Download PDF
Thromb Haemost 2004; 91(02): 308-314
DOI: 10.1160/TH03-02-0038
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Increased fasting total homocysteine plasma levels as a risk factor for thromboembolism in children

Andrea Kosch   *
1   Department of Pediatric Hematology/Oncology, University Children’s Hospital Münster, Germany
,
Hans Georg Koch   *
2   Department of Pediatrics, University Children’s Hospital Münster, Germany
,
Achim Heinecke
3   Institute of Medical Informatics and Biomathematics, University of Münster, Germany
,
Karin Kurnik
4   Department of Pediatrics, University Children’s Hospital Munich, Germany
,
Christine Heller
5   Department of Pediatric Hematology/Oncology, University Children’s Hospital Frankfurt am Main, Germany
,
Ulrike Nowak-Göttl
1   Department of Pediatric Hematology/Oncology, University Children’s Hospital Münster, Germany
,
for the Childhood Thrombophilia Study Group › Author AffiliationsFinancial support: The study was supported by an unrestricted grant awarded by the Karl Bröcker Stiftung.
Further Information

Publication History

Received 18 January 2003

Accepted after resubmission 12 November 2003

Publication Date:
01 December 2017 (online)

    Permissions and Reprints

Summary

Elevated total homocysteine (tHcy) concentrations are an inde- pendent risk factor for thromboembolic events in adults. In children with moderate hyperhomocysteinemia data are sparse. Therefore, between 1995 and 2002 we consecutively recruited 163 white pediatric patients with a first symptomatic thromboembolic event and 255 healthy controls (mean age: 6.4 years in patients vs. 6.6 years in controls, range: 3 months to 18 years) and measured fasting tHcy levels. Median tHcy levels in patients were significantly higher (6.6 µmol/l, range 2.9-20.4 µmol/l) than in controls (5.7 µmol/l, 2.0-14.0 µmol/l, p<0.0001). 48 of the 163 patients with thromboembolism (29.5%) versus 26 of the 255 controls (10.2%) had tHcy levels above the age- specific normal 90th percentile (OR 2.9, 95%CI: 1.7-4.8). The odds ratio for children in the highest quintile compared to chil- dren with levels in the lowest quintile was 4.3 (1.6-8.1; highest quintile: median tHcy level 9.6 µmol, range 8.0-20.4), showing a significantly increased risk for thromboembolic disease with even mild hyperhomocysteinemia. We conclude that hyperho- mocysteinemia above the age-specific cut-off values is a risk fac- tor for thromboembolic events in children. Therefore, screen- ing for elevated fasting tHcy levels of patients with thromboem- bolism is recommended to stratify the risk of thromboembo- lism.

Keywords

Homocysteine - hyperhomocysteinemia - thromboembolism - children

* A. Kosch and H.G. Koch contributed equally


 

  • References

  • 1 Andrew M, David M, Adams M. et al. Venous thromboembolic complications (VTE) in chil- dren: first analyses of the Canadian Registry of VTE. Blood 1994; 83: 1251-7.
    PubMedGoogle Scholar
  • 2 Van Beynum IM, Smeitink JAM, den Heijer M. et al. Hyperhomocysteinemia - A risk fac- tor for ischemic stroke in children. Circulation 1999; 99: 2070-2.
    CrossrefPubMedGoogle Scholar
  • 3 Mudd SH, Skovby F, Levy HL. et al. The nat- ural history of homocystinuria due to cystathi- onine beta-synthase deficiency. Am J Hum Genet 1985; 37: 1-31.
    PubMedGoogle Scholar
  • 4 Frosst P, Blom HJ, Milos R. et al. A candidate genetic risk factor for vascular disease: a com- mon mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3.
    CrossrefPubMedGoogle Scholar
  • 5 Junker R, Nowak-Göttl U, Fobker M. The Methylenetetrahydrofolate-reductase (MTHFR) C677T-polymorphism and other genetic causes of hyperhomocysteinemia in venous thrombosis. J Lab Med 2001; 25: 239-53.
    PubMedGoogle Scholar
  • 6 Jacques PF, Rosenberg IH, Rogers G. et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr 1999; 69: 482-9.
    CrossrefPubMedGoogle Scholar
  • 7 Nowak-Göttl U, Wermes C, Junker R. et al. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood 1999; 93: 1595-9.
    PubMedGoogle Scholar
  • 8 Karg JD, Sinnreich R, Rosenberg IH. et al. Plasma homocysteine and parental myocardial infarction in young adults in Jerusalem. Circulation 2002; 105: 2725-9.
    CrossrefPubMedGoogle Scholar
  • 9 Boushey CJ, Beresford SAA, Omenn GS. et al. A quantitative assessment of plasma homo- cysteine as a risk factor for vascular disease. JAMA 1995; 274: 1049-57.
    CrossrefPubMedGoogle Scholar
  • 10 Den Heijer M, Koster T, Blom HJ. et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-62.
    CrossrefPubMedGoogle Scholar
  • 11 Lin JS, Shen MC, Cheng WC. et al. Age, sex and vitamin status affect plasma level of homocysteine, but hyperhomocysteinaemia is possibly not an important risk factor for venous thrombophilia in Taiwanese Chinese. Br J Haematol 2002; 117: 159-63.
    CrossrefPubMedGoogle Scholar
  • 12 Osganian SK, Stampfer MJ, Spiegelman D. et al. Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health. JAMA 1999; 281: 1189-96.
    CrossrefPubMedGoogle Scholar
  • 13 Merouani A, Lambert M, Delvin EE. et al. Plasma homocysteine concentration in chil- dren with chronic renal failure. Pediatr Nephrol 2001; 16: 805-11.
    CrossrefPubMedGoogle Scholar
  • 14 Cardo E, Vilaseca MA, Campistol J. et al. Evaluation of hyperhomocysteinaemia in chil- dren with stroke. Eur J Paediatr Neurol 1999; 03: 113-7.
    CrossrefPubMedGoogle Scholar
  • 15 Verrotti A, Pascarella R, Trotta D. et al. Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine. Epilepsy Res 2000; 42: 253-7.
    PubMedGoogle Scholar
  • 16 Selhub J, Jacques PF, Bostom AG. et al. Relationship between plasma homocysteine and vitamin status in the Framingham study population Impact of folic acid fortification. Public Health Rev 2000; 28: 117-45.
    PubMedGoogle Scholar
  • 17 Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high performance liquid chromatography with fluo- rescence detection. J Chromatogr 1987; 422: 43-52.
    CrossrefPubMedGoogle Scholar
  • 18 Nowak-Göttl U, Junker R, Hartmeier M. et al. Increased lipoprotein (a) is an important risk factor for venous thromboembolism in child- hood. Circulation 1999; 100: 743-8.
    CrossrefPubMedGoogle Scholar
  • 19 Schlesselman JJ. Case control studies: design, conduct, analysis. Oxford University Press; Oxford, New York: 1982
    Google Scholar
  • 20 Hosmer DW, Lemeshow S. Applied logistic regression. New York: Wiley; 1989
    Google Scholar
  • 21 Key NS, McGlennen RC. Hyperhomocyst (e)inemia and Thrombophilia. Arch Pathol Lab Med 2002; 126: 1367-75.
    PubMedGoogle Scholar
  • 22 Brouwer IA, van Dusseldorp M, Thomas CMG. et al. Low-dose folic acid supplementation decreases plasma homocysteine concen- trations: a randomised trial. Indian Heart J 2000; 52: S53-8.
    PubMedGoogle Scholar
  • 23 Rothenberg SP. Increasing the dietary intake of folate: pros and cons. Semin Hematol 1999; 36: 65-74.
    PubMedGoogle Scholar
  • 24 Ray JG. Meta-analysis of hyperhomocysteine- mia as a risk factor for venous thromboembol- ic disease. Arch Intern Med 1998; 158: 2101-6.
    CrossrefPubMedGoogle Scholar
  • 25 Falcon CR, Cattaneo M, Panzeri D. et al. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb 1994; 14: 1080-3.
    CrossrefPubMedGoogle Scholar
  • 26 Tonstad S, Refsum H, Sivertsen M. et al. Relation of total homocysteine and lipid levels in children to premature cardiovascular death in male relatives. Pediatr Res 1996; 40: 47-52.
    CrossrefPubMedGoogle Scholar
  • 27 Balasa VV, Gruppo RA, Glueck CJ. et al. The relationship of mutations in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin and PAI1 in children and adults. Thromb Haemost 1999; 81: 739-44.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Delvin EE, Rozen R. Merouani, et al. Influence of methylenetetrahydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children. Am J Clin Nutr 2000; 72: 1469-73.
    CrossrefPubMedGoogle Scholar
  • 29 Rauh M, Verwied S, Knerr I. et al. Homocysteine concentrations in a German cohort of 5000 individuals: reference ranges and determinants of plasma levels in healthy children and their parents. Amino Acids 2001; 20: 409-18.
    CrossrefPubMedGoogle Scholar
  • 30 Minniti G, Cerone R, Piana A. et al. Plasma and serum total homocysteine concentrations in paediatric patients, evaluated by high-performance liquid chromatography with fluorescence. Clin Chem Lab Med 2000; 38: 675-6.
    PubMedGoogle Scholar
  • 31 Reddy MN. Reference ranges for total homo- cysteine in children. Clin Chim Acta 1997; 262: 153-5.
    CrossrefPubMedGoogle Scholar
  • 32 Vilaseca MA, Moyano D, Ferrer I. et al. Total homcysteine in pediatric patients. Clin Chem 1997; 43: 690-2.
    PubMedGoogle Scholar
  • 33 De Laet C, Wautrecht JC, Brasseur D. et al. Plasma homocysteine concentration in a Belgian school-age population. Am J Clin Nutr 1999; 69: 968-72.
    CrossrefPubMedGoogle Scholar
  • 34 Undas A, Williams EB, Butenas S. et al. Homocysteine inhibits inactivation of factor Va by activated protein C. J Biol Chem 2001; 276: 4389-97.
    CrossrefPubMedGoogle Scholar
  • 35 Lentz SR, Piegors DJ, Fernandez JA. et al. Effect of hyperhomocysteinemia on protein C activation and activity. Blood 2002; 100: 2108-12.
    CrossrefPubMedGoogle Scholar
  • 36 Koch HG, Nabel P, Junker R. et al. The 677T genotype of the common MTHFR thermola- bile variant and fasting homocysteine in child- hood venous thrombosis. Eur J Pediatr 1999; 158: 113-6.
    CrossrefPubMedGoogle Scholar