Serum EphA4 is Associated with both Parenchymal Hematoma and Increased Blood–Brain Barrier Permeability after Ischemic Stroke

The receptor tyrosine kinase AR4-type receptor in erythropoietin-producing hepatocellular carcinoma (EphA4) has been linked to disruption of the blood–brain barrier (BBB) and hemorrhagic transformation after acute ischemic stroke. Here, we explored whether EphA4 may be involved in parenchymal hematoma (PH) after ischemic stroke.

Data were analyzed from patients who were admitted to West China Hospital of Sichuan University within 48 h of stroke onset between January 2017 and December 2019. EphA4 levels in serum were measured within 24 h after admission, and baseline computed tomography perfusion was performed immediately upon admission. Potential relationships of EphA4 levels or ipsilateral flow extraction product (FED) with occurrence of PH were explored using logistic regression.

Of the 578 patients (337 men) analyzed, who were a median age of 69 years old, 56 (9.69%) developed PH. Serum EphA4 levels were higher in patients with PH than in those without PH (44.96 vs. 37.86 ng/mL, P = 0.036). After adjustment for confounders, higher serum EphA4 levels (≥ 32.21 ng/mL) were significantly associated with PH (odds ratio [OR] 3.84, 95% confidence interval [CI] 1.66–8.90, P = 0.002). Among the 230 patients in whom brain perfusion was analyzed using computed tomography perfusion, ipsilateral FED was significantly associated with PH after adjusting for confounders (OR 2.43, 95% CI 1.63–3.63, P < 0.001). The two parameters of EphA4 level and ipsilateral FED interacted in their association with PH (P_interaction = 0.037): higher EphA4 level was associated with PH in those with higher ipsilateral FED (OR 1.04, 95% CI 1.01–1.07, P = 0.006), not in those with lower FED.

Elevated EphA4 levels in serum are associated with higher risk of PH after ischemic stroke, especially among patients showing greater permeability of the BBB as reflected in higher ipsilateral FED on computed tomography perfusion.