Download PDF
Semin Thromb Hemost 2011; 37(7): 802-809
DOI: 10.1055/s-0031-1297171
© Thieme Medical Publishers

Impact of Persistent Antiphospholipid Antibodies on Risk of Incident Symptomatic Thromboembolism in Children: A Systematic Review and Meta-Analysis

Gili Kenet1 , Sofia Aronis2 , Yackov Berkun3 , Mariana Bonduel4 , Anthony Chan5 , Neil A. Goldenberg6 , Susanne Holzhauer7 , Alfonso Iorio8 , Janna Journeycake9 , Ralf Junker10 , Christoph Male11 , Marilyn Manco-Johnson5 , Patti Massicotte12 , Rolf Mesters13 , Paul Monagle14 , Heleen van Ommen15 , Leslie Rafini16 , Paolo Simioni17 , Guy Young18 , Ulrike Nowak-Göttl10
  • 1The Israel National Haemophilia Centre, Sheba Medical Centre, Tel-Hashomer, Israel
  • 2Haemophilia Centre-Haemostasis Unit, Aghia Sophia Children's Hospital, Athens, Greece
  • 3The Department of Pediatrics, Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
  • 4Servicio de Hematolgía y Oncología, Hospital de Pediatría “Prof. Dr. JP Garrahan,” Buenos Aires, Argentina
  • 5Thrombosis and Atherosclerosis Research Institute McMaster University, Hamilton, Ontario, Canada
  • 6Department of Pediatrics and Medicine, Hematology/Oncology/BMT, University of Colorado and The Children's Hospital, Denver, Colorado
  • 7Department of Pediatric Hematology/Oncology, Charite, Berlin, Germany
  • 8Departments of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Ontario, Canada
  • 9Department of Pediatrics, Children's Medical Centre Dallas, University of TX Southwestern, Medical Centre Dallas, Texas
  • 10Department of Clinical Chemistry, University Hospital of Kiel, Kiel, Germany
  • 11Department for Pediatrics, Medical University Vienna, Vienna, Austria
  • 12Department of Pediatrics, University Children Hospital Alberta, Canada
  • 13Department of Internal Medicine, University Hospital of Münster, Münster, Germany
  • 14The Royal Children's Hospital, Victoria, Australia
  • 15Department of Pediatric Hematology, Emma Children's Hospital AMC, Amsterdam, The Netherlands
  • 16Division of Hematology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  • 17Department of Medical & Surgical Sciences, University of Padua, Padua, Italy
  • 18Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California
Further Information

Publication History

Publication Date:
20 December 2011 (online)

   Permissions and Reprints

ABSTRACT

The aim of this study was to estimate the impact of antiphospholipid (aPL) antibodies on the risk of incident thromboembolism (TE; arterial and venous) in children via meta-analysis of published observational studies. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1966 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, TE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using either fixed-effects or random-effects models. Of 504, 16 pediatric studies met the inclusion criteria. In total 1403 patients and 1667 population-based controls ≤18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. Thus, data from arterial and venous TE were analyzed together. In addition, meta-regression analysis did not reveal statistically significant differences between site of TE, age at first TE, country, or publication year. A statistically significant association with a first TE was demonstrated for persistent aPL antibodies, with an overall summary ORs/CI of 5.9/3.6–9.7 (arterial 6.6/3.5–12.4; deep vein thrombosis 4.9/2.2–10.9). The present meta-analysis indicates that detection of persistent aPL is clinically meaningful in children with, or at risk for, TE and underscores the importance of pediatric thrombophilia screening programs.

KEYWORDS

Antiphospholipid antibodies - thromboembolism - recurrence - children - meta-analysis

REFERENCES

  • 1 Miyakis S, Lockshin M D, Atsumi T et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4 (2) 295-306
    Google Scholar
  • 2 Levine J S, Branch D W, Rauch J. The antiphospholipid syndrome.  N Engl J Med. 2002;  346 (10) 752-763
    Google Scholar
  • 3 Levy D M, Massicotte M P, Harvey E, Hebert D, Silverman E D. Thromboembolism in paediatric lupus patients.  Lupus. 2003;  12 (10) 741-746
    Google Scholar
  • 4 Campos L M, Kiss M H, D'Amico E A, Silva C A. Antiphospholipid antibodies and antiphospholipid syndrome in 57 children and adolescents with systemic lupus erythematosus.  Lupus. 2003;  12 (11) 820-826
    Google Scholar
  • 5 Cervera R, Piette J C, Font J Euro-Phospholipid Project Group et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.  Arthritis Rheum. 2002;  46 (4) 1019-1027
    Google Scholar
  • 6 Avcin T, Cimaz R, Rozman B. Ped-APS Registry Collaborative Group . The Ped-APS Registry: the antiphospholipid syndrome in childhood.  Lupus. 2009;  18 (10) 894-899
    Google Scholar
  • 7 Berkun Y, Padeh S, Barash J et al.. Antiphospholipid syndrome and recurrent thrombosis in children.  Arthritis Rheum. 2006;  55 (6) 850-855
    Google Scholar
  • 8 Kenet G, Lütkhoff L K, Albisetti M et al.. Impact of inherited thrombophilia on arterial ischemic stroke and cerebral sinovenous thrombosis in children: a systematic review and meta-analysis of observational studies.  Circulation. 2010;  121 1838-1847
    Google Scholar
  • 9 Male C, Mitchell L, Julian J et al.. Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus.  Blood. 2001;  97 (4) 844-849
    Google Scholar
  • 10 Levy D M, Massicotte M P, Harvey E, Hebert D, Silverman E D. Thromboembolism in paediatric lupus patients.  Lupus. 2003;  12 (10) 741-746
    Google Scholar
  • 11 Bonduel M, Sciuccati G, Hepner M et al.. Factor V Leiden and prothrombin gene G20210A mutation in children with cerebral thromboembolism.  Am J Hematol. 2003;  73 (2) 81-86
    Google Scholar
  • 12 Günes A M, Baytan B, Günay U. The influence of risk factors in promoting thrombosis during childhood: the role of acquired factors.  Pediatr Hematol Oncol. 2006;  23 (5) 399-410
    Google Scholar
  • 13 Nowak-Göttl U, Junker R, Hartmeier M et al.. Increased lipoprotein(a) is an important risk factor for venous thromboembolism in childhood.  Circulation. 1999a;  100 (7) 743-748
    Google Scholar
  • 14 Sträter R, Vielhaber H, Kassenböhmer R, von Kries R, Göbel U, Nowak-Göttl U. Genetic risk factors of thrombophilia in ischaemic childhood stroke of cardiac origin. A prospective ESPED survey.  Eur J Pediatr. 1999;  158 (Suppl 3) S122-S125
    Google Scholar
  • 15 Heller C, Schobess R, Kurnik K For the Childhood Thrombophilia Study Group et al. Abdominal venous thrombosis in neonates and infants: role of prothrombotic risk factors - a multicentre case-control study.  Br J Haematol. 2000;  111 (2) 534-539
    Google Scholar
  • 16 Günther G, Junker R, Sträter R Childhood Stroke Study Group et al. Symptomatic ischemic stroke in full-term neonates : role of acquired and genetic prothrombotic risk factors.  Stroke. 2000;  31 (10) 2437-2441
    Google Scholar
  • 17 Kenet G, Sadetzki S, Murad H et al.. Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children.  Stroke. 2000;  31 (6) 1283-1288
    Google Scholar
  • 18 Heller C, Heinecke A, Junker R Childhood Stroke Study Group et al. Cerebral venous thrombosis in children: a multifactorial origin.  Circulation. 2003;  108 (11) 1362-1367
    Google Scholar
  • 19 Kurnik K, Kosch A, Sträter R, Schobess R, Heller C, Nowak-Göttl U. Childhood Stroke Study Group . Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: a prospective follow-up study.  Stroke. 2003;  34 (12) 2887-2892
    Google Scholar
  • 20 Gürgey A, Balta G, Gumruk F, Altay C. Analysis of some clinical and laboratory aspects of adolescent patients with thrombosis.  Blood Coagul Fibrinolysis. 2004;  15 (8) 657-662
    Google Scholar
  • 21 Kenet G, Waldman D, Lubetsky A et al.. Paediatric cerebral sinus vein thrombosis. A multi-center, case-controlled study.  Thromb Haemost. 2004;  92 (4) 713-718
    Google Scholar
  • 22 Kosch A, Kuwertz-Bröking E, Heller C, Kurnik K, Schobess R, Nowak-Göttl U. Renal venous thrombosis in neonates: prothrombotic risk factors and long-term follow-up.  Blood. 2004;  104 (5) 1356-1360
    Google Scholar
  • 23 Duran R, Biner B, Demir M, Celtik C, Karasalihoğlu S. Factor V Leiden mutation and other thrombophilia markers in childhood ischemic stroke.  Clin Appl Thromb Hemost. 2005;  11 (1) 83-88
    Google Scholar
  • 24 Ünal S, Varan A, Yalçin B, Büyükpamukçu M, Gürgey A. Evaluation of thrombotic children with malignancy.  Ann Hematol. 2005;  84 (6) 395-399
    Google Scholar
  • 25 Bonduel M, Sciuccati G, Hepner M et al.. Arterial ischemic stroke and cerebral venous thrombosis in children: a 12-year Argentinean registry.  Acta Haematol. 2006;  115 (3-4) 180-185
    Google Scholar
  • 26 Nowak-Göttl U, Langer C, Bergs S, Thedieck S, Sträter R, Stoll M. Genetics of hemostasis: differential effects of heritability and household components influencing lipid concentrations and clotting factor levels in 282 pediatric stroke families.  Environ Health Perspect. 2008;  116 (6) 839-843
    Google Scholar
  • 27 Simchen M J, Goldstein G, Lubetsky A, Strauss T, Schiff E, Kenet G. Factor v Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke.  Stroke. 2009;  40 (1) 65-70
    Google Scholar
  • 28 Avcin T, Ambrozic A, Kuhar M, Kveder T, Rozman B. Anticardiolipin and β2 glycoprotein I antibodies in sera of 61 apparently healthy children at regular preventive visits.  Rheumatology. 2001;  40 555-573
    Google Scholar
  • 29 Berkun Y, Kenet G. Pediatric antiphospholipid syndrome.  Isr Med Assoc J. 2008;  10 (1) 45-47
    Google Scholar
  • 30 Vandenbroucke J P, von Elm E, Altman D G STROBE initiative et al. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration.  Ann Intern Med. 2007;  147 (8) W163-94
    Google Scholar
  • 31 Mayer D. Essential Evidence-Based Medicine. UK, Cambridge University Press; 2004: 347-360
    Google Scholar
  • 32 Kirkwood B R, Sterne JAC. Medical Statistics. 2nd ed. Oxford, Blackwell Science; 2003: 180-387
    Google Scholar
  • 33 Higgins JPT, Thompson S G, Deeks J J, Altman D G. Measuring inconsistency in meta-analyses.  BMJ. 2003;  327 (7414) 557-560
    Google Scholar
  • 34 Harbord R M, Egger M, Sterne JAC. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints.  Stat Med. 2006;  25 (20) 3443-3457
    Google Scholar
  • 35 Avčin T, Cimaz R, Silverman E D et al.. Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients in an international registry.  Pediatrics. 2008;  122 (5) e1100-e1107
    Google Scholar
  • 36 Avcin T, Cimaz R, Meroni PL. Recent advances in antiphospholipid antibodies and antiphospholipid syndromes in pediatric populations.  Lupus. 2002;  11 (1) 4-10
    Google Scholar
  • 37 Boffa MCAM, Aurousseau M H, Lachassinne E et al.. European register of babies born to mothers with antiphospholipid syndrome.  Lupus. 2004;  13 (9) 713-717
    Google Scholar
  • 38 Boffa M C, Lachassinne E. Infant perinatal thrombosis and antiphospholipid antibodies: a review.  Lupus. 2007;  16 (8) 634-641
    Google Scholar

Ulrike Nowak-GöttlM.D. 

Hemostasis Unit, Department of Clinical Chemistry, University Hospital of Kiel

Arnold-Heller-Str. 3, D-24105 Kiel, Germany

Email: leagottl@gmail.com

      >