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

Ischemic stroke in young adults often occurs in the absence of advanced atherosclerosis, suggesting the involvement of nonatherosclerotic prothrombotic mechanisms. Factor VIII (FVIII) and von Willebrand factor (VWF) link endothelial activation, platelet adhesion, and coagulation; however, their integrated clinical and molecular relevance in early-onset stroke remains incompletely defined. 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 levels were measured and analyzed using multivariable logistic regression and receiver operating characteristic curve analysis. To provide mechanistic context, FVIII-VWF pathway activity was assessed in three independent ischemic stroke transcriptomic datasets (GSE16561, GSE202518, and GSE22255; total n = 119) using single-sample gene set enrichment analysis and random effects meta-analysis. FVIII and VWF levels were significantly higher in patients with stroke than in controls, independently of age and sex, with expected modulation by ABO blood group. FVIII, but not VWF, remained independently associated with ischemic stroke (adjusted odds ratio: 1.05, 95% confidence interval: 1.01-1.09) and showed strong discriminatory performance (area under the curve: 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 and homogeneous pooled effect for FVIII-VWF UP scores (Hedges' g = 0.76, p < 0.0001), whereas activation of the regulatory pathway was variable and nonsignificant. These findings provide complementary clinical and transcriptomic evidence supporting a central role for FVIII-driven FVIII-VWF axis activation in the prothrombotic milieu of early-onset ischemic stroke.