Coagulation Pathways as Determinants of Acute Subdural Hematoma Resolution - Genetic Evidence From Human Data

Sep 30, 2026

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Acute subdural hematoma (ASDH) after traumatic brain injury carries high mortality and disability, and spontaneous hematoma resolution strongly influences functional recovery. Coagulopathy is common in ASDH, but causality between coagulation dysfunction and hematoma dynamics is unclear. A two-sample Mendelian randomization study tested causal effects of coagulation traits on resolution using genetic instruments from large GWAS and proxy outcomes, applying inverse-variance weighted estimates with robust sensitivity analyses.

LanguageEnglish

CategoryHealthcare

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Pages11

Reading Time28 min

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Abstract

Introduction

Methods

Results

Conclusions

CNS Neuroscience & Therapeutics ORIGINAL ARTICLE OPEN ACCESS Coagulation Pathways as Determinants of Acute Subdural Hematoma Resolution: Genetic Evidence From Human Data Qizhong Wu1 | Tingting Xu2 | Bo Tan2 1Department of Critical Care Medicine, Guangyuan Central Hospital, Guangyaun, Sichuan, China | 2Department of Neurosurgery, Guangyuan Central Hospital, Guangyuan, Sichuan, China Correspondence: Bo Tan ([tb860417@hotmail.com](tb860417@hotmail.com)) Received: 22 September 2025 | Revised: 14 December 2025 | Accepted: 30 December 2025 Keywords: acute subdural hematoma | coagulation | factor VIII | factor XI | fibrinogen γ' | Mendelian randomization ABSTRACT Background: Acute subdural hematoma (ASDH) is a severe complication of traumatic brain injury, with high mortality and disability. Spontaneous hematoma resolution is an important determinant of functional recovery, but the biological mechanisms underlying this process remain poorly understood. Coagulopathy, common in ASDH, may influence hematoma dynamics, but its causal role remains uncertain. Methods: We conducted a two-sample Mendelian randomization (MR) study to investigate the causal effects of coagulation traits on hematoma resolution. Genetic instruments for fibrinogen isoforms, coagulation factors VIII, XI, V, VII, natural anticoagulants, and platelet traits were obtained from large genome-wide association studies. Due to the absence of ASDH-specific GWAS data, we used genetic susceptibility to intracerebral hemorrhage (ICH) and poststroke functional outcome as indirect proxies for hematoma persistence and clearance. We acknowledge that these proxies cannot fully capture the unique pathophysiology of ASDH, but they represent pragmatic, biologically relevant surrogates. Causal estimates were obtained using inversevariance weighted MR with robust sensitivity analyses. Results: Genetically higher fibrinogen γ' levels were associated with increased odds of hematoma resolution (OR 1.25, 95% CI 1.10–1.42). Higher factor VIII and XI levels were associated with reduced odds of Resolution (OR 0.82, 95% CI 0.72–0.94; OR 0.88, 95% CI 0.78–1.00). Secondary analyses using poststroke functional outcome yielded similar patterns but did not reach statistical significance (OR ~1.10, p = 0.15) . Conclusions: Our findings provide genetic evidence suggesting coagulation pathways, particularly fibrinogen γ' and factors VIII and XI, may influence hematoma resolution in ASDH. However, due to the indirect nature of the proxies used, these results should be considered hypothesis-generating and require further validation in ASDH-specific cohorts. 1 | Introduction Acute subdural hematoma (ASDH) represents one of the most devastating complications of traumatic brain injury, with persistently high rates of mortality and disability worldwide [1–3] . Although surgical evacuation remains the mainstay of treatment, spontaneous hematoma resolution is increasingly recognized as an important determinant of functional recovery in carefully selected patients [4–6] . However, the biological mechanisms that underlie such spontaneous absorption remain poorly understood, limiting our ability to stratify patients and to optimize both surgical and conservative management [5, 6] . Coagulopathy, either pre-existing or trauma-induced, is frequently observed in ASDH and has been associated with hematoma expansion, impaired clearance, and poor outcome [7–9] . Yet, conventional observational studies cannot fully disentangle This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2026 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. CNS Neuroscience & Therapeutics, 2026; 32:e70741 1 of 11 [https://doi.org/10.1002/cns.70741](https://doi.org/10.1002/cns.70741) whether coagulation dysfunction is caus

FAQs

Why investigate coagulation pathways in acute subdural hematoma resolution?

ASDH often involves coagulopathy, and spontaneous resolution affects functional recovery, but the causal biological mechanisms remain uncertain. The study evaluates whether coagulation traits causally influence resolution rather than merely reflecting injury severity.

How was causal inference tested in the study?

The authors used a two-sample Mendelian randomization design with genetic instruments for fibrinogen isoforms and coagulation factors. Inverse-variance weighted MR was combined with robust sensitivity analyses to assess causal effects.

Which genetic coagulation traits were linked to hematoma resolution?

Higher fibrinogen γ' levels were associated with increased odds of resolution. In contrast, higher factor VIII and factor XI levels were associated with reduced odds of resolution, based on the reported ORs and confidence intervals.

Why were proxies used instead of ASDH-specific genetic data?

ASDH-specific GWAS data for hematoma absorption were not available, so the study used genetic susceptibility to intracerebral hemorrhage and poststroke functional outcomes as indirect proxies for persistence and clearance. The authors note these proxies cannot fully capture ASDH-specific biology and should be validated in ASDH cohorts.

Sep 30, 2026

Uploaded by kopisore