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Markers of coagulation activation, inflammation and fibrinolysis as predictors of poor outcomes after pediatric venous thromboembolism: A systematic review and meta-analysis.

ABSTRACT: Sequelae of venous thromboembolism (VTE) in children include recurrence, development of post thrombotic syndrome (PTS) when venous return from a limb is affected and chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Identification of laboratory-based risk factors may be useful for individualized risk assessment for VTE sequelae. Coagulation activation and inflammation may contribute to their pathophysiology. We performed a systematic review to investigate the association between biomarkers of coagulation activation, inflammation and fibrinolysis and adverse VTE outcomes in children and young adults.A systematic search of electronic databases, PubMed (NIH), EMBASE (Ovid), Web of Science (Thompson Reuters), and SCOPUS (Elsevier) for studies published through November 2016 was conducted using "VTE" including MeSH terms for "coagulation activation," "inflammation" and "fibrinolysis," with no limit on publication date. A study was eligible for inclusion when it evaluated patients (< 21years) with VTE and biomarkers of coagulation activation, inflammation, and fibrinolysis and assessed for their association with development of adverse thrombotic outcomes. A modified Newcastle Ottawa Scale was applied to examine the quality of included studies.Our search strategy yielded 200 references. A total of 3 cohort studies representing 220 patients with VTE were included. Two authors independently assessed all references for inclusion. Three studies (2 prospective cohort and one mixed cohort study) were identified that reported on biomarkers of coagulation activation, inflammation and fibrinolysis, checked at least once after VTE diagnosis and assessed association with primary outcomes of recurrent VTE, PTS and CTEPH. Studies varied with regards to definition of outcomes, the type of biomarkers measured and time point of measurement. We were unable to meta-analyze results due to marked clinical heterogeneity and <3 studies available for each biomarker. Descriptively, a significant association was found for elevated plasma levels of FVIII and D-dimer for a compound outcome of PTS, recurrence and progression in one study, and positive lupus anticoagulant at DVT diagnosis and subsequent PTS by another study. No studies were found for CTEPH.Elevated D-dimer, FVIII and lupus anticoagulant show promise for predicting recurrent VTE and PTS in children and young adults. Further research is needed to elucidate whether these markers might be useful to predict development of adverse outcomes after VTE in children.

SUBMITTER: Zia A

PROVIDER: S-EPMC5831248 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Markers of coagulation activation, inflammation and fibrinolysis as predictors of poor outcomes after pediatric venous thromboembolism: A systematic review and meta-analysis.

Zia Ayesha A Russell Joy J Sarode Ravi R Veeram Surendranath R SR Josephs Shellie S Malone Kendra K Zhang Song S Journeycake Janna J

Thrombosis research 20171007

<h4>Background</h4>Sequelae of venous thromboembolism (VTE) in children include recurrence, development of post thrombotic syndrome (PTS) when venous return from a limb is affected and chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Identification of laboratory-based risk factors may be useful for individualized risk assessment for VTE sequelae. Coagulation activation and inflammation may contribute to their pathophysiology. We performed a systematic review to inv ...[more]

PMID: 29078111

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Project description:BackgroundVenous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.MethodsWe present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.ResultsIn our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.ConclusionsOur cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

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Markers of coagulation activation, inflammation and fibrinolysis as predictors of poor outcomes after pediatric venous thromboembolism: A systematic review and meta-analysis.

Publications

Markers of coagulation activation, inflammation and fibrinolysis as predictors of poor outcomes after pediatric venous thromboembolism: A systematic review and meta-analysis.

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