Published Online
on September 8, 2008

A more recent version of this article appeared on September 23, 2008

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Submitted on January 3, 2008
Accepted on July 11, 2008

Impact of Inherited Thrombophilia on Venous Thromboembolism in Children. A Systematic Review and Meta-Analysis of Observational Studies

Guy Young MD, Manuela Albisetti MD, Mariana Bonduel MD, Leonardo Brandao MD, Anthony Chan MD, Frauke Friedrichs PhD, Neil A. Goldenberg MD, Eric Grabowski MD, Christine Heller MD, Janna Journeycake MD, Gili Kenet MD, Anne Krümpel MD, Karin Kurnik MD, Aaron Lubetsky MD, Christoph Male MD, Marilyn Manco-Johnson MD, Prasad Mathew MD, Paul Monagle MD, Heleen van Ommen MD, Paolo Simioni MD, Pavel Svirin MD, Daniela Tormene MD, and Ulrike Nowak-Göttl MD^*

From the Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, Calif (G.Y.); Division of Hematology, University Children's Hospital, Zurich, Switzerland (M.A.); Servicio de Hematolgía y Oncología, Hospital de Pediatría "Prof. Dr. J.P. Garrahan," Buenos Aires, Argentina (M.B.); Hospital for Sick Children, Toronto, Canada (L.B.); McMaster University, Hamilton, Canada (A.C.); Leibniz Institute for Arteriosclerosis Research, University of Münster, Münster, Germany (F.F.); Department of Pediatrics, Hematology/Oncology/BMT, University of Colorado and the Children's Hospital, Denver (N.A.G., M.M.-J.); Massachusetts General Hospital, Harvard Medical School, Boston, Mass (E.G.); Department of Pediatric Hematology/Oncology, University Hospital Frankfurt, Frankfurt, Germany (C.H.); Department of Pediatrics, Children's Medical Centre Dallas, University of Texas Southwestern Medical Center, Dallas (J.J.); Israel National Haemophilia Centre, Sheba Medical Centre, Tel-Hashomer, Israel (G.K., A.L.); Department of Pediatric Hematology/Oncology, University Hospital Münster, Münster, Germany (A.K., U.N.-G.); Department of Pediatrics, University Hospital Munich, Munich, Germany (K.K.); Department for Pediatrics, Medical University, Vienna, Austria (C.M.); Department of Pediatrics, University of New Mexico, Albuquerque (P. Mathew); The Royal Children's Hospital, Victoria, Australia (P. Monagle); Department of Pediatric Hematology, Emma Children's Hospital AMC, Amsterdam, the Netherlands (H.v.O.); Department of Medical and Surgical Sciences, University of Padua, Padua, Italy (P. Simioni, D.T.); and Russian National Center of Pediatric Hematology/Oncology, Moscow State Medical University, Moscow, Russian Federation (P. Svirin).

^* To whom correspondence should be addressed. E-mail: leagottl{at}uni-muenster.de.

Background—The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies.

Methods and Results—A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a).

Conclusions—The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.

Key words: meta-analysis • pediatrics • recurrence • thrombosis

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