Patho-physiological role of BDNF in fibrin clotting

Circulating levels of Brain Derived Neurotrophic Factor (BDNF) are lower in coronary heart disease (CHD) than in healthy subjects and are associated with coronary events and mortality. However, the mechanism(s) underling this association is not fully understood. We hypothesize that BDNF may influence fibrin fiber structure and clot stability, favoring clot lysis and thrombus resolution. We showed that recombinant BDNF (rh-BDNF) influenced with clot formation in a concentration-dependent manner in both purified fibrinogen and plasma from healthy subjects. In particular, rh-BDNF reduced the density of fibrin fibers, the maximum clot firmness (MCF) and the maximum clot turbidity, and affected the lysis of clot. In addition, both thrombin and reptilase clotting time were prolonged by rh-BDNF, despite the amount of thrombin formed was greater. Intriguingly, CHD patients had lower levels of BDNF, greater fibrin fibers density, higher MCF than control subjects, and a negative correlation between BDNF and MCF was found. Of note, rh-BDNF markedly modified fibrin clot profile restoring physiological clot morphology in CHD plasma. In conclusion, we provide evidence that low levels of BDNF correlate with the formation of bigger thrombi (in vitro) and that this effect is mediated, at least partially, by the alteration of fibrin fibers formation.冠心病（coronary heart disease, CHD）患者体内的脑源性神经营养因子（Brain Derived Neurotrophic Factor, BDNF）循环水平低于健康人群，且该水平与冠状动脉事件及死亡率相关。然而，这一关联背后的分子机制尚未完全阐明。本研究提出假说：BDNF可影响纤维蛋白纤维结构与血凝块稳定性，促进血凝块溶解与血栓消退。我们发现，重组脑源性神经营养因子（recombinant BDNF, rh-BDNF）可通过浓度依赖性方式，在纯化纤维蛋白原体系以及健康人群血浆中均对血凝块形成产生调控作用。具体而言，rh-BDNF可降低纤维蛋白纤维密度、最大血凝块坚固度（maximum clot firmness, MCF）与最大血凝块浊度，并对血凝块溶解过程产生影响。此外，尽管凝血酶生成量有所增加，rh-BDNF仍可延长凝血酶时间与爬虫酶凝血时间。值得注意的是，CHD患者的BDNF水平较对照组更低，其纤维蛋白纤维密度更高、MCF也更高，且BDNF水平与MCF呈负相关。尤为关键的是，rh-BDNF可显著改变CHD患者血浆中的血凝块特征，使其恢复至生理状态下的血凝块形态。综上所述，本研究证实低水平BDNF与体外形成更大体积血栓存在关联，且这一效应至少部分是通过改变纤维蛋白纤维形成过程所介导的。