Homozygous and double heterozygous Factor V Leiden and Factor II G20210A genotypes predispose infants to thromboembolism but are not associated with an increase of foetal loss

Patrick Hundsdoerfer; Barbara Vetter; Brigitte Stöver; Christian Bassir; Tristess Scholz; Ingrid Grimmer; Eberhard Mönch; Sabine Ziemer; Rainer Rossi; Andreas E. Kulozik

doi:10.1160/TH03-02-0096

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(04): 628-635
DOI: 10.1160/TH03-02-0096

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Homozygous and double heterozygous Factor V Leiden and Factor II G20210A genotypes predispose infants to thromboembolism but are not associated with an increase of foetal loss

Patrick Hundsdoerfer

¹Department of General Paediatrics, Charité, Humboldt University, Berlin, Germany

²Department of Paediatric Oncology / Haematology, Charité, Humboldt University, Berlin, Germany

,

Barbara Vetter

¹Department of General Paediatrics, Charité, Humboldt University, Berlin, Germany

,

Brigitte Stöver

³Department of Paediatric Radiology, Charité, Humboldt University, Berlin, Germany

,

Christian Bassir

³Department of Paediatric Radiology, Charité, Humboldt University, Berlin, Germany

,

Tristess Scholz

⁴Department of Neonatalogy, Charité, Humboldt University, Berlin, Germany

,

Ingrid Grimmer

⁴Department of Neonatalogy, Charité, Humboldt University, Berlin, Germany

,

Eberhard Mönch

¹Department of General Paediatrics, Charité, Humboldt University, Berlin, Germany

,

Sabine Ziemer

¹Department of General Paediatrics, Charité, Humboldt University, Berlin, Germany

,

Rainer Rossi

¹Department of General Paediatrics, Charité, Humboldt University, Berlin, Germany

,

Andreas E. Kulozik

¹Department of General Paediatrics, Charité, Humboldt University, Berlin, Germany

› Author Affiliations

Abstract

Summary

Prospective and controlled data about the individual risk profile in asymptomatic children with homozygous or double heterozygous risk genotypes for Factor V Leiden (FVL) and factor II (FII) G20210A are currently unavailable. The systematic and prospective observational study presented here was designed to determine the impact of the homozygous and double heterozygous FVL and FII G20210A genotypes on the prenatal and postnatal risk profiles of affected children. Risk infants and heterozygous controls were identified by screening of 85,304 neonates. Follow-up included the comparison of prenatal and postnatal development, ultrasonography of brain and kidneys, and a panel of independent determinants of thrombophilia. The numbers of identified or expected FVL homozygotes and double heterozygotes did not differ significantly (FVL: 116 ver-sus 91, p=0.08; FVL/FII: 94 versus 76, p=0.17), indicating the absence of a prenatal disadvantage. A prenatal advantage was suggested in FII homozygotes, whose identified number far exceeded the expected (19 versus 4, p=0.002). Clinical and/or imaging abnormalities indicated spontaneous thromboembolic events in 4 of 129 risk infants (3%) but in none of the 178 controls (p=0.02). Physical and neurological development was normal in both groups during the first 2 years of life. The risk genotypes appear to confer a significant predisposition for spontaneous thromboembolic events in infancy without impeding development within the first two years of life. Foetal risk genotypes do not cause an increased foetal loss rate. Moreover, homozygous FII G20210A appears to be associated with a prenatal advantage.

Keywords

Factor V Leiden - neonatal screening - prothrombin G20210A - thrombophilia in childhood

Full Text

References

References
1 van Ommen CH, Heijboer H, Büller HR. et al. Venous thromboembolism in childhood: A prospective two-year registry in the Netherlands. J Pediat 2001; 139 (05) 676-81.
2 Andrew M, David M, Adams M. et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83 (05) 1251-7.
3 Nowak-Gottl U, von Kries R, Gobel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed 1997; 76 (03) F163-7.
4 Aschka I, Aumann V, Bergmann F. et al. Prevalence of factor V Leiden in children with thromboembolism. Eur J Pediatr 1996; 155 (12) 1009-14.
5 Monagle P, Adams M, Mahoney M. et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000; 47 (06) 763-6.
6 Gurakan F, Gurgey A, Bakkaloglu A. et al. Homozygous factor V Leiden mutation in a child with Budd-Chiari syndrome. J Pediatr Gastroenterol Nutr 1999; 28 (05) 516-7.
7 Gurgey A. Clinical manifestations in thrombotic children with factor V Leiden mutation. Pediatr Hematol Oncol 1999; 16 (03) 233-7.
8 Gruppo R, Glueck CJ, Wall E. et al. Legg-Perthes disease in three siblings, two heterozygous and one homozygous for the factor V Leiden mutation. J Pediatr 1998; 132 (05) 885-8.
9 Heresbach D, Pagenault M, Gueret P. et al. Leiden factor V mutation in four patients with small bowel infarctions. Gastroenterology 1997; 113 (01) 322-5.
10 Nowak-Gottl U, Koch HG, Aschka I. et al. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol 1996; 92 (04) 992-8.
11 Zenz W, Bodo Z, Plotho J. et al. Factor V Leiden and prothrombin gene G 20210 A variant in children with ischemic stroke. Thromb Haemost 1998; 80 (05) 763-6.
12 Hagstrom JN, Walter J, Bluebond Langner R. et al. Prevalence of the factor V leiden mutation in children and neonates with thromboembolic disease. J Pediatr 1998; 133 (06) 777-81.
13 deVeber G, Monagle P, Chan A. et al. Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol 1998; 55 (12) 1539-43.
14 Ganesan V, Kelsey H, Cookson J. et al. Activated protein C resistance in childhood stroke. Lancet 1996; 347 8996 260
15 Heller C, Schobess R, Kurnik K. et al. Abdominal venous thrombosis in neonates and infants: role of prothrombotic risk factors - a multicentre case-control study. Br J Haematol 2000; 111 (02) 534-9.
16 Gunther G, Junker R, Strater R. et al. Symptomatic ischemic stroke in full-term neonates : role of acquired and genetic prothrombotic risk factors. Stroke 2000; 31 (10) 2437-41.
17 Tormene D, Simioni P, Prandoni P. et al. The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study. Blood 2002; 100 (07) 2403-5.
18 Kodish E, Potter C, Kirschbaum NE. et al. Activated protein C resistance in a neonate with venous thrombosis. J Pediatr 1995; 127 (04) 645-8.
19 Haffner D, Wuhl E, Zieger B. et al. Bilateral renal venous thrombosis in a neonate associated with resistance to activated protein C. Pediatr Nephrol 1996; 10 (06) 737-9.
20 Klinge J, Scharf J, Rupprecht T. et al. Selective thrombolysis in a newborn with bilateral renal venous and cerebral thrombosis and heterozygous APC resistance. Nephrol Dial Transplant 1998; 13 (12) 3205-7.
21 Preston FE, Rosendaal FR, Walker ID. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348 9032 913-916.
22 Martinelli I, Taioli E, Cetin I. et al. Mutations in coagulation factors in women with une-plained late fetal loss. N Engl J Med 2000; 343 (14) 1015-8.
23 Uttenreuther Fischer MM, Vetter B, Hellmann C. et al. Paediatric thromboembolism: the influence of non-genetic factors and the role of activated protein C resistance and protein C deficiency. Eur J Pediatr 1997; 156 (04) 277-81.
24 Nowak-Gottl U, Junker R, Kreuz W. et al. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97 (04) 858-62.
25 Zawadzki C, Gaveriaux V, Trillot N. et al. Homozygous G20210A transition in the pro-thrombin gene associated with severe venous thrombotic disease: two cases in a French family. Thromb Haemost 1998; 80 (06) 1027-8.
26 Kosch A, Junker R, Kurnik K. et al. Prothrombotic risk factors in children with spontaneous venous thrombosis and their asymptomatic parents: a family study. Thromb Res 2000; 99 (06) 531-7.
27 Hundsdoerfer P, Vetter B, Stover B. et al. Design of a prospective neonatal cohort study of homozygous and double heterozygous factor V Leiden and factor II G20210A. Klin Padiatr 2000; 212 (04) 159-62.
28 Harum KH, Hoon Jr AH, Kato GJ. et al. Homozygous factor-v mutation as a genetic cause for perinatal thrombosis and cerebral palsy. Develop Med Child Neurol 1999; 41: 777-780.
29 Sipahi T, Duru F, Yarah N. et al. Compound heterozygosity for factor V Leiden and pro-thrombin G20210A mutations in a child with Budd-Chiari syndrome. Eur J Pediatr 2001; 160 (03) 198
30 Heiser A, Grimmer I, Metze B. et al. Parent´s estimation of psychomotor development in very low birthweight (VLBW) infants. Early Human Develop 1995; 42: 131-9.
31 Frankenburg WK, Fandal AW, Thornton SM. Revision of Denver Prescreening Developmental Questionnaire. J Pediatr 1987; 110 (04) 653-7.
32 Griffith R. The abilities of young children. A comprehensive system of mental measurement for the first year of life. London: Child Development Research Centre; 1970
33 Falk G, Almquist A, Nordenhem A. et al. Allele specific PCR for detection of a sequence polymorphism in the promotor region of the plasminogen activator inhibitor-1 (PAI-1) gene. Fibrinolysis 1995; 9: 170-4.
34 Doggen CJ, Bertina RM, Cats VM. et al. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with myocardial infarction. Thromb Haemost 1999; 82 (01) 115-20.
35 Ueland PM, Refsum H, Stabler SP. et al. Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem 1993; 39 (09) 1764-79.
36 Gopel W, Kim D, Gortner L. Prothrombotic mutations as a risk factor for preterm birth. Lancet 1999; 353 9162 1411-2.
37 von Kries R, Junker R, Oberle D. et al. Foetal growth restriction in children with prothrombotic risk factors. Thromb Haemost 2001; 86 (04) 1012-6.
38 Kupferminc MJ, Eldor A, Steinman N. et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340 (01) 9-13.
39 Lucotte G, Mercier G. Population genetics of factor V leiden in europe. Blood Cells Mol Dis 2001; 27 (02) 362-7.
40 Jakobson H, Kaiser S, Granholm T. et al. Neonatal adrenal haemorrhage at bone szintingraphy: a case report. Pediatr Radiol 1998; 28: 896-8.
41 Fox B. Venous infarction of the adrenal glands. J Pathol 1976; 119 (02) 65-89.
42 Infante-Rivard C, Rivard G-E, Yotov WV. et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med 2002; 347 (01) 19-25.
43 Gopel W, Ludwig M, Junge AK. et al. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet 2001; 358: 1238-9.
44 Juul K, Tybjaerg-Hansen A, Nordestgaard BG. Factor V Leiden: relation to fertility?. Lancet 2002; 359: 894
45 Scholz T, Bartholomäus S, Grimmer I. et al. Problems of multiple births after ART: medical, psychological, social and financial aspects. Human Reproduction 1999; 14 (12) 2932-7.
46 Poort SR, Rosendaal FR, Reitsma PH. et al. 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 (10) 3698-703.
47 Gehring N, Frede U, Neu-Yilik G. et al. Increased efficiency of mRNA 3’ end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet 2001; 28 (04) 389-92.
48 Pollak ES, Lam H-S, Russell JE. The G20210A mutation does not affect the stability of prothrombin mRNA in vivo. Blood 2002; 100 (01) 359-62.
49 Griffin CT, Srinivasan Y, Zheng YW. et al. A role for thrombin receptor signaling in endothelial cells during embryonic development. Science 2001; 293: 1666-70.