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Thromb Haemost 1999; 81(04): 502-505
DOI: 10.1055/s-0037-1614513
Rapid Communication
Schattauer GmbH

Factor V Leiden (Arg506Gln), a Confounding Genetic Risk Factor but not Mandatory for the Occurrence of Venous Thromboembolism in Homozygotes and Obligate Heterozygotes for Cystathionine β-synthase Deficiency

S. Yap
1   From the National Centre for Inherited Metabolic Disorders, Dublin, Ireland
,
K. A. O’Donnell
2   Department of Pathology, Dublin, Ireland
,
C. O’Neill
2   Department of Pathology, Dublin, Ireland
,
P. D. Mayne
2   Department of Pathology, Dublin, Ireland
,
P. Thornton
1   From the National Centre for Inherited Metabolic Disorders, Dublin, Ireland
,
E. Naughten
1   From the National Centre for Inherited Metabolic Disorders, Dublin, Ireland
› Author Affiliations
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Publication History

Received 14 April 1998

Accepted after resubmission 06 January 1999

Publication Date:
09 December 2017 (online)

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Summary

Thrombosis is the major cause of morbidity and mortality in individuals with untreated classical homocystinuria (HCU) due to cystathionine β-synthase deficiency and characterised by severe hyperhomocysteinaemia. In addition, mild and moderate hyperhomocysteinaemia and Factor V Leiden (FVL; Arg506Gln) have recently been identified as thrombotic risk factors. FVL, which renders resistance to activated Protein C, is the most common inherited genetic risk factor for thrombosis with a high allelic frequency amongst Caucasians. As thrombophilia is a multigenic disorder, 26 individuals with HCU (median age 17.6 years, range 3.5-32.8 years) and 36 obligate heterozygotes (median age 51.5 years, range 34-74 years) were screened for FVL. All the HCU individuals received treatment, except one, within 6 weeks of birth for those who were diagnosed at birth through the national newborn screening programme (n = 20) and at the time of diagnosis for those late detected (n = 5, mean age of starting treatment 4.9 years, range 1.4-11 years). All had been free from venous thrombosis, except one HCU individual and one HCU obligate heterozygote. Neither of the two individuals with venous thrombosis carried FVL. Two independent individuals with HCU (male 14.8 years; female 18.2 years) were heterozygous for FVL (allelic frequency 3.8%) and three independent HCU obligate heterozygotes (males 40 and 45.8 years; female 45.6 years) were also heterozygous for FVL (allelic frequency 4.16%). The findings in this small group suggest that FVL is not a mandatory but a significant confounding risk factor for the occurrence of thrombosis in HCU individuals and additional contributing factors may be required for thrombosis to occur in HCU obligate heterozygotes with FVL heterozygosity. Our data also suggest that treatment of HCU not only reduces the thrombotic risk in patients with isolated HCU but also in those with the additional FVL heterozygosity.

 

  • References

  • 1 Naughten ER, Yap S, Mayne PD. Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr 1998; 157 (02) Suppl S84-7.
    CrossrefPubMedSearch in Google Scholar
  • 2 Perry TL, Hansen S, MacDougall L, Warrington PD. Sulphur-containing amino acids in the plasma and urine of homocystinurics. Clin Chim Acta 1967; 15: 409-20.
    CrossrefPubMedSearch in Google Scholar
  • 3 Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GHJ, Bromberg IL, Cerone R, Fowler B, Grobe H, Schmidt H, Schweitzer L. The natural history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet 1985; 37: 1-31.
    PubMedSearch in Google Scholar
  • 4 Carson NAJ. Homocystinuria: clinical and biochemical heterogeneity. In Cockburn F, Gitzelmann R. eds Inborn errors of metabolism in humans. Lancaster England: MTP Press Limited; 1982: 53-67.
    CrossrefSearch in Google Scholar
  • 5 Mudd SH, Levy HL, Skovby F. In Scriver CR, Beaudet AL, Sly WS, Valle D. eds The Metabolic and Molecular Bases of Inherited Disease, 7th. edn. New York: McGraw-Hill; 1995: 1279-327.
    Search in Google Scholar
  • 6 Wilcken DEL, Wilcken B. The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest 1976; 57: 1079-82.
    CrossrefPubMedSearch in Google Scholar
  • 7 Den Heijer M, Koster H, Blom HJ, Bos GMJ, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinaemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-62.
    CrossrefPubMedSearch in Google Scholar
  • 8 Boers GHJ, Smals AGH, Trijbels JMF, Fowler B, Bakkeren JAJM, Schoonderwaldt HC, Kleijer WJ, Kloppenberg PWC. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Eng J Med 1985; 313: 709-15.
    CrossrefPubMedSearch in Google Scholar
  • 9 Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocystinemia: an independent risk factor for vascular disease. N Eng J Med 1991; 324: 1149-55.
    CrossrefPubMedSearch in Google Scholar
  • 10 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
    CrossrefPubMedSearch in Google Scholar
  • 11 Bertina RM, Koelman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van den Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
    CrossrefPubMedSearch in Google Scholar
  • 12 Dahlback B. Inherited thrombophilia: Resistance to activated protein C as a pathogenic factor of venous thromboembolism. Review Article. Blood 1995; 85 (03) 607-14.
    PubMedSearch in Google Scholar
  • 13 Koelman BPC, Reitsma PH, Allart RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-5.
    PubMedSearch in Google Scholar
  • 14 Koelman BPC, van Rumpt D, Hamulyak K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families?. Thromb Haemost 1995; 74: 580-3.
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Vanderbroucke JP, Koster T, Briet E, Reistma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.
    CrossrefPubMedSearch in Google Scholar
  • 16 Yap S, Naughten E. Homocystinuria due to cystathionine β-synthase deficiency in Ireland: 25 years experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inher Metab 1998; Dis 12: 738-47.
    PubMedSearch in Google Scholar
  • 17 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 Arg506→ Gln mutation in the gene for factor V. N Eng J Med 1997; 336: 399-403.
    CrossrefPubMedSearch in Google Scholar
  • 18 Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocystinuria and factor V Leiden – Effect on thrombosis. N Eng J Med 1996; 335: 763-8.
    PubMedSearch in Google Scholar
  • 19 Quere I, Lamarti H, Chadefaux-Vekemans B. Thrombophilia, homocystinuria, and muatation of the factor V gene. N Eng J Med 1996; 335: 289
    CrossrefPubMedSearch in Google Scholar
  • 20 Kluijtmans LAJ, Boers GHJ, Verbruggen B, Trijbels FJM, Novakova IRQ, Blom HJ. Homozygous cystathionine β-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis. Blood 1998; 91: 2015-8.
    PubMedSearch in Google Scholar
  • 21 Seligsohn U, Zivelin A. Thrombophilia as a Multigenic Disorder. Thromb Haemost 1997; 78 (01) 297-301.
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Rosendaal FR. Thrombosis in the Young: Epidemiology and Risk Factors. A Focus on Venous Thrombosis. Thromb Haemost 1997; 78 (01) 1-6.
    Thieme ConnectPubMedSearch in Google Scholar