Thrombophilia in the young

Summary

Venous thromboembolism (VTE) is a rare disease that is being increasingly diagnosed and recognized in paediatrics in the past decade, usually as a secondary complication of primary severe underlying diseases. Apart from acquired thrombophilic risk factors, such as lupus anticoagulants, inherited thrombophilias (IT) have been established as risk factors for venous thromboembolic events in adults. In children with idiopathic VTE and in paediatric populations in which thromboses were associated with underlying medical diseases, IT have been described as additional prothrombotic risk factors. Follow-up data for VTE recurrence in children are available and suggest a recurrence rate of approximately 3% in neonates and 8% in other children. Here we present a review of the impact of IT on early onset of VTE and recurrence in children. Statistically significant associations between the IT traits investigated, e.g. factor V G1691A, factor II G20210A, protein C-, protein S-, antithrombin deficiency, elevated lipoprotein (a), combined IT and VTE onset were reported. In addition, statistically significant associations with recurrent VTE were calculated for protein S-, antithrombin-deficiency, and the factor II variant and combined IT. The absolute risk increase for VTE recurrence associated with IT ranged from 9.8 % for children carrying the factorII variant to 26% and 29% in children with combined IT and protein S-deficiency, respectively. Data obtained gave evidence that the detection of IT is clinically meaningful in children with VTE and underlines the importance of a paediatric thrombophilia screening program. Based on these data treatment algorithms have to be discussed.

Zusammenfassung

Venöse Thromboembolien (VTE) sind bei Kindern und Jugendlichen seltene Erkrankungen, die aber im vergangenen Jahrzehnt zunehmend diagnostiziert wurden, üblicherweise als Komplikation einer schwerwiegenden Grunderkrankung. Abgesehen von erworbenen Thrombophilie- Risikofaktoren (z. B. Lupus Antikoagulanz) wurden hereditäre Thrombophilien als Risikofaktoren für VTE im Erwachsenenalter etabliert. Bei Kindern mit idiopathischer VTE und in pädiatrischen Populationen mit an Grunderkrankungen assoziierten Thrombosen wurden hereditäre Thrombophilien als zusätzliche prothrombotische Risikofaktoren beschrieben. Inzwischen zeigen Verlaufsdaten für VTE-Rezidive bei Kindern eine Rezidivrate von etwa 3% bei Neugeborenen und 8% bei älteren Kindern.

Hier präsentieren wir einen Überblick über den Einfluss von hereditärer Thrombophilie auf das frühe Auftreten von VTE und Rezidiven bei Kindern. Es wurde über statistisch signifikante Zusammenhänge zwischen den untersuchten Risikomerkmalen (z. B. Faktor-V-G1691A-Mutation, Faktor- II-G2021A-Mutation, Protein-C-, Protein-S- oder Antithrombin- Mangel, erhöhtes Lipoprotein(a) sowie kombinierte Defekte) und dem Auftreten von VTE berichtet. Zusätzlich ergaben sich statistisch signifikante Zusammenhänge für wiederholte VTE mit Protein-S- und Antithrombin- Mangel sowie mit der Prothrombinmutation und kombinierten Defekten. Der absolute Risikoanstieg für ein mit einer hereditären Thrombophilie assoziiertes VTE-Rezidiv lag zwischen 10% für Kinder mit Prothrombinmutation und 26% bzw. 29% für Kinder mit kombinierten Defekten bzw. Protein-S-Mangel. Die Daten verdeutlichen, dass der Nachweis einer hereditären Thrombophilie bei Kindern mit VTE klinische Bedeutung hat und unterstreichen die Dringlichkeit eines pädiatrischen Thrombophilie-Screening-Programms. Behandlungsalgorhythmen müssen auf dieser Datenbasis entwickelt werden.

Keywords

Venous thromboembolism

Schlüsselwörter

Venöse Thromboembolien

• References

• 1 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: 1251-1257.
• 2 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96: 939-943.
• 3 Journeycake JM, Buchanan GR. Thrombotic complications of central venous catheters in children. Cur Opin Hematol 2003; 10: 369-374.
• 4 Revel-Vilk S. Central venous line-related thrombosis in children. Acta Haematol 2006; 115: 201-206.
• 5 Nowak-Göttl U, von Kries R, Göbel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed 1997; 76: F163-F167.
• 6 Revel-Vilk S, Sharathkumar A, Massicotte P. et al. Natural history of arterial and venous thrombosis in children treated with low molecular weight heparin: a longitudinal study by ultrasound. J Thromb Haemost 2004; 2: 42-46.
• 7 Journeycake J, Eshelman D, Buchanan GR. Post-thrombotic syndrome is uncommon in childhood cancer survivors. J Pediatr 2006; 148: 275-277.
• 8 Goldenberg NA. Long-term outcomes of venous thrombosis in children. Cur Opin Hematol 2005; 12: 370-376.
• 9 Kuhle S, Koloshuk B, Marzinotto V. et al. A crosssectional study evaluating post-thrombotic syndrome in children. Thromb Res 2003; 111: 227-233.
• 10 Massicotte MP, Dix D, Monagle P. et al. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133: 770-776.
• 11 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: 763-766.
• 12 Van Ommen CH, Heijboer H, Büller HR. et al. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001; 139: 676-681.
• 13 Levy DM, Massicotte MP, Harvey E. et al. Thromboembolism in paediatric lupus patients. Lupus 2003; 12: 741-746.
• 14 Berkun Y, Padeh S, Barash J. et al. Antiphospholipid syndrome and recurrent thrombosis in children. Arthritis Rheum 2006; 55: 850-855.
• 15 Günes AM, Baytan B, Günay U. The influence of risk factors in promoting thrombosis during childhood: the role of acquired factors. Pediatr Hematol Oncol 2006; 23: 399-410.
• 16 Salomon O, Steinberg DM, Zivelin A. et al. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol 1999; 19: 511-518.
• 17 Ehrenforth S, von Depka Prondsinski M, Aygören-Pürsün E. et al. Study of the prothrombin gene 20201 GA variant in FV: Q 506 carriers in relationship to the presence or absence of juvenile venous thromboembolism. Arterioscler Thromb Vac Biol 1999; 19: 276-280.
• 18 Prandoni P, Noventa F, Ghirarduzzi A. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92: 199-205.
• 19 Van den Belt AG, Sanson BJ, Simioni P. et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med 1997; 157: 2227-2232.
• 20 Simioni P, Sanson BJ, Prandoni P. et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81: 198-202.
• 21 Sofi F, Marcucci R, Abbate R. et al. Lipoprotein (a) and venous thromboembolism in adults: a metaanalysis. Am J Med 2007; 120: 728-733.
• 22 Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatrics 1995; 96: 291-294.
• 23 Nowak-Göttl 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: 992-998.
• 24 Aschka I, Aumann V, Bergmann F. et al. Prevalence of factor V Leiden in children with thromboembolism. Eur J Pediatr 1996; 155: 1009-1014.
• 25 Uttenreuther-Fischer MM, Vetter B, Hellmann C. et al. Paediatric thrombo-embolism: the influence of non-genetic factors and the role of activated protein C resistance and protein C deficiency. Eur J Pediatr 1997; 156: 277-281.
• 26 Sifontes MT, Nuss R, Hunger SP. et al. The factor V Leiden mutation in children with cancer and thrombosis. Br J Haematol 1997; 96: 484-489.
• 27 Toumi NH, Khaldi F, Ben Becheur S. et al. Thrombosis in congenital deficiencies of AT III protein C or protein S: a study of 44 children. Hematol Cell Ther 1997; 39: 295-299.
• 28 Sifontes MT, Nuss R, Hunger SP. et al. Activated protein C resistance and the factor V Leiden mutation in children with thrombosis. Am J Hematol 1998; 57: 29-32.
• 29 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: 777-781.
• 30 Ehrenforth S, Junker R, Koch HG. et al. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group. Eur J Pediatr 1999; 158: S97-S104.
• 31 Schobess R, Junker R, Auberger K. et al. Factor V G1691A and prothrombin G20210A in childhood spontaneous venous thrombosis – Evidence of an age-dependent thrombotic onset in carriers of the factor V G1691A and prothrombin G20210A mutation. Eur J Pediatr 1999; 158: S105-S108.
• 32 Nowak-Göttl U, Junker R, Hartmeier M. et al. Increased lipoprotein(a) is an important risk factor for venous thromboembolism in Childhood. Circulation 1999; 100: 743-748.
• 33 Lawson SE, Butler D, Enayat MS. et al. Congenital thrombophilia and thrombosis: a study in a single centre. Arch Dis Child 1999; 81: 176-178.
• 34 Junker R, Koch HG, Auberger K. et al. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol 1999; 19: 2568-2572.
• 35 Kuhle S, Lane DA, Jochmanns K. et al. Homozygous antithrombin deficiency type II (99 Leu to Phe mutation) and childhood thromboembolism. Thromb Haemost 2001; 86: 1007-1011.
• 36 Nowak-Göttl U, Junker R, Kreuz W. et al. Childhood Thrombophilia Study Group. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97: 858-862.
• 37 De Veber G, Andrew M, Adams C. et al. Cerebral sinovenous thrombosis in children. N Engl J Med 2001; 345: 417-423.
• 38 Revel-Vilk S, Chan A, Bauman M. et al. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost 2003; 1: 915-921.
• 39 Bonduel M, Hepner M, Sciuccati G. et al. Factor V Leiden and prothrombin gene G20210A mutation in children with venous thromboembolism. Thromb Haemost 2002; 87: 972-977.
• 40 Van Ommen CH, Heijboer H, van den Dool EJ. et al. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost 2003; 1: 2516-2522.
• 41 Young G, Manco-Johnson M, Gill JC. et al. Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study. J Thromb Haemost 2003; 1: 958-962.
• 42 Atasay B, Arsan S, Günlemez A. et al. Factor V Leiden and prothrombin gene 20210A variant in neonatal thromboembolism and in healthy neonates and adults: a study in a single center. Pediatr Hematol Oncol 2003; 20: 627-634.
• 43 Heller C, Heinecke A, Junker R. et al. Cerebral venous thrombosis in children: a multifactorial origin. Circulation 2003; 108: 1362-1367.
• 44 El-Karaksy H, El-Koofy N, El-Hawary M. et al. Prevalence of factor V Leiden mutation and other hereditary thrombophilic factors in Egyptian children with portal vein thrombosis: results of a single-center case-control study. Ann Hematol 2004; 83: 712-715.
• 45 Kenet G, Waldman D, Lubetsky A. et al. Paediatric cerebral sinus veil thrombosis. A multi-center, case-controlled study. Thromb Haemost 2004; 92: 713-718.
• 46 Goldenberg NA, Knapp-Clevenger R, Manco-Johnson MJ. Mountain States Regional Thrombophilia Group.. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. New Engl J Med 2004; 351: 1081-1088.
• 47 Kosch A, Kuwertz-Bröking E, Heller C. et al. Renal venous thrombosis in neonates: prothrombotic risk factors and long-term follow-up. Blood 2004; 104: 1356-1360.
• 48 Rask O, Berntorp E, Ljung R. Risk factors for venous thrombosis in Swedish children and adolescents. Acta Paediatr 2005; 94: 717-722.
• 49 Marks SD, Massicotte P, Steele BT. et al. Neonatal renal venous thrombosis: clinical outcomes and prevalence of prothrombotic disorders. J Pediatr 2005; 146: 811-816.
• 50 Brandão LR, Williams S, Kahr WH. et al. Exercise- induced deep vein thrombosis of the upper extremity 2. A case series in children. Acta Haematol 2006; 115: 214-220.
• 51 Tavil B, Ozyurek E, Gumruk F. et al. Antiphospholipid antibodies in Turkish children with thrombosis. Blood Coagul Fibrinol 2007; 18: 347-352.
• 52 Kreuz W, Stoll M, Junker R. et al. Familial elevated factor VIII in children with symptomatic venous thrombosis and post-thrombotic syndrome: results of a multicenter study. Arterioscler Thromb Vasc Biol 2006; 26: 1901-1906.
• 53 Albisetti M, Moeller A, Waldvogel K. et al. Congenital prothrombotic disorders in children with peripheral venous and arterial thromboses. Acta Haematol 2007; 117: 149-155.
• 54 Kenet G, Kirkham F, Niederstadt T. et al. Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study. Lancet Neurol 2007; 6: 595-603.
• 55 Ozyurek E, Balta G, Degerliyurt A. et al. Significance of factor V, prothrombin, MTHFR, and PAI-1 genotypes in childhood cerebral thrombosis. Clin Appl Thromb Hemost 2007; 13: 154-160.
• 56 Oren H, Devecioglu O, Ertem M. et al. Analysis of pediatric thrombosis patients in Turkey. Pediatr Hematol Oncol 2004; 21: 573-583.
• 57 Male C, Chait P, Andrew M. et al. PARKAA Investigators. Central venous line-related thrombosis in children: association with central venous line location and insertion technique. Blood 2003; 101: 4273-4278.
• 58 Young G, Albisetti M, Bonduel M. et al. Impact of inherited thrombophilia on symptomatic venous thrombo-embolism (VTE) in children: A systematic review & meta-analysis of 56 studies including 3070 pediatric patients. Blood 2007; 110: 936A-937A.
• 59 Vossen CY, Walker ID, Svensson P. et al. Recurrence rate after first venous thrombosis in patients with familial thrombophilia. Arterioscler Thromb Vasc Biol 2005; 25: 1992-1997.
• 60 De Stefano V, Rossi E, Paciaroni K. et al. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica 2002; 87: 1095-1108.
• 61 Prandoni P, Lensing AW, Cogo A. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
• 62 González-Porras JR, García-Sanz R, Alberca I. et al. Risk of recurrent venous thrombosis in patients with G20210A mutation in the prothrombin gene or factor V Leiden mutation. Blood Coagul Fibrinol 2006; 17: 23-28.
• 63 De Stefano V, Simioni P, Rossi E. et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C, and protein S. Haematologica 2006; 91: 695-698.
• 64 Ho WK, Hankey GJ, Quinlan DJ. et al. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166: 729-736.
• 65 Sass AE, Neufeld EJ. Risk factors for thromboembolism teens: when should I test?. Cur Opin Pediatr 2002; 14: 370-378.
• 66 Ruud E, Holmström H, Brosstad F. et al. Diagnostic value of family histories of thrombosis to identify children with thrombophilia. Pediatr Hematol Oncol 2005; 22: 453-462.
• 67 Johal SC, Garg BP, Heiny ME. et al. Family history is a poor screen for prothrombotic genes in children with stroke. J Pediatr 2006; 148: 68-71.
• 68 Dietrich JE, Hertweck SP, Perlman SE. Efficacy of familial history in determining thrombophilia risk. J Pediatr Adolesc Gynecol 2007; 20: 221-224.
• 69 Büller H, Agnelli G, Hull RD. et al. Antithrombotic therapy for venous thromboembolic disease. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: S401-S428.
• 70 Monagle P, Chan A, Chalmers E. et al. Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: S645-S687.