Factor V Leiden and Prothrombin Gene G20210A Mutation in Children with Venous Thromboembolism

Summary

To determine whether factor V Leiden (FVL) and/or prothrombin gene G20210A mutation (PT20210A) are risk factors for venous thromboembolism (VTE) in Argentinean children. One hundred and thirty consecutive children with VTE were prospectively assisted at a single centre. Blood samples were available from 110 of them for detailed haematological analysis. The prevalence of both mutations was compared with a control group. The odds ratio for VTE was significantly increased in patients with FVL (OR 3.64; 95% CI: 1.14-11.6, p <0.029) whereas odds ratio for VTE was not significantly increased in patients with PT20210A (OR 1.06; 95% CI: 0.24-4.73, p = 0.938). Combined disorders were found in 5 of the 10 children with the aforementioned mutations. In 21 children (19%) without these mutations other inherited and acquired disorders were detected. Our data show that FVL is a risk factor for VTE whereas PT20210A does not seem to be a risk factor in our paediatric population.

Keywords

Venous thromboembolism - Factor V Leiden - prothrombin gene G20210A mutation - children - prothrombotic abnormalities

• References

• 1 Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, Bernstein M, Brisson L, Cairney B, DeSai D, Grant R, Israels S, Jardine L, Luke B, Massicotte P, Silva M. Venous thromboembolic complications (VTE) in children: first analysis of the Canadian Registry of VTE. Blood 1994; 83: 1251-7.
• 2 Blanco A, Bonduel M, Peñalva L, Hepner M, Lazzari M. Deep vein thrombosis in a 13-year-old boy with hereditary protein S deficiency and a review of the pediatric literature. Am J Hematol 1994; 45: 330-4.
• 3 Manco-Johnson MJ, Nuss R. Lupus anticoagulant in children with thrombosis. Am J Hematol 1995; 48: 240-3.
• 4 Nuss R, Hays T, Manco-Johnson M. Childhood Thrombosis. Pediatrics 1995; 96: 291-4.
• 5 Seaman DE, Londino Jr AV, Kwoh CK, Medsger Jr TA, Manzi S. Antiphospholipid antibodies in pediatric systemic lupus erythematosus. Pediatrics 1995; 96: 1040-5.
• 6 Aschka I, Aumann V, Bergmann F, Budde U, Eberl W, Eckhof-Donovan S, Krey S, Nowak-Göttl U, Schobess R, Sutor AH, Wendish J, Schneppenheim R. Prevalence of factor V Leiden in children with thrombo-embolism. Eur J Pediatr 1996; 155: 1009-14.
• 7 Manco-Johnson MJ. Disorders of hemostasis in childhood: Risk factors for venous thromboembolism. Thromb Haemost 1997; 78: 710-4.
• 8 Nowak-Göttl U, Dübbers A, Kececioglu D, Koch HG, Kotthoff S, Runde J, Vielhaber H. Factor V Leiden, protein C, and lipoprotein (a) in catheterrelated thrombosis in childhood: A prospective study. J Pediatr 1997; 131: 608-12.
• 9 Nuss R, Hays T, Chudgar U, Manco-Johnson M. Antiphospholipid antibodies and coagulation regulatory protein abnormalities in children with pulmonary emboli. J Pediatr Hematol Oncol 1997; 19: 202-7.
• 10 Junker R, Koch HG, Auberger K, Münchow N, Ehrenforth S, Nowak-Göttl U. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol 1999; 19: 2568-72.
• 11 Schobess R, Junker R, Auberger K, Münchow N, Burdach S, Nowak-Göttl U. Factor V G1691A and prothrombin G20210A in childhood spontaneous venous thrombosis – Evidence of an age-dependent thrombotic onset in carriers of factor V G1691A and prothrombin G20210A mutation. Eur J Pediatr 1999; 158 (Suppl. 03) 105-8.
• 12 Bonduel M, Hepner M, Sciuccati G, Feliú ATorres, Pieroni G, Frontroth JP. Prothrombotic abnormalities in children with venous thromboembolism. J Pediatr Hematol Oncol 2000; 22: 66-72.
• 13 Andrew M, Monagle PT, Brooker L. Congenital prothrombotic disorders: presentation during infancy and childhood. In: Thromboembolic complications during infancy and childhood. Andrew M, Monagle PT, Brooker L, Hamilton BC. eds. London: Decker Inc; 2000: 47-110.
• 14 Nowak-Göttl U, Junker R, Kreuz W, von Eckardstein A, Koch A, Nohe N, Schobess R, Ehrenforth S. for the childhood thrombophilia study group. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97: 858-62.
• 15 Nowak-Göttl U, Kosch A, Schlegel N. Thromboembolism in newborns, infants and children. Thromb Haemost 2001; 86: 464-75.
• 16 Bertina RM, 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: 64-9.
• 17 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: 3698-703.
• 18 Nowak-Göttl U, Auberger K, Göbel U, Kreuz W, Schneppenheim R, Vielhaber H, Zenz W, Zieger B. Inherited defects of the protein C anticoagulant system in childhood thrombo-embolism. Eur J Pediatr 1996; 155: 921-7.
• 19 Seixas CA, Hessel G, Ribeiro CC, Arruda VR, Annichino-Bizzacchi JM. Factor V Leiden is not common in children with portal vein thrombosis. Thromb Haemost 1997; 77: 258-61.
• 20 Sifontes MT, Nuss R, Hunger SP, Waters J, Jacobson LJ, Manco-Johnson MJ. Activated protein C resistance and the factor V Leiden mutation in children with thrombosis. Am J Hematol 1998; 57: 29-32.
• 21 Fabri D, Belangero VMS, Annichino-Bizzacchi JM, Arruda VR. Inherited risk factors for thrombophilia in children with nephrotic syndrome. Eur J Pediatr 1998; 157: 939-42.
• 22 Hagstrom JN, Walter J, Bluebond-Langner R, Amatniek JC, Manno CS, High KA. Prevalence of the factor V Leiden mutation in children and neonates with thromboembolic disease. J Pediatr 1998; 133: 777-81.
• 23 Gurgey A. Clinical manifestations in thrombotic children with factor V Leiden mutation. Pediatr Hematol Oncol 1999; 16: 233-7.
• 24 Heller C, Schobess R, Kurnik K, Junker R, Günter G, Kreuz W, Nowak-Göttl U. Abdominal venous thrombosis in neonates and infants: role of prothrombotic risk factors – a multicentre case-control study. Br J Haematol 2000; 111: 534-9.
• 25 Laurell CB. Electroimmuno assay. Scand J Clin Lab Invest 1972; 29: 21-37.
• 26 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with thrombosis. J Clin Invest 1984; 74: 2082-8.
• 27 Brandt JT, Triplett DA, Alvin B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: An update. On behalf of the Subcommittee on lupus anticoagulant/antiphospholipid antibody of the scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 74: 1185-90.
• 28 Triplett DA, Brandt JT, Kaczor D, Schaeffer J. Laboratory diagnosis of lupus inhibitors: a comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983; 79: 678-82.
• 29 Harris EN, Gharavi AE, Patel SP, Hughes GR. Evaluation of the anticardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol 1987; 68: 215-22.
• 30 Harris EN, Khamashta MA, Hughes GRV. Antiphospholipid antibody syndrome. In: Arthritis and Allied Conditions. Mc DJCarthy, Koopman WJ. eds. 12th ed.. Lea & Febiger: Philadelphia; 1991: 1201-12.
• 31 Hézard N, Cornillet-Lefebyre P, Gillot L, Potron L, Nguyen P. Multiplex ASA PCR for a simultaneous determination of factor V Leiden gene, G→A 20210 prothrombin gene and C→T 677 MTHFR gene mutations. Thromb Haemost 1998; 79: 1054-5.
• 32 David M, Andrew M. Venous thromboembolic complications in children. J Pediatr 1993; 123: 337-46.
• 33 Andrew M, Monagle PT, Brooker L. Epidemiology of venous thromboembolic events. In: Thromboembolic complications during infancy and chilhood. Andrew M, Monagle PT, Brooker L. eds. B.C. Hamilton, London: Decker Inc; 2000: 111-46.
• 34 Rosendaal FR. Risk factors for venous thrombosis: prevalence, risk, and interaction. Sem Haematol 1997; 34: 171-87.
• 35 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-31.
• 36 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: 651-62.
• 37 Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haematol 1996; 95: 579-86.
• 38 Koster T, Rosendaal FR, De Donde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated Protein C: Leiden thrombophilia study. Lancet 1993; 342: 1503-6.
• 39 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in the majority of thrombophilic patients. Blood 1993; 82: 1989-93.
• 40 Svenson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Eng J Med 1994; 330: 517-22.
• 41 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: 706-8.
• 42 Martinelli 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: 1223-9.
• 43 Koeleman BP, Reitsma PH, Allart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families. Blood 1994; 84: 1031-5.
• 44 Zoller B, Berntsdotter A, García de Frutos P, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-23.
• 45 Ireland H, Bayston T, Chowdhury V, Lay SThein, Conard J, Pabinger I, Lane D. Factor V Leiden as an independent risk factor for thrombosis and antithrombin deficiency type II: Heparin binding site (Abstract). Thromb Haemost 1995; 73: 1764.
• 46 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-29.
• 47 Salomon O, Steinberg DM, Zivelin A, Gitel S, Dardik R, Rosenberg N, Berliner S, Inbal A, Many A, Lubetsky A, Varon D, Martinowitz U, Seligsohn U. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol 1999; 19: 511-8.
• 48 Hepner M, Roldan A, Pieroni G, Frontroth JP, Serviddio RM, Feliú ATorres, Sciuccati G, Bonduel M. Factor V Leiden mutation in the Argentinian population. Thromb Haemost 1999; 81: 989.