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

TL;DR

This study uses genetic data to show that coagulation factors like fibrinogen gamma prime and factors VIII and XI may influence the resolution of acute subdural hematomas.

Contribution

The study provides the first genetic evidence linking coagulation pathways to hematoma resolution in traumatic brain injury.

Findings

Higher fibrinogen γ' levels were associated with increased odds of hematoma resolution.

Elevated factor VIII and XI levels were linked to reduced odds of hematoma resolution.

Other coagulation factors and platelet traits showed no significant effects on hematoma clearance.

Abstract

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.

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 inverse‐variance weighted MR with robust sensitivity analyses.

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).

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.

This study applied a two‐sample Mendelian randomization framework to investigate the causal effects of coagulation pathways on the spontaneous resolution of acute subdural hematoma (ASDH). Genetic variants influencing coagulation traits were analyzed using GWAS data as instrumental variables. The results demonstrated that higher fibrinogen γ′ levels significantly increased the likelihood of hematoma clearance, whereas elevated factor VIII and factor XI activity reduced the probability of resolution. Other coagulation factors, natural anticoagulants, and platelet traits showed no significant effects. These findings provide the first genetic evidence that coagulation pathways modulate ASDH dynamics and suggest that targeted modulation of fibrinogen isoform composition or inhibition of factors VIII/XI may represent novel therapeutic strategies to enhance hematoma absorption and improve neurotrauma outcomes.

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