Download PDF
Thromb Haemost 1999; 81(02): 198-202
DOI: 10.1055/s-0037-1614442
Review Articles
Schattauer GmbH

Incidence of Venous Thromboembolism in Families with Inherited Thrombophilia

Paolo Simioni
1   From the Department of Medical and Surgical Sciences, University Hospital of Padua, Italy
,
Bernd-Jan Sanson
2   Department of Clinical Epidemiology and Biostatistics Amsterdam, The Netherlands
,
Paolo Prandoni
1   From the Department of Medical and Surgical Sciences, University Hospital of Padua, Italy
,
Daniela Tormene
1   From the Department of Medical and Surgical Sciences, University Hospital of Padua, Italy
,
Philip W. Friederich
2   Department of Clinical Epidemiology and Biostatistics Amsterdam, The Netherlands
,
Bruno Girolami
1   From the Department of Medical and Surgical Sciences, University Hospital of Padua, Italy
,
Sabrina Gavasso
1   From the Department of Medical and Surgical Sciences, University Hospital of Padua, Italy
,
Menno V. Huisman
3   Centre for Haemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic Medical Centre, Amsterdam, The Netherlands
,
Harry R. Büller
3   Centre for Haemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic Medical Centre, Amsterdam, The Netherlands
,
Jan Wouter ten Cate
3   Centre for Haemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic Medical Centre, Amsterdam, The Netherlands
,
Antonio Girolami
1   From the Department of Medical and Surgical Sciences, University Hospital of Padua, Italy
,
Martin H. Prins
2   Department of Clinical Epidemiology and Biostatistics Amsterdam, The Netherlands
› Author AffiliationsThis paper is supported in part by Grant from Regione del Veneto, Giunta Regionale, Ricerca Sanitaria Finalizzata n. 483/03/94 and 783/01/97, Venezia, Italy (to PS).
Further Information

Publication History

Received25 May 1998

Accepted after resubmission30 October 1998

Publication Date:
08 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

The risk of spontaneous or risk-period related venous thromboembolism in family members of symptomatic carriers of antithrombin (AT), protein C (PC) or protein S (PS) defects, as well as of the Factor V Leiden mutation is still undefined. We performed a retrospective cohort study in family members (n = 793) of unselected patients with a documented venous thromboembolism and one of these deficiencies to make an estimate of this risk. The annual incidences of total and spontaneous venous thromboembolic events in carriers of AT, PC or PS defects (n = 181) were 1.01% and 0.40%, respectively, as compared to 0.10% and 0.04% in non-carriers, respectively (relative risks both 10.6). In carriers of Factor V Leiden (n = 224), the annual incidences of total and spontaneous venous thromboembolism were 0.28% and 0.11%, respectively, as compared to 0.09% and 0.04% in non-carriers, respectively (relative risks 2.8 and 2.5). Additional risk factors (immobilisation, surgery and trauma; oral contraceptive use; and pregnancy/ post-partum) increased the risk of thrombosis in carriers of AT, PC and PS defects as compared to non-carriers (relative risks 8.3, 6.4 and 8.2, respectively). Oral contraceptive use and pregnancy/ post-partum period increased the risk of thrombosis in carriers of Factor V Leiden to 3.3-fold and 4.2-fold, respectively, whereas other risk factors had only a minor effect.

These data lend some support to the practice of screening family members of symptomatic carriers of a AT, PC and PS deficiency. For family members of symptomatic carriers of Factor V Leiden, screening does not seem to be justified except for women in fertile age.

 

  • References

  • 1 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-30.
    PubMedGoogle Scholar
  • 2 Griffin JH, Evatt B, Zimmerman T, Kleiss A, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-3.
    CrossrefPubMedGoogle Scholar
  • 3 Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 24: 1525-8.
    PubMedGoogle Scholar
  • 4 Schwartz HP, Fisher M, Hopmeier P, Batard M, Griffin J. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-300.
    PubMedGoogle Scholar
  • 5 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-8.
    CrossrefPubMedGoogle Scholar
  • 6 Bertina R M, Koeleman BPC, 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: 64-7.
    CrossrefPubMedGoogle Scholar
  • 7 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: 1512-6.
    CrossrefPubMedGoogle Scholar
  • 8 Pabinger I, Brucker S, Kyrle PA, Schneider B, Korninger HC, Niessner H, Lechner K. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coag Fibrinol 1992; 3: 547-53.
    CrossrefPubMedGoogle Scholar
  • 9 De Stefano V, Leone G, Mastrangelo S, Tripodi A, Rodeghiero F, Castaman G, Barbui T, Finazzi G, Bizzi B, Mannucci PM. Clinical manifestation 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: 352-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Finazzi G, Barbui T. Difference incidence of venous thrombosis in patients with inherited deficiencies of antithrombin III, protein C and protein S. Thromb Haemost 1994; 71: 15-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Koster T, Rosendaal FR, Briët E, van der Meer FJM, Colly LP, Trienekens PH, Poort SR, Reitsma PH, 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: 2756-61.
    PubMedGoogle Scholar
  • 12 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
    CrossrefPubMedGoogle Scholar
  • 13 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-22.
    CrossrefPubMedGoogle Scholar
  • 14 Pabinger I, Kyrle PA, 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: 441-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 van den Belt AGM, Prins MH, Huisman MV, Hirsh J. Familial thrombophilia. A review analysis. Clin Appl Thromb Hemost 1996; 2: 227-36.
    CrossrefPubMedGoogle Scholar
  • 16 Middeldorp S, Henkens CMA, Koopman MMW, van Pampus ECM, Hamulyak K, van der Meer J, Prins MH, Büller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Int Med 1998; 128: 15-20.
    CrossrefPubMedGoogle Scholar
  • 17 Lensen RPM, Rosendaal FR, Koster T, Allaart CF, de Ronde H, Vandenbroucke JP, Reitsma PH, Bertina RM. Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients. Blood 1996; 88: 4205-8.
    PubMedGoogle Scholar
  • 18 Villalta S, Prandoni P, Cogo A, Bagatella P, Piccioli A, Bernardi E, Simioni P, Scarano L, Girolami A. The utility of non-invasive tests for the detection of previous proximal vein thrombosis. Thromb Haemost 1995; 73: 592-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Friederich PW, Sanson B-J, Simioni P, Zanardi S, Huisman MV, Kindt I, Prandoni P, Buller HR, Girolami A, Prins MH. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis. Ann Int Med 1996; 125: 955-60.
    CrossrefPubMedGoogle Scholar
  • 20 van Boven HH, Lane DA. Antithrombin and its inherited deficiency states. Semin Hematol 1998; 34: 188-204.
    PubMedGoogle Scholar
  • 21 Aiach M, Borgel D, Gaussem P, Emmerich J, Ahlenc-Gelas M, Gandrille S. Protein C and protein S deficiencies. Semin Hematol 1998; 34: 205-17.
    PubMedGoogle Scholar
  • 22 Simioni P, Scudeller A, Radossi P, Gavasso S, Girolami B, Tormene D, Girolami A. Pseudo-homozygous activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds. Thromb Haemost 1996; 75: 422-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Simioni P, Prandoni P, Lensing AWA, Scudeller A, Sardella C, Prins MH, Villalta S, Dazzi F, Girolami A. The risk of recurrent venous thromboembolism in patients with an Arg506 --- Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997; 336: 399-403.
    CrossrefPubMedGoogle Scholar
  • 24 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: 155-60.
    CrossrefPubMedGoogle Scholar
  • 25 Engesser L, Broekmans AW, Briet E, Brommer EJP, Bertina RM. Hereditary protein S deficiency: clinical manifestations. Ann Int Med 1987; 106: 677-82.
    CrossrefPubMedGoogle Scholar
  • 26 Pabinger I, Schneider B. for the GTH Study Group on Natural Inhibitors. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. Arterioscler Thromb Vasc Biol 1996; 16: 742-8.
    CrossrefPubMedGoogle Scholar