凝血因子XI（FXI）突变Gly397Ala是本课题组在易栓症患者中首次发现的，目前已知唯一的可升高FXI凝血活性的功能获得性突变。Gly397位氨基酸残基邻近FXI裂解活化位点，是FXI酶原向酶转化过程中分子结构运动的枢纽，参与FXI酶活性构象的形成和维持。由于丙氨酸（Ala）具有比甘氨酸（Gly）更强的结构刚性，推测突变Gly397Ala可能使FXI局部结构更为稳定，从而通过加速酶原活化、提升催化活性或／和对抑制物抵抗以及增强旁路凝血作用等机制单独或协同作用提升FXI凝血活性。本研究将应用结构分析和动力学模拟，荧光结构分析、酶化学功能测定以及体内外凝血功能检测来阐明FXI功能获得性突变Gly397Ala高凝血活性的分子机制。在此基础上，进一步在体外和动物模型中评估该高凝血活性FXI突变体经旁路途径纠正由于FVIII/FIX缺陷导致的凝血障碍的能力，为血友病A/B探索新的治疗方法。

A gain-of-function mutation FXI Gly397Ala was identified in a thrombophilia patient. The FXI mutant exhibits elevated FXI specific clotting activity and enhanced procoagulant activity in global coagulation assay. The amino acid residue Gly397 lies approximately to FXI zymogen cleavage site and may function as turning point of activation region of serine protease catalytic domain. We propose computer assisted structural modeling; fluorescence based structural analysis and enzymatic function assay to probe the structural changes brought by the mutation and its implication for FXI procoagulatant activity. We will also explore the non-canonical coagulation activity of FXI mutant Gly397Ala in vitro and in vivo to evaluate its possible application in management of hemophilia.