Skip to main content
SpringerLink
Log in

Prevalence of factor V Leiden in children with thrombo-embolism

  • Hematology/Oncology
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Abstract

Hereditary resistance to the anticoagulatory action of activated protein C (APC resistance, APCR) was identified as a possible new thrombophilic factor in a high percentage (17%–60%) of young adults with thrombotic events. A single missense mutation (R506Q) due to a G/A transition (G1691A) in exon 10 of the factor V gene is regarded as the causative molecular defect, resulting in factor V Leiden which is correlated with APCR. Identification of this mutation by polymerase chain reaction-based methods is easy to perform and prevents pre-analytical and analytical errors in the coagulometric assay for APCR. Since the impact of this mutation in children with thrombo-embolic disease has not been determined to date, we initiated a multi centre prevalence study in two paediatric populations, with and without thrombo-embolic events. We compared 125 paediatric patients with thrombosis, divided into three different age groups (0 to <0.5 years; >0.5 to <10 years; >10 to <18 years) with a normal population of 159 children. Although the mutation G1691A was found with an unexpectedly high prevalence of 12% in our normal controls, the prevalence was significantly higher in the age groups: 0 to <0.5 years (26%) and >10 to <18 years (30%). In patients between >0.5 and <10 years the overall prevalence was similar to that of the control group (13%). However, in patients of this age with spontaneous thrombosis, G1691A was also a significant risk factor (5/17≊29%). Homozygosity for G1691A was detected in three patients but not in the control group. Including deficiencies of protein C, protein S, antithrombin, and the presence of anti-phospholipid antibodies, thrombosis was correlated with endogenous thrombophilic factors in 38/125 patients (30.4%).

Conclusion

Our results emphasize the impact of factor V Leiden on thrombogenesis in children. However, the significance is age-dependent and may reflect the different physiology of haemostasis in the three age groups. The diagnostic workup of children with thrombosis should inelude tests for factor V Leiden. The correlation of factor V Leiden with the clinical course of thrombo-embolism in children is essential to establish rational guidelines for therapy and prophylaxis of APCR-related thrombosis which are not yet available.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

APC :

activated protein C

APCR :

activated protein C resistance

PCR :

polymerase chain reaction

References

  1. Allaart CF, Poort S, Rosendal F, Reitsma P, Bertina R (1993) Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 341: 134–138

    Article  PubMed  CAS  Google Scholar 

  2. Andrew M (1995) Developmental haemostasis: relevance to thrombo-embolic complications in paediatric patients. Thromb Haemostas 74: 415–425

    CAS  Google Scholar 

  3. Andrew M, Paes B, Milner R, Johnston M (1990) Development of the haemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 12: 95–104

    Article  PubMed  CAS  Google Scholar 

  4. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L (1992) Maturation of the haemostatic system during childhood. Blood 80: 1998–2005

    PubMed  CAS  Google Scholar 

  5. Andrew M, David M, Adams M (1993) Venous thrombo-embolic complications in children. J Pediatr 123: 337–346

    Article  PubMed  Google Scholar 

  6. Arnout J, Vanrusselt M, Vermylen J (1995) Resistance to activated protein C in a population of patients with antiphospholipid antibodies. Thromb Haemostas 73:1275

    Google Scholar 

  7. Bandello F, Vigano-D'Angelo S, Parlavecchia M, Tavola A, Della-Valle P Brancato R, D'Angelo A (1994) Hypercoagulability and high lipoprotein(a) levels in patients with central retinal vein occlusion. Thromb Haemostas 72: 39–43

    CAS  Google Scholar 

  8. Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, Ronde H de, Velden PA van der, Reitsma PH (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369: 64–67

    Article  PubMed  CAS  Google Scholar 

  9. Bick R L, Baker WF Jr (1994) The antiphospholipid and thrombosis syndromes. Med Clin North Am 78: 667–684

    PubMed  CAS  Google Scholar 

  10. Bovill EG, Bauer KA, Dickermann JD, Callas P, West B (1989) The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 73: 712–717

    PubMed  CAS  Google Scholar 

  11. Budowle B, Chakraborty R, Giusti AM, Eisenberg A J, Allen R C (1991) Analysis of the VNTR locus DIS80 by the PCR followed by high resolution PAGE. Am J Hum Genet 48: 137–144

    PubMed  CAS  Google Scholar 

  12. Cooper PC, Hampton KK, Makris M, Abuzenadah A, Paul B, Preston FE (1994) Further evidence that activated protein C resistance can be misdiagnosed as inherited functional protein S dieficiency. Br J Haematol 88: 201–203

    PubMed  CAS  Google Scholar 

  13. Cripe L D, Moore K D, Kane W H (1992) Structure of the gene for human coagulation factor V. Biochemistry 31: 3777–3785

    Article  PubMed  CAS  Google Scholar 

  14. Dahlbäck B (1995) New molecular insights into the genetics of thrombophilia. Resistance to activated protein C caused by Arg 506 to Gln mutation in factor V as a pathogenetic risk factor. Thromb Haemostas 74: 139–148

    Google Scholar 

  15. Dahlbäck B, Carlsson M, Svensson PJ (1993) Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Aca Sci USA 90: 1004–1008

    Article  Google Scholar 

  16. D'Angelo SV, Mazzola G, Valle PD, Testa S, Pattarini E, D'Angelo A (1995) Variable interference of activated protein C resistance in the measurement of protein S activity by commerical assays. Thromb Res 77: 375–378

    Article  PubMed  Google Scholar 

  17. David M, Andrew M (1993) Venous thrombo-embolic complications in children [see comments]. J Pediatr 123: 337–346

    Article  PubMed  CAS  Google Scholar 

  18. David M, Manco-Johnson M, Andrew M (1995) Diagnosis and treatment of venous thrombo-embolism in children and adolescents. On behalf of the subcommittee on peri-natal haemostasis of the scientific and standardization committee of the ISTH. Thomb Haemostas 74: 791–792

    CAS  Google Scholar 

  19. Faioni EM, Boyer-Neumann C, Franchi F, Wolf M, Meyer D, Mannucci P (1994) Another protein S functional assay is sensitive to resistance to activated protein C. Thromb Haemostas 72: 643–651

    Google Scholar 

  20. Heeb M J, Kojima Y, Greengard J S, Griffin J H (1995) Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V. Blood 85: 3405

    PubMed  CAS  Google Scholar 

  21. Hellgren M, Svensson P J, Dahlbäck B (1995) Resistance to activated protein C as a basis for venous thrombo-embolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol 173: 210

    Article  PubMed  CAS  Google Scholar 

  22. Kalafatis M, Rand M D, Mann K G (1994) The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 269: 31869

    PubMed  CAS  Google Scholar 

  23. Kalafatis M, Bertina R M, Rand M D, Mann K G (1995) Characterization of the molecular defect in factor VR506Q. J Biol Chem 270: 4053–4057

    Article  PubMed  CAS  Google Scholar 

  24. Kane W H, Davie E W (1986) Cloning of a cDNA coding for human factor V, a blood coagulation factor homologous to factor VIII and ceruloplasmin. Proc Natl Acad Sci USA 83: 6800–6804

    Article  PubMed  CAS  Google Scholar 

  25. Kodish E, Potter C, Kirschbaum N, Foster P (1995) Activated protein C resistance in a neonate with venous thrombosis. J Pediatr 127: 645–648

    Article  PubMed  CAS  Google Scholar 

  26. Koster T, Rosendaal FR, Ronde H de, Briet E, Vandenbroucke JP, Bertina RM Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 342: 1503–1506

  27. Lowe T, Sharefkin, J, Yang S Q, Dieffenbach C W (1990) A computer program for selection of oligonucleotide primers for polymerase chain reactions. Nucleic Acids Res 18: 1757–1761

    PubMed  CAS  Google Scholar 

  28. Mannucci PM, Tripodi A (1987) Laboratory screening of inherited thrombotic syndromes. Thromb Haemostas 57: 247–251

    CAS  Google Scholar 

  29. Nowak-Göttl U, Aschka I, Koch HG, Boos J, Dockhorn-Dworniczak B, Deufel T, Jürgens H, Kohlhase B, Kuhn N, Laupert A, Rath B, Wolff JEA, Schneppenheim R (1995) Resistance to activated protein C (APCR) in children with acute lymphoblastic leukaemia — the need for a prospective multicentre study. Blood Coag Fibrinol 6: 761–764

    Google Scholar 

  30. Nowak-Göttl U, Koch HG, Aschka I, Kohlhase B, Vielhaber H, Kurlemann G, Oleszuk-Rasche K, Kehl HG, Jürgens H, Schneppenheim R (1996) Resistance to activated protein C (APCR) in children with venous or arterial thrombo-embolism. Br J Haematol 92: 992–998

    Article  PubMed  Google Scholar 

  31. Nowak-Göttl U, Kohlhase B, Vielhaber H, Aschka I, Schneppenheim R, Jürgens H (1996) APC Resistance in neonates and infants: adjustment of the aPTT-based method. Thromb Res 81: 665–670

    Article  PubMed  Google Scholar 

  32. Nuss R, Hays T, Manco-Johnson M (1995) Childhood thrombosis. Paediatrics 96: 291–294

    CAS  Google Scholar 

  33. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T (1989) Detection of polymorphism of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 86: 2766–2770

    Article  PubMed  CAS  Google Scholar 

  34. Petäjä J, Jalanko H, Holmberg C, Kinunen S, Syrjälä (1995) Resistance to activated protein C as an underlying cause of recurrent venous thrombosis during relapsing nephrotic syndrome. J Pediatr 127: 103–105

    Article  PubMed  Google Scholar 

  35. Schmidt B, Andrew M (1995) Neonatal thrombosis: report of a prospective Canadian and international registry. Paediatrics 96: 939–943

    CAS  Google Scholar 

  36. Simioni P, De Ronde H, Prandoni P, Saladini M, Bertina RM, Girolami A (1995) Ischemic stroke in young patients with activated protein C resistance. A report of three cases belonging to three different kindreds. Stroke 26: 885–890

    PubMed  CAS  Google Scholar 

  37. Svensson PJ, Dahlbäck B (1994) Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 330: 517–522

    Article  PubMed  CAS  Google Scholar 

  38. Vandenbroucke J P, Koster T, Briet E, Reitsma P H, Bertina R M, Rosendaal F R (1994) Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 344: 1453

    Article  PubMed  CAS  Google Scholar 

  39. Zens W, Muntean W, Gallistl S, Leschnik B, Beitzke A (1994) Inherited resistance to activated protein C in a boy with multiple thromboses in early infancy. Eur J Pediatr 154: 285–288

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Universitäts-Kinderklinik Kiel, Schwanenweg 20, D-24105, Kiel, Germany

    I. Aschka, S. Krey & R. Schneppenheim

  2. University Children's Hospital Magdeburg, Magdeburg, Germany

    V. Aumann

  3. Children's Hospital, Medical School Hannover, Hannover, Germany

    F. Bergmann

  4. General Hospital Harburg, Hamburg, Germany

    U. Budde

  5. Children's Hospital Braunschweig, Braunschweig, Germany

    W. Eberl

  6. University Children's Hospital Düsseldorf, Düsseldorf, Germany

    S. Eckhof-Donovan

  7. University Children's Hospital Münster, Münster, Germany

    U. Nowak-Göttl

  8. University Children's Hospital Halle, Halle, Germany

    R. Schobess

  9. University Children's Hospital Freiburg, Freiburg, Germany

    A. H. Sutor

  10. University Children's Hospital Dresden, Dresden, Germany

    J. Wendisch

Authors
  1. I. Aschka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Aumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Bergmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. U. Budde
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. Eberl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Eckhof-Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Krey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. U. Nowak-Göttl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. Schobess
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. H. Sutor
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J. Wendisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. R. Schneppenheim
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aschka, I., Aumann, V., Bergmann, F. et al. Prevalence of factor V Leiden in children with thrombo-embolism. Eur J Pediatr 155, 1009–1014 (1996). https://doi.org/10.1007/BF02532520

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02532520

Key words

Search

Navigation