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Inherited thrombophilia and life‐time risk of venous thromboembolism: is the burden reducible?

2004; Elsevier BV; Volume: 2; Issue: 9 Linguagem: Inglês

10.1111/j.1538-7836.2004.00863.x

1538-7933

Valerio De Stefano,

Acute Myocardial Infarction Research

Risk is defined by the World Health Organization as a probability of an adverse outcome, or a factor that raises this probability; the identification of high‐risk individuals enables targeted risk factor modification, and the potential for tailored treatment [1World Health Organization.The World Health Report. WHO, 2002Google Scholar]. Inherited traits clearly associated with an increased risk for venous thromboembolism (VTE) are nowadays detectable in about 40% of patients and in more than 5% of the general population [2De Stefano V. Rossi E. Paciaroni K. Leone G. Screening for inherited thrombophilia: indications and therapeutic implications.Haematologica. 2002; 87: 1095-108PubMed Google Scholar]. Thus the possibility of identifying individuals more prone to VTE than the baseline (0.1% person‐years [3Nordstrom 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: 155-60Crossref PubMed Google Scholar]) should prompt laboratory screening in order to improve primary or secondary antithrombotic measures. Unfortunately, in spite of recent advances in this field, the tendency to first or recurrent VTE appears to date only roughly predictable among single individuals, carriers or not of thrombophilic gene mutations. This produces uncertainty in the approach to patient management [4Bauer KA. The thrombophilias: well‐defined risk factors with uncertain therapeutic implications.Ann Intern Med. 2001; 135: 367-73Crossref PubMed Google Scholar, 5Bauer KA, Rosendaal FR, Heit JA. Hypercoagulability: too many tests, too much conflicting data. Hematology (Am Soc Hematol Educ Program) 2002; 353–68.Google Scholar]; moreover, the opportunity of screening asymptomatic relatives of index VTE patients with thrombophilia has been debated and questioned as not cost‐effective, claiming in them a low absolute risk for VTE [6Green D. Genetic hypercoagulability: screening should be an informed choice.Blood. 2001; 98: 20Crossref PubMed Scopus (0) Google Scholar, 7Mannucci PM. Genetic hypercoagulability: prevention suggests testing family members.Blood. 2001; 98: 21-2Crossref PubMed Scopus (0) Google Scholar, 8Martinelli I. Pros and cons of thrombophilia testing: pros.J Thromb Haemost. 2003; 1: 410-1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 9Machin SJ. Pros and cons of thrombophilia testing: cons.J Thromb Haemost. 2003; 1: 412-3Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 10Middeldorp S. Henkens C.M. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.Ann Intern Med. 1998; 128: 15-20Crossref PubMed Google Scholar, 11Middeldorp S. Meinardi J.R. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism.Ann Intern Med. 2001; 135: 322-7Crossref PubMed Google Scholar]. Several retrospective or prospective family studies investigated the risk for VTE among the relatives of thrombotic patients with thrombophilia, as recently reviewed [12Langlois N.J. Wells PS. Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review.Thromb Haemost. 2003; 90: 17-26Crossref PubMed Scopus (56) Google Scholar]. In a first small prospective study on 44 asymptomatic relatives with protein C (PC) or protein S (PS) deficiency the incidence of VTE was 2.5% patient‐years and 3.2% patient‐years, respectively [13Pabinger I. Kyrle P.A. Heistinger M. Eichinger S. Wittmann E. Lechner K. The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study.Thromb Haemost. 1994; 71: 441-5Crossref PubMed Scopus (120) Google Scholar]. In a prospective investigation on 208 asymptomatic relatives with antithrombin (AT), PC, or PS deficiency the overall incidence of VTE was 1.5% patient‐years (4.0 for AT deficiency, 0.98 for PC deficiency, and 0.7 for PS deficiency) [14Sanson B.J. Simioni P. Tormene D. Moia M. Friederich P.W. Huisman M.V. Prandoni P. Bura A. Rejto L. Wells P. Mannucci P.M. Girolami A. Buller H.R. Prins MH. 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: 3702-6PubMed Google Scholar]. A lower incidence of VTE was reported in two large prospective studies on 470 and 313 asymptomatic relatives with factor (F)V Leiden (0.58 and 0.67% patient‐years, respectively) [11Middeldorp S. Meinardi J.R. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism.Ann Intern Med. 2001; 135: 322-7Crossref PubMed Google Scholar, 15Simioni P. Tormene D. Prandoni P. Zerbinati P. Gavasso S. Cefalo P. Girolami A. Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study.Blood. 2002; 99: 1938-42Crossref PubMed Scopus (96) Google Scholar]. However the average observation time of such studies was never longer than 5 years [11Middeldorp S. Meinardi J.R. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism.Ann Intern Med. 2001; 135: 322-7Crossref PubMed Google Scholar, 13Pabinger I. Kyrle P.A. Heistinger M. Eichinger S. Wittmann E. Lechner K. The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study.Thromb Haemost. 1994; 71: 441-5Crossref PubMed Scopus (120) Google Scholar, 14Sanson B.J. Simioni P. Tormene D. Moia M. Friederich P.W. Huisman M.V. Prandoni P. Bura A. Rejto L. Wells P. Mannucci P.M. Girolami A. Buller H.R. Prins MH. 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: 3702-6PubMed Google Scholar, 15Simioni P. Tormene D. Prandoni P. Zerbinati P. Gavasso S. Cefalo P. Girolami A. Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study.Blood. 2002; 99: 1938-42Crossref PubMed Scopus (96) Google Scholar]; therefore, a more reliable estimate of the life‐time risk for VTE among the relatives of proband patients with thrombophilia has been achieved from several retrospective investigations, with some obvious limitations [10Middeldorp S. Henkens C.M. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.Ann Intern Med. 1998; 128: 15-20Crossref PubMed Google Scholar, 16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 18Bucciarelli P. Rosendaal F.R. Tripodi A. Mannucci P.M. De Stefano V. Palareti G. Finazzi G. Baudo F. Quintavalla R. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.Arterioscler Thromb Vasc Biol. 1999; 19: 1026-33Crossref PubMed Google Scholar, 19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar, 20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar]. The number of recruited affected relatives ranged from 181 to 290 for AT, PC, or PS deficiency [16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 18Bucciarelli P. Rosendaal F.R. Tripodi A. Mannucci P.M. De Stefano V. Palareti G. Finazzi G. Baudo F. Quintavalla R. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.Arterioscler Thromb Vasc Biol. 1999; 19: 1026-33Crossref PubMed Google Scholar, 19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar] and from 200 to 447 for FV Leiden [10Middeldorp S. Henkens C.M. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.Ann Intern Med. 1998; 128: 15-20Crossref PubMed Google Scholar, 16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 18Bucciarelli P. Rosendaal F.R. Tripodi A. Mannucci P.M. De Stefano V. Palareti G. Finazzi G. Baudo F. Quintavalla R. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.Arterioscler Thromb Vasc Biol. 1999; 19: 1026-33Crossref PubMed Google Scholar, 20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar], with a total of 6524–26 488 life‐years computed [10Middeldorp S. Henkens C.M. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.Ann Intern Med. 1998; 128: 15-20Crossref PubMed Google Scholar, 16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 18Bucciarelli P. Rosendaal F.R. Tripodi A. Mannucci P.M. De Stefano V. Palareti G. Finazzi G. Baudo F. Quintavalla R. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.Arterioscler Thromb Vasc Biol. 1999; 19: 1026-33Crossref PubMed Google Scholar, 20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar]. The incidence of VTE percentage patient‐years was 1.0–2.94 for AT deficiency, 0.36–0.72 for PC deficiency, 0.5–1.04 for PS deficiency [16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 18Bucciarelli P. Rosendaal F.R. Tripodi A. Mannucci P.M. De Stefano V. Palareti G. Finazzi G. Baudo F. Quintavalla R. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.Arterioscler Thromb Vasc Biol. 1999; 19: 1026-33Crossref PubMed Google Scholar, 19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar], and 0.19–0.30 for FV Leiden [10Middeldorp S. Henkens C.M. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.Ann Intern Med. 1998; 128: 15-20Crossref PubMed Google Scholar, 16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 18Bucciarelli P. Rosendaal F.R. Tripodi A. Mannucci P.M. De Stefano V. Palareti G. Finazzi G. Baudo F. Quintavalla R. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.Arterioscler Thromb Vasc Biol. 1999; 19: 1026-33Crossref PubMed Google Scholar, 20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar]. In two family studies on 89 and 158 affected relatives with prothrombin (PT) 20210A the incidence of VTE percentage patient‐years was 0.23 and 0.13, respectively [19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar, 20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar]. In the investigations employing the unaffected relatives as reference group the increase in risk for VTE was about 6–10‐fold for AT, PC, or PS deficiency, the higher risk being associated with AT deficiency [16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar], 2.8–6.6‐fold for FV Leiden [10Middeldorp S. Henkens C.M. Koopman M.M. Van Pampus E.C. Hamulyak K. Van Der Meer J. Prins M.H. Buller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.Ann Intern Med. 1998; 128: 15-20Crossref PubMed Google Scholar, 15Simioni P. Tormene D. Prandoni P. Zerbinati P. Gavasso S. Cefalo P. Girolami A. Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study.Blood. 2002; 99: 1938-42Crossref PubMed Scopus (96) Google Scholar, 16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar], and 2–4.2‐fold for PT 20210A [19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar, 20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar]. Fewer data are available concerning the risk for VTE among relatives with multiple defects. In two investigations recruiting 14 and 35 relatives with combined defects, the incidence of VTE percentage patient‐years was 0.42 and 0.67, respectively [18Bucciarelli P. Rosendaal F.R. Tripodi A. Mannucci P.M. De Stefano V. Palareti G. Finazzi G. Baudo F. Quintavalla R. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.Arterioscler Thromb Vasc Biol. 1999; 19: 1026-33Crossref PubMed Google Scholar, 20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar], with a relative risk vs. non‐carrier relatives of 6.4‐fold [20Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM. 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: 1223-9Crossref PubMed Scopus (115) Google Scholar]. A family study reported data on 722 relatives of probands with AT, PC, or PS deficiency, of whom 67 had combined defects. The increase in risk for VTE was 5.3–20.4‐fold for various combinations of multiple defects in comparison with non‐carrier relatives [19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar]. However, such figures are susceptible to underestimation, since the investigated subjects are generally censored after the first VTE event. Moreover, it should be remembered that family studies exclude the index patients. This strategy avoids any referral bias but undoubtely does not allow a complete estimate of the overall thrombophilia‐related risk of the whole kindred, having excluded the individuals presumably at higher risk. In the present issue of the journal Vossen et al. [21Vossen C.Y. Conard J. Fontcuberta J. Makris M. Van Der Meer F.J.M. Pabinger I. Palareti G. Preston F.E. Scharrer I. Souto J.C. Svensson P. Walker I.D. Rosendaal FR. Familial thrombophilia and life‐time risk of venous thrombosis.J Thromb Haemost. 2004; 2: 1526-32Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] report the data concerning the clinical histories of the individuals enrolled in the European Prospective Cohort on Thrombophilia (EPCOT) prior to study entry. Inclusion of the participants took place mostly in 1994 and 1995, explaining the relatively low number of individuals with FV Leiden. Data concern 600 probands and 846 affected relatives in comparison with 1212 unrelated controls. Among the relatives 526 carried AT, PC, or PS deficiency, 225 FV Leiden, and 95 combined defects (including PT 20210A, successively tested in 64% of the participants). The total life‐years computed in relatives are 31 660 (19 152 for AT, PC, or PS deficiency and 3322 for the combined defects). Thus this cohort is the largest so far reported on individuals with AT, PC, or PS deficiency or with multiple defects, producing highly reliable information. Among relatives the incidence of VTE percentage patient‐years was 0.71 for AT deficiency, 0.44 for PC deficiency, 0.31 for PS deficiency, 0.15 for FV Leiden, and 0.84 for the multiple defects. Such incidences are slightly lower than those previously reported for AT, PC, or PS deficiency [13Pabinger I. Kyrle P.A. Heistinger M. Eichinger S. Wittmann E. Lechner K. The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study.Thromb Haemost. 1994; 71: 441-5Crossref PubMed Scopus (120) Google Scholar, 14Sanson B.J. Simioni P. Tormene D. Moia M. Friederich P.W. Huisman M.V. Prandoni P. Bura A. Rejto L. Wells P. Mannucci P.M. Girolami A. Buller H.R. Prins MH. 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: 3702-6PubMed Google Scholar, 16Simioni P. Sanson B.J. Prandoni P. Tormene D. Friederich P.W. Girolami B. Gavasso S. Huisman M.V. Buller H.R. Wouter ten Cate J. Girolami A. Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia.Thromb Haemost. 1999; 81: 198-202Crossref PubMed Scopus (310) Google Scholar, 17Martinelli I. Mannucci P.M. De Stefano V. Taioli E. Rossi V. Crosti F. Paciaroni K. Leone G. Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.Blood. 1998; 92: 2353-8Crossref PubMed Google Scholar, 18Bucciarelli P. Rosendaal F.R. Tripodi A. Mannucci P.M. De Stefano V. Palareti G. Finazzi G. Baudo F. Quintavalla R. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study.Arterioscler Thromb Vasc Biol. 1999; 19: 1026-33Crossref PubMed Google Scholar, 19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar]. This may be due to a higher efficiency in detection of combined defects, in the older studies in part labeled as single deficiencies: in a report from Spain 49 of 245 (20%) affected relatives of probands with AT, PC, or PS deficiency also carried FV Leiden or PT 20210A [19Tirado I. Mateo J. Soria J.M. Oliver A. Borrell M. Coll I. Vallve C. Souto J.C. Martinez‐Sanchez E. Fontcuberta J. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.Haematologica. 2001; 86: 1200-8PubMed Google Scholar]. However, the control group in the paper of Vossen et al. [21Vossen C.Y. Conard J. Fontcuberta J. Makris M. Van Der Meer F.J.M. Pabinger I. Palareti G. Preston F.E. Scharrer I. Souto J.C. Svensson P. Walker I.D. Rosendaal FR. Familial thrombophilia and life‐time risk of venous thrombosis.J Thromb Haemost. 2004; 2: 1526-32Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] also showed a relatively low incidence of VTE (0.03% person‐years). Thus the increase in risk for VTE was 11–26‐fold for AT, PC, or PS deficiency, 5‐fold for FV Leiden, and 31‐fold for combined defects, confirming the higher risk in individuals with deficiency in natural anticoagulants or with combined defects. Although relatively rare, such genotypes are in any case present in at least 10% of patients with VTE and should justify per se laboratory screening among probands and their relatives [2De Stefano V. Rossi E. Paciaroni K. Leone G. Screening for inherited thrombophilia: indications and therapeutic implications.Haematologica. 2002; 87: 1095-108PubMed Google Scholar]. Overall, the incidence of VTE increases with age (from 0.44% patient‐year in the whole cohort of relatives to 1.09 after 45 years of age); yet the relative risk for VTE decreases with age (from 15.7‐fold in the whole cohort to 10.2‐fold after 45 years), probably due to a more pronounced effect of aging on the risk for VTE among the controls [21Vossen C.Y. Conard J. Fontcuberta J. Makris M. Van Der Meer F.J.M. Pabinger I. Palareti G. Preston F.E. Scharrer I. Souto J.C. Svensson P. Walker I.D. Rosendaal FR. Familial thrombophilia and life‐time risk of venous thrombosis.J Thromb Haemost. 2004; 2: 1526-32Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. This mirrors the lower probability of being free of VTE at 45 years among relatives with severe thrombophilia (deficiency of natural anticoagulants or multiple defects) in comparison with controls (74–87% for AT, PC, or PS deficiency, 67% for multiple defects, and 96% for controls); it is noteworthy that 94% of carriers of FV Leiden were thrombosis‐free at 45 years [21Vossen C.Y. Conard J. Fontcuberta J. Makris M. Van Der Meer F.J.M. Pabinger I. Palareti G. Preston F.E. Scharrer I. Souto J.C. Svensson P. Walker I.D. Rosendaal FR. Familial thrombophilia and life‐time risk of venous thrombosis.J Thromb Haemost. 2004; 2: 1526-32Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Such figures confirm previous observations suggesting an aging‐related risk for VTE more pronounced in carriers of mild thrombophilia (FV Leiden or PT 20210A) and a clinical onset at young age more typical for carriers of severe thrombophilia [22Ridker P.M. Glynn R.J. Miletich J.P. Goldhaber S.Z. Stampfer M.J. Hennekens CH. Age‐specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation.Ann Intern Med. 1997; 126: 528-31Crossref PubMed Google Scholar, 23De Stefano V. Rossi E. Paciaroni K. D'Orazio A. Cina G. Marchitelli E. Pepe R. Leone G. Different circumstances of the first venous thromboembolism among younger or older heterozygous carriers of the G20210A polymorphism in the prothrombin gene.Haematologica. 2003; 88: 61-6PubMed Google Scholar]. The degree of association of circumstantial (transient)