Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: A systematic review and meta-analysis of observational studies

Gili Kenet, Lisa K. Lütkhoff, Manuela Albisetti, Timothy Bernard, Mariana Bonduel, Leonardo Brandao, Stephane Chabrier, Anthony Chan, Gabrielle Deveber, Barbara Fiedler, Heather J. Fullerton, Neil A. Goldenberg, Eric Grabowski, Gudrun Günther, Christine Heller, Susanne Holzhauer, Alfonso Iorio, Janna Journeycake, Ralf Junker, Fenella J. KirkhamKarin Kurnik, John K. Lynch, Christoph Male, Marilyn Manco-Johnson, Rolf Mesters, Paul Monagle, C. Heleen Van Ommen, Leslie Raffini, Kevin Rostásy, Paolo Simioni, Ronald D. Sträter, Guy Young, Ulrike Nowak-Göttl

Research output: Contribution to journalArticle

251 Citations (Scopus)

Abstract

Background: The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and results: A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). Conclusions: The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.

Original languageEnglish (US)
Pages (from-to)1838-1847
Number of pages10
JournalCirculation
Volume121
Issue number16
DOIs
StatePublished - Apr 2010

Fingerprint

Intracranial Thrombosis
Thrombophilia
Observational Studies
Meta-Analysis
Stroke
Newborn Infant
Confidence Intervals
Intracranial Sinus Thrombosis
Venous Thrombosis
Publication Bias
Odds Ratio
Prothrombin
Protein S Deficiency
Protein C Deficiency
Antiphospholipid Antibodies
Lipoprotein(a)
Factor V
Antithrombins
PubMed
Libraries

Keywords

  • Cerebrovascular disorders
  • Meta-analysis
  • Pediatrics
  • Thrombophilia

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children : A systematic review and meta-analysis of observational studies. / Kenet, Gili; Lütkhoff, Lisa K.; Albisetti, Manuela; Bernard, Timothy; Bonduel, Mariana; Brandao, Leonardo; Chabrier, Stephane; Chan, Anthony; Deveber, Gabrielle; Fiedler, Barbara; Fullerton, Heather J.; Goldenberg, Neil A.; Grabowski, Eric; Günther, Gudrun; Heller, Christine; Holzhauer, Susanne; Iorio, Alfonso; Journeycake, Janna; Junker, Ralf; Kirkham, Fenella J.; Kurnik, Karin; Lynch, John K.; Male, Christoph; Manco-Johnson, Marilyn; Mesters, Rolf; Monagle, Paul; Van Ommen, C. Heleen; Raffini, Leslie; Rostásy, Kevin; Simioni, Paolo; Sträter, Ronald D.; Young, Guy; Nowak-Göttl, Ulrike.

In: Circulation, Vol. 121, No. 16, 04.2010, p. 1838-1847.

Research output: Contribution to journalArticle

Kenet, G, Lütkhoff, LK, Albisetti, M, Bernard, T, Bonduel, M, Brandao, L, Chabrier, S, Chan, A, Deveber, G, Fiedler, B, Fullerton, HJ, Goldenberg, NA, Grabowski, E, Günther, G, Heller, C, Holzhauer, S, Iorio, A, Journeycake, J, Junker, R, Kirkham, FJ, Kurnik, K, Lynch, JK, Male, C, Manco-Johnson, M, Mesters, R, Monagle, P, Van Ommen, CH, Raffini, L, Rostásy, K, Simioni, P, Sträter, RD, Young, G & Nowak-Göttl, U 2010, 'Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: A systematic review and meta-analysis of observational studies', Circulation, vol. 121, no. 16, pp. 1838-1847. https://doi.org/10.1161/CIRCULATIONAHA.109.913673
Kenet, Gili ; Lütkhoff, Lisa K. ; Albisetti, Manuela ; Bernard, Timothy ; Bonduel, Mariana ; Brandao, Leonardo ; Chabrier, Stephane ; Chan, Anthony ; Deveber, Gabrielle ; Fiedler, Barbara ; Fullerton, Heather J. ; Goldenberg, Neil A. ; Grabowski, Eric ; Günther, Gudrun ; Heller, Christine ; Holzhauer, Susanne ; Iorio, Alfonso ; Journeycake, Janna ; Junker, Ralf ; Kirkham, Fenella J. ; Kurnik, Karin ; Lynch, John K. ; Male, Christoph ; Manco-Johnson, Marilyn ; Mesters, Rolf ; Monagle, Paul ; Van Ommen, C. Heleen ; Raffini, Leslie ; Rostásy, Kevin ; Simioni, Paolo ; Sträter, Ronald D. ; Young, Guy ; Nowak-Göttl, Ulrike. / Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children : A systematic review and meta-analysis of observational studies. In: Circulation. 2010 ; Vol. 121, No. 16. pp. 1838-1847.
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abstract = "Background: The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and results: A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95{\%} confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95{\%} CI, 2.44 to 22.42); protein C deficiency, 8.76 (95{\%} CI, 4.53 to 16.96); protein S deficiency, 3.20 (95{\%} CI, 1.22 to 8.40), factor V G1691A, 3.26 (95{\%} CI, 2.59 to 4.10); factor II G20210A, 2.43 (95{\%} CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95{\%} CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95{\%} CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95{\%} CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95{\%} CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95{\%} CI, 2.29 to 5.53); and factor II, 2.02 (95{\%} CI, 1.02 to 3.99). Conclusions: The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.",
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TY - JOUR

T1 - Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children

T2 - A systematic review and meta-analysis of observational studies

AU - Kenet, Gili

AU - Lütkhoff, Lisa K.

AU - Albisetti, Manuela

AU - Bernard, Timothy

AU - Bonduel, Mariana

AU - Brandao, Leonardo

AU - Chabrier, Stephane

AU - Chan, Anthony

AU - Deveber, Gabrielle

AU - Fiedler, Barbara

AU - Fullerton, Heather J.

AU - Goldenberg, Neil A.

AU - Grabowski, Eric

AU - Günther, Gudrun

AU - Heller, Christine

AU - Holzhauer, Susanne

AU - Iorio, Alfonso

AU - Journeycake, Janna

AU - Junker, Ralf

AU - Kirkham, Fenella J.

AU - Kurnik, Karin

AU - Lynch, John K.

AU - Male, Christoph

AU - Manco-Johnson, Marilyn

AU - Mesters, Rolf

AU - Monagle, Paul

AU - Van Ommen, C. Heleen

AU - Raffini, Leslie

AU - Rostásy, Kevin

AU - Simioni, Paolo

AU - Sträter, Ronald D.

AU - Young, Guy

AU - Nowak-Göttl, Ulrike

PY - 2010/4

Y1 - 2010/4

N2 - Background: The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and results: A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). Conclusions: The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.

AB - Background: The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and results: A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). Conclusions: The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.

KW - Cerebrovascular disorders

KW - Meta-analysis

KW - Pediatrics

KW - Thrombophilia

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