The mediating role of coagulation factor VIII in the effect of chronic inflammation on recurrent thrombotic events in children with non-central line deep vein thrombosis
Bibliographic record
Abstract
Introduction Pediatric patients who had a first venous thromboembolic event are at risk of experiencing a thrombosis recurrence, which in turn is associated with high morbidity and mortality. Thus, predicting recurrence is relevant for clinical management. In a previous study, we have shown that chronic inflammation independently predicted recurrent thrombotic events in children with an index non-central venous catheter (non-CVC) related deep vein thrombosis (DVT). In that study, coagulation factor VIII (FVIII) did not predict thrombosis recurrence. However, FVIII is an acute phase protein that can be increased in the context of inflammatory conditions. Therefore we investigated the extent to which the effect of chronic inflammation on the outcome of thrombosis recurrence is mediated by FVIII. Method Children aged 0-18 years diagnosed with an index non-CVC related DVT between 1993-2020 were included in this single-center retrospective cohort study. Ethics approval was obtained. The primary outcome was thrombosis recurrence as per ISTH definitions. Two chart reviewers independently assessed the underlying conditions of each child and adjudicated whether there was an underlying chronic inflammatory condition present. FVIII was measured≥30 days after acute DVT diagnosis. Regression-based causal mediation analysis was conducted to assess the extent to which the effect of chronic inflammation on the outcome of thrombosis recurrence was mediated by FVIII ([ Fig. 1 ]), adjusting for sex and age at the time of the index DVT. Blood group was included in an exploratory mediation analysis. The natural indirect effect, natural direct effect, total effect, and proportion mediated were calculated and measured on the odds ratio scale. Fig. 1 Mediation Analysis ; Direct acyclic graph of the assumed causal effects between underlying diseases with chronic inflammation (exposure) on recurrent thrombosis (outcome) through factor VIII (mediator). The natural indirect effect, natural direct effect, and total effect are depicted by arrows. Their effect size is shown on the Odds ratio scale with 95% confidence intervals. The proportion mediated by FVIII reduced the total effect by 2%. Covariates: sex, age; Legend: Factor VIII (FVIII), Odds Ratio (OR), Confidence Interval (CI) Results A total of 139 children with an index non-CVC related DVT were included. Of these, 39 (28%) children had a recurrent thrombosis at a median of 206 days (P25-75 56-642 days) after the index DVT. Demographics and clinical characteristics are shown in [ Fig. 2 ]. Fig. 2 Demographics and clinical characteristics of study population by thrombosis recurrence ; 1 Median (P25 – P75); n (%); 2 Wilcoxon rank sum test; Pearson’s Chi-squared test; 3 n=101; Legend: deep vein thrombosis (DVT), Factor VIII (FVIII) The mediation effect of FVIII on the association of chronic inflammation and recurrent thrombosis is shown in [ Fig. 1 ]. Chronic inflammation had a significant total effect and a significant natural direct effect on recurrent thrombosis, with no evidence of mediation by FVIII (natural indirect effect). The proportion mediated indicated that FVIII reduced the total effect by 2%. When adding blood group as a covariate in exploratory analysis, the results of the mediation analysis did not change (data not shown) [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]. Conclusion Mediation analysis showed no evidence that factor VIII acts as a mediator in the effect of chronic inflammation on recurrent thrombosis. Hence, assessing the presence or absence of underlying conditions with chronic inflammation was more informative than measuring factor VIII to predict the outcome of recurrent thrombosis in children with non-central venous catheter-related thrombosis. These findings have implications for clinical practice. Acknowledgements: A.B. was supported by the Rudolf-Marx-Research-Grant of the German Society for Thrombosis and Haemostasis Research e.V. (GTH) and by the Clinical Medicine Plus Scholarship of the Prof. Dr. Max Cloetta Foundation. K.J.B. was supported by the Norwegian Childhood Cancer association. Publication History Article published online: 26 February 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".