Dysregulation of the FVIII–VWF Axis in Early-Onset Ischemic Stroke

Background: Ischemic stroke in young adults often occurs without advanced atherosclerosis, implicating non-atherosclerotic prothrombotic mechanisms. Factor VIII (FVIII) and von Willebrand factor (VWF) link endothelial activation, platelet adhesion, and coagulation, yet their integrated clinical and molecular relevance in early-onset stroke remains incompletely defined. Methods: We conducted a retrospective case–control study including 25 young adults with ischemic stroke and 26 age matched controls. Plasma FVIII activity and VWF antigen were measured and analyzed using multivariable logistic regression and ROC curves. To provide mechanistic context, FVIII–VWF pathway activity was assessed in three independent ischemic stroke transcriptomic datasets (GSE16561, GSE202518, GSE22255; total n=119) using single-sample gene set enrichment analysis and random-effects meta-analysis. Results: FVIII and VWF levels were significantly higher in stroke patients than controls, independent of age and sex, with expected modulation by ABO blood group. FVIII, but not VWF, remained independently associated with ischemic stroke (adjusted OR 1.05, 95% CI 1.01–1.09) and showed strong discriminatory performance (AUC 0.86). Transcriptomic analyses revealed heterogeneous gene level changes but consistent upregulation of the FVIII–VWF prothrombotic pathway across datasets. Meta-analysis confirmed a significant, homogeneous pooled effect for FVIII–VWF UP scores (Hedges’ g 0.76, p<0.0001), whereas regulatory pathway activation was variable and non-significant. Conclusions: Young-onset ischemic stroke is associated with FVIII-driven prothrombotic pathway activation, helping explain stroke occurrence in patients lacking traditional vascular risk factors. These findings provide complementary clinical and transcriptomic evidence supporting a central role for the FVIII–VWF axis in prothrombotic pathway activation in early-onset ischemic stroke.