Clinical and laboratory characteristics of paediatric and adolescent index cases with venous thromboembolism and antithrombin deficiency

Summary

Venous thromboembolism [TE] is a multifactorial disease and antithrombin deficiency [ATD] constitutes a major risk factor. In the present study the prevalence of ATD and the clinical presentation at TE onset in a cohort of paediatric index cases are reported. In 319 un - selected paediatric patients (0.1–18 years) from 313 families, recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. 21 of 319 paediatric patients (6.6%), corresponding to 16 of 313 families (5.1%), were AT-deficient with confirmed underlying AT gene mutations. Mean age at first TE onset was 14 years (range 0.1 to 17). Thrombotic locations were renal veins (n=2), cerebral veins (n=5), deep veins (DVT) of the leg (n=9), DVT & pulmonary embolism (n=4) and pelvic veins (n=1). ATD co-occurred with the factor- V-Leiden mutation in one and the prothrombin G20210A mutation in two children. In 57.2% of patients a concomitant risk factor for TE was identified, whereas 42.8% of patients developed TE spontaneously. A second TE event within primarily healthy siblings occurred in three of 313 families and a third event among siblings was observed in one family. In an unselected cohort of paediatric patients with symptomatic TE, the prevalence of ATD adjusted for family status was 5.1%. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high risk population.

Keywords

Antithrombin deficiency - genetics - children

^* Present adress: Laboratoire d’Hématologie, AP-HP, CHU Bicêtre, Université Paris Sud, Le Kremlin-Bicêtre, France.

• References

• 1 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
• 2 Young G, Albisetti M, Bonduel M. et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation 2008; 118: 1373-1382.
• 3 Kenet G, Lütkhoff LK, Albisetti M. et al. Impact of thrombophilia on risk or arterial stroke or cerebral sinovenous thrombosis in neonates and children: A systematic review and meta-analysis of observational studies. Circulation 2010; 121: 1838-1847.
• 4 Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients?. Br J Haematol 2008; 143: 321-335.
• 5 Silverman GA, Bird PI, Carrell RW. et al. The serpins are an expanding super-family of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and revised nomenclature. J Biol Chem 2001; 276: 33293-33296.
• 6 Kurachi K, Fujikawa K, Schmer G, Davie EW. Inhibition of bovine factor IXa and factor Xabeta by antithrombin III. Biochemistry 1976; 15: 373-377.
• 7 Buchanan MR, Boneu B, Ofosu F, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombitic effects of heparin. Blood 1985; 65: 198-201.
• 8 Björk I, Olson ST. Antithrombin. A bloody important serpin. Adv. Exp Med Biol 1997; 425: 17-33.
• 9 Bock SC, Wion KL, Vehar GA. et al. Cloning and expression of the cDNA for human antithrombin III. Nucleic Acids Res 1982; 10: 8113-8125.
• 10 Olds RJ, Lane DA, Chowdhury V. et al. Complete nucleotide sequence of the antithrombin gene: evidence for homologous recombination causing thrombophilia. Biochemistry 1993; 32: 4216-4224.
• 11 Corral J, Hernandez-Espinosa D, Soria JM. et al. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis. Blood 2007; 109: 4258-4263.
• 12 Kuhle S, Lane D, Jochmanns K. et al. Homozygous antithrombin deficiency type II (99 Leu to Phe mutation) and childhood thromboembolism. Thromb Haemost 2001; 86: 1007-1011.
• 13 Rossi E, Chiusolo P, Za T. et al. Report of a novel kindred with antithrombin heparin-binding site variant (47 Arg to His): Demand for an automated progressive antithrombin assay to detect molecular variants with low thrombotic risk. Thromb Haemost 2007; 98: 695-697.
• 14 Olds RJ, Lane DA, Boisclair M, Sas G, Bocl SC, Thein SL. Antithrombin Budapest 3. An antithrombin variant with reduced heparin-affinity resulting from the substitution L99F. FEBS 1992; 300: 241-246.
• 15 Lane A. Antithrombin mutation database. Department of Haematology, Imperial Colledge London, Hammersmith Campus; 2012. http://www1.imperial.ac.uk/departmentofmedicine/divisions/experimentalmedicine/haematology/coag/antithrombin/
• 16 Beauchchamp NJ, Makris M, Preston FE, Peake IR, Daly ME. Major structural defects in the antithrombin gene in four families with type I antithrombin deficiency-- partial/complete deletions and rearrangement of the antithrombin gene. Thromb Haemost 2000; 83: 715-721.
• 17 Pavlova A, El-Maarri O, Luxembourg B. et al. Detection of heterozygous large deletions in the antithrombin gene using multiplex polymerase chain reaction and denaturation high performance liquid chromatography. Haematologica 2006; 91: 1264-1267.
• 18 Picard V, Nowak-Göttl U, Biron-Andreani C. et al. Molecular basis of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene. Hum Mut 2006; 27: 600.
• 19 Picard V, Chen JM, Tardy B. et al. Detection and characterisation of large SERPINC1 deletions in type 1 inherited antithrombin deficiency. Hum Genetics 2010; 127: 45-53.
• 20 Luxembourg B, Delev D, Geisen C. et al. Molecular basis of antithrombin deficiency. Thromb Haemost 2011; 105: 635-646.
• 21 Caspers M, Pavlova A, Driesen J. et al. Deficiencies of antithrombin, protein C and protein S - practical experience in genetic analysis of a large patient cohort. Thromb Haemost 2012; 108: 247-257.
• 22 Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2013 Epub ahead of print.
• 23 Goodeve AC, Reitsma PH, McVey JH. Nomenclature of genetic variants in hemostasis. J Thromb Haemost 2011; 09: 852-855.
• 24 den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion. Hum Mut 2000; 15: 7-12.
• 25 Kromeyer-Hauschild K, Wabitsch M, Kunze D. et al. Perzentile für den Body-Mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Monatsschr Kinderheilkd 2001; 149: 807-818.
• 26 Cole TJ, Green PJ. Smoothing reference centile curves: the LMS method and penalized likelihood. Stat Med 1992; 11: 1305-1319.
• 27 Holzhauer S, Goldenberg NA, Junker R. et al. Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study. Blood 2012; 120: 1510-1515.
• 28 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-662.
• 29 Van Ommen CH, Heijboer H, Büller HR. et al. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Paediatr 2001; 139: 676-681.
• 30 Ehrenforth S, Junker R, Koch HG. et al. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Eur J Paediatr 1999; 158 (Suppl. 03) S97-S104.
• 31 Chowdhury V, Lane DA, Mille B. et al. Homozygous antithrombin deficiency: report of two new cases (99 Leu to Phe) associated with arterial and venous thrombosis. Thromb Haemost 1994; 72: 198-202.
• 32 Hrachovinova I, Habart D, Salaj P, Matyskova M, Vorlova Z. Molekulani podstata vrozeneho defektu antithrombinu u deseti Ceskych rodin. [Molecular basis of hereditary antithrombin defects in 10 Czech families]. Cas Lel Ces 2000; 19: 596-598.
• 33 Brown SA, Mitchell M, Cutler JA, Moore G, Smith MP, Savidge GF. Rapid genetic diagnosis in neonatal pulmonary artery thrombosis caused by homozygous antithrombin Budapest 3. Clin Appl Thromb Haemost 2000; 06: 181-183.
• 34 Olivieri M, Bidlingmaier C, Schetzeck S, Borggräfe I, Geisen C, Kurnik K. Arterial thrombosis in homozygous antithrombin deficiency. Haemostaseologie 2012; 32 (Suppl. 01) S79-S82.
• 35 Sas G, Peto I, Banhegyi D. et al. Heterogeneity of the "classical" antithrombin deficiency. Thromb Haemost 1980; 43: 133.
• 36 Martinez-Martinez I, Navarro-Fernandez J, Ostergaard A. et al. Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism. Blood 2012; 26: 900-904.
• 37 Ishiguro K, Kojima T, Kadomatsu K. et al. Complete antithrombin deficiency in mice results in embyonic lethality. J Clin Invest 2000; 106: 873-878.
• 38 Clagett GP, Anderson Jr FA, Heit J, Levine MN, Wheeler HB. Prevention of venous thromboembolism. Chest 1996; 108: 312S-334S.
• 39 Coppola A, Tufano A, Cerbone AM, Di Minno G. Inherited thrombophilia: implications for prevention and treatment of venous thromboembolism. Semin Thromb Hemost 2009; 35: 683-694.
• 40 Lijfering WM, Brouwer JL, Veeger NJ. et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009; 113: 5314-5322.
• 41 Couturaud F, Kearon C. Predictors of thrombosis in relatives of patients with venous thromboembolism. Current Opinion in Pulmonary Medicine 2010; 16: 453-458.
• 42 Cohn DM, Roshani S, Middeldorp S. Thrombophilia and venous thromboembolism: implications for testing. Semin Thromb Hemost 2007; 33: 573-581.
• 43 Fischer R, Sachs U, Heidinger KS. et al. Prevalence of hereditary antithrombin mutations is higher than estimated in patients with thrombotic events. Blood Coag Fibrinol 2013; 24: 444-448.
• 44 Merz M Böhm-Weigert M, Braun S. et al. Clinical multicenter evaluation of a new FXa-based Antithrombin assay. Int Jnl Lab Hem 2011; 33: 498-506.
• 45 Kumar R, Chan AKC, Dawson JE. et al. Clinical Presentation and Molecular Basis of Congenital Antithrombin Deficiency in Children: a Cohort Study. Br J Haematol 2014; 166: 130-139.