In families with inherited thrombophilia the risk of venous thromboembolism is dependent on the clinical phenotype of the proband

Elena Rossi; Angela Ciminello; Tommaso Za; Silvia Betti; Giuseppe Leone; Valerio De Stefano

doi:10.1160/TH11-02-0080

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2011; 106(04): 646-654
DOI: 10.1160/TH11-02-0080

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

In families with inherited thrombophilia the risk of venous thromboembolism is dependent on the clinical phenotype of the proband

Elena Rossi

¹Institute of Hematology, Catholic University, Rome, Italy

,

Angela Ciminello

¹Institute of Hematology, Catholic University, Rome, Italy

,

Tommaso Za

¹Institute of Hematology, Catholic University, Rome, Italy

,

Silvia Betti

¹Institute of Hematology, Catholic University, Rome, Italy

,

Giuseppe Leone

¹Institute of Hematology, Catholic University, Rome, Italy

,

Valerio De Stefano

¹Institute of Hematology, Catholic University, Rome, Italy

› Institutsangaben

Abstract

Summary

The utility of laboratory investigation of relatives of individuals with inherited thrombophilia is uncertain. To assess the risk of venous thromboembolism (VTE) among the carriers, we investigated a family cohort of 1,720 relatives of probands with thrombophilia who were evaluated because of VTE (n=1,088), premature arterial thrombosis (n=113), obstetric complication (n=257), or universal screening before pregnancy or hormonal contraception or therapy (n=262); 968 relatives were carriers of thrombophilia. A first deep venous thrombosis (DVT) occurred in 44 carriers and 10 non-carriers during 37,688 and 29,548 observationyears from birth, respectively. The risk of DVT among the carriers compared with non-carriers was estimated as a hazard ratio (HR). If the proband had VTE and factor V Leiden (FVL) and/or prothrombin (PT)20210A, the HR for DVT was 2.77 (95%CI 1.21–4.82) in the carriers overall, and 5.54 (95%CI 3.20–187.00) in those homozygous or double heterozygous for FVL and PT20210A. If the proband had VTE and a deficiency of antithrombin (AT), protein C or S, the HR for DVT was 5.14 (95%CI 0.88–10.03) in the carriers overall, and 12.86 (95%CI 2.46–59.90) in those with AT deficiency. No increase in risk was found among the carriers who were relatives of the probands who were evaluated for reasons other than VTE. In conclusion, familial investigation for inherited thrombophilia seems justified for probands with previous VTE, but appears of doubtful utility for the relatives of probands without VTE. This should be taken with caution regarding families with deficiency of natural anticoagulants, given the low number of cases analysed.

Keywords

Inherited thrombophilia - familial screening - risk factors - deep venous thrombosis

Volltext

Referenzen

References
1 De Stefano V, Rossi E, Paciaroni K. et al. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica 2002; 87: 1095-108.
2 De Stefano V. Inherited thrombophilia and life-time risk of venous thromboembolism: is the burden reducible?. J Thromb Haemost 2004; 2: 1522-1525.
3 Vossen CY, Conard J, Fontcuberta J. et al. Familial thrombophilia and life-time risk of venous thrombosis. J Thromb Haemost 2004; 2: 1526-1532.
4 Vossen CY, Conard J, Fontcuberta J. et al. Risk of a 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.
5 Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients?. Br J Haematol 2008; 143: 321-335.
6 Makris M. Thrombophilia: grading the risk. Blood 2009; 113: 5038-5039.
7 Lijfering WM, Brouwer JL, Veeger NJ. et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009; 113: 5314-5322.
8 Kearon C, Kahn SR, Agnelli G. et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 454S-545S.
9 Baglin T, Gray E, Greaves M. et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149: 209-220.
10 De Moerloose P, Boehlen F. Inherited thrombophilia in arterial disease: a selective review. Semin Hematol 2007; 44: 106-113.
11 Lussana F, Dentali F, Abbate R. et al. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009; 124: e19-25.
12 Dallapiccola B, Torrente I, Morena A. et al. Genetic testing in Italy, year 2004. Eur J Hum Genet 2006; 14: 911-916.
13 Suthers G.. Report of the Australian Genetic Testing Survey 2006. Royal College of Pathologists of Australasia, 2009. Available at http://www.rcpa.edu.au/static/File/Assetlibrary/publicdocuments/MediaReleasesAAustralianGeneSurvey2006.pdf
14 Coppens M, van Mourik JA, Eckmann CM. et al. Current practise of testing for inherited thrombophilia. J Thromb Haemost 2007; 5: 1979-1981.
15 Laberge AM, Psaty BM, Hindorff LA. et al. Use of Factor V Leiden genetic testing in practice and impact on management. Genet Med 2009; 11: 750-756.
16 Gartner V, Weber M, Eichinger S. The emotional impact of genetic testing and aspects of counseling prior to prescription of oral contraceptives. Contraception 2008; 78: 392-398.
17 Green D. Genetic hypercoagulability: screening should be an informed choice. Blood 2001; 98: 20.
18 Mannucci PM. Genetic hypercoagulability: prevention suggests testing family members. Blood 2001; 98: 21-22.
19 Martinelli I. Pros and cons of thrombophilia testing: pros. J Thromb Haemost 2003; 1: 410-411.
20 Machin SJ. Pros and cons of thrombophilia testing: cons. J Thromb Haemost 2003; 1: 412-413.
21 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.
22 Sanson BJ, 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.
23 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.
24 Mahmoodi BK, Brouwer JL, Ten Kate MK. et al. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost 2010; 8: 1193-1200.
25 Bank I, Scavenius MP, Büller HR. et al. Social aspects of genetic testing for factor V Leiden mutation in healthy individuals and their importance for daily practice. Thromb Res 2004; 113: 7-12.
26 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.
27 Noboa S, Le Gal G, Lacut K. et al. Family history as a risk factor for venous thromboembolism. Thromb Res 2008; 122: 624-629.
28 Bezemer ID, van der Meer FJ, Eikenboom JC. et al. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med 2009; 169: 610-615.
29 Zöller B, Li X, Sundquist J. et al. Parental history and venous thromboembolism: a nationwide study of age-specific and sex-specific familial risks in Sweden. J Thromb Haemost 2011; 9: 64-70.
30 Sørensen HT, Riis AH, Diaz LJ. et al. Familial risk of venous thromboembolism: a nationwide cohort study. J Thromb Haemost 2011; 9: 320-324.
31 Lensen RP, Bertina RM, de Ronde H. et al. Venous thrombotic risk in family members of unselected individuals with factor V Leiden. Thromb Haemost 2000; 83: 817-821.
32 American College of Obstetricians and Gynecologists. ACOG Committee on Practice Bulletins – Obstetrics. ACOG Practice Bulletin No. 33, January 2002. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2002; 99: 159-167.
33 Audibert F, Friedman SA, Frangieh AY. et al. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 1996; 175: 460-464.
34 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-481.
35 Pabinger I, Kyrle PA, 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.
36 Middeldorp S, Meinardi JR, Koopman MM. et al. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Intern Med 2001; 135: 322-327.
37 Coppens M, van de Poel MH, Bank I. et al. A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation. Blood 2006; 108: 2604-2607.
38 Martinelli I, Mannucci PM, De Stefano V. et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92: 2353-2358.
39 Middeldorp S, Henkens CM, Koopman MM. 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.
40 Bucciarelli P, Rosendaal FR, Tripodi A. et al. 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: 1026-1033.
41 Simioni P, Sanson BJ, Prandoni P. et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81: 198-202.
42 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.
43 Tirado I, Mateo J, Soria JM. 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.
44 Tormene D, Simioni P, Pagnan A. et al. The G20210A prothrombin gene mutation: is there room for screening families?. J Thromb Haemost 2004; 2: 1487-1488.
45 Bank I, Libourel EJ, 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.
46 Brouwer JL, Veeger NJ, Kluin-Nelemans HC. et al. The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes. Ann Intern Med 2006; 145: 807-815.
47 Couturaud F, Kearon C, Leroyer C. et al. Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. Thromb Haemost 2006; 96: 744-749.