D et al.. Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency of antithrombin.  Am J Med. 1989;  87(suppl 3B) 53S-60S
• 120 Marlar R A, Montgomery R R, Broekmans A W. Diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party on Homozygous Protein C Deficiency of the Subcommittee on Protein C and Protein S. International Committee on Thrombosis and Haemostasis.  J Pediatr. 1989;  114 528-534
• 121 De Stefano V, Mastrangelo S, Schwarz H P et al.. Replacement therapy with a purified protein C concentrate during initiation of oral anticoagulation in severe protein C congenital deficiency.  Thromb Haemost. 1993;  70 247-249
• 122 Prandoni P, Lensing AWA, Cogo A et al.. The long-term clinical corse of acute deep venous thrombosis.  Ann Intern Med. 1996;  125 1-7
• 123 Hansson P O, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors.  Arch Intern Med. 2000;  160 769-774
• 124 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
• 125 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
• 126 Simioni P. Risk of recurrent venous thromboembolism and thrombophilia: does discrepancy make complexity or vice versa?.  J Thromb Haemost. 2003;  1 16-18
• 127 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;  166 729-736
• 128 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
• 129 De Stefano V, Simioni P, Rossi E et al.. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C, and protein S.  Haematologica. 2006;  91 695-698
• 130 Vossen C Y, Walker I D, Svensson P et al.. Recurrence rate after a first venous thrombosis in patients with familial thrombophilia.  Arterioscler Thromb Vasc Biol. 2005;  25 1992-1997
• 131 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
• 132 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 1583-1587
• 133 Nowak-Göttl U, Junker R, Kreuz W et al.. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.  Blood. 2001;  97 858-862
• 134 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;  116 625-631
• 135 The Procare Group . Is recurrent venous thromboembolism more frequent in homozygous patients for the factor V Leiden mutation than in heterozygous patients?.  Blood Coagul Fibrinolysis. 2003;  14 523-529
• 136 Hirsh J, Lee A Y. How we diagnose and treat deep vein thrombosis.  Blood. 2002;  99 3102-3110
• 137 Bauer K A. Management of thrombophilia.  J Thromb Haemost. 2003;  1 1429-1434
• 138 Schulman S. Clinical practice. Care of patients receiving long-term anticoagulant therapy.  N Engl J Med. 2003;  349 675-683
• 139 Bates S M, Ginsberg J S. Clinical practice. Treatment of deep-vein thrombosis.  N Engl J Med. 2004;  351 268-277
• 140 Kearon C. Long-term management of patients after venous thromboembolism.  Circulation. 2004;  110(suppl 1) I-10-I-18
• 141 Santamaria M G, Agnelli G, Taliani M R et al.. Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment.  Thromb Res. 2005;  116 301-306
• 142 Finazzi G, Barbui T. for the ad hoc Study Group . A retrospective study on oral anticoagulant prophylaxis in 103 Italian patients with hereditary thrombophilia and thrombosis.  Res Clin Lab. 1990;  20 245-252
• 143 De Stefano V, Martinelli T, Rossi E et al.. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis.  Br J Haematol. 2006;  135 386-391
• 144 Hoibraaten E, Qvigstad E, Arnesen H et al.. Increased risk of recurrent venous thromboembolism during hormone replacement therapy. Results of the randomized, double-blind, placebo controlled estrogen in venous thromboembolism trial (EVTET).  Thromb Haemost. 2000;  84 961-969