Plasma BDNF Is Reduced in Acute Ischemic Stroke Patients With Type 2 Diabetes Mellitus and Associated With Fibrin-Rich Thrombi.

Aim: Acute ischemic stroke (AIS) patients with diabetes mellitus (DM) have significantly lower brain-derived neurotrophic factor (BDNF) levels compared to nondiabetic patients. However, the impact of BDNF on thrombus characteristics is unclear. The relationship between the plasma BDNF and fibrin ultrastructure of thrombi was investigated. Methods: This study analyzed 72 AIS patients (35 with T2DM) with first-ever stroke and 10 healthy controls. All patients were assessed for severity and type of stroke, risk factors, and levels of plasma BDNF in the acute stroke. Retrieved arterial thrombi from AIS patients underwent histopathological (immunohistochemical, Martius scarlet blue staining, and immunofluorescence), ultrastructural (scanning/transmission electron microscopy), and permeability (CT/CTA) analyses. In vitro effects of recombinant BDNF (rHu-BDNF) on fibrin polymerization (turbidity assay), clot firmness (thromboelastography), and lysis were assessed in plasma pools. Results: AIS/DM patients exhibited significantly lower plasma BDNF versus AIS/non-DM patients (6.83 ± 0.81 vs. 8.70 ± 0.73 ng/mL, p < 0.001) and controls (9.81 ± 0.59 ng/mL). Meanwhile, AIS/DM patients had higher baseline NIHSS scores than AIS/non-DM patients (17.09 ± 8.29 vs. 13.22 ± 6.15, p = 0.027). AIS/DM thrombi histopathological showed lower BDNF staining intensity, higher fibrin density, and reduced permeability. Moreover, BDNF levels positively correlated with thrombus permeability (r = 0.862, p < 0.001). We showed that rHu-BDNF reduced the density of fibrin fiber (p < 0.001), turbidity (p < 0.05), and maximum clot firmness (p < 0.05), while increasing the diameter of fibrin (p < 0.05), prolonging thrombin time (p < 0.001), and accelerating lysis (p < 0.001) in a concentration-dependent manner in plasma from AIS/DM patients. Conclusion: This study demonstrates that low BDNF levels in AIS/DM patients promote fibrin-rich, dense clot formation, partly via altered fibrin fiber structure and fibrin polymerization. BDNF may serve as a novel biomarker for thrombus heterogeneity and a potential target to improve thrombolysis in diabetic stroke.