Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia.
Biophys J. 2012 Nov 21;103(10):2233-40. doi: 10.1016/j.bpj.2012.10.011. Epub 2012 Nov 20.
Injury-induced bleeding is stopped by a hemostatic plug formation that is controlled by a complex nonlinear and spatially heterogeneous biochemical network of proteolytic enzymes called blood coagulation. We studied spatial dynamics of thrombin, the central enzyme of this network, by developing a fluorogenic substrate-based method for time- and space-resolved imaging of thrombin enzymatic activity. Clotting stimulation by immobilized tissue factor induced localized thrombin activity impulse that propagated in space and possessed all characteristic traits of a traveling excitation wave: constant spatial velocity, constant amplitude, and insensitivity to the initial stimulation once it exceeded activation threshold. The parameters of this traveling wave were controlled by the availability of phospholipids or platelets, and the wave did not form in plasmas from hemophilia A or C patients who lack factors VIII and XI, which are mediators of the two principal positive feedbacks of coagulation. Stimulation of the negative feedback of the protein C pathway with thrombomodulin produced nonstationary patterns of wave formation followed by deceleration and annihilation. This indicates that blood can function as an excitable medium that conducts traveling waves of coagulation.
损伤诱导的出血通过止血塞的形成来控制，止血塞的形成由称为血液凝固的复杂非线性和空间异质的蛋白水解酶生化网络控制。我们通过开发基于荧光底物的方法来研究凝血酶的空间动力学，该方法用于时间和空间分辨成像凝血酶的酶活性。固定化组织因子的凝血刺激诱导局部凝血酶活性脉冲在空间传播，并且具有传播兴奋波的所有特征：恒定的空间速度、恒定的幅度以及一旦超过激活阈值，对初始刺激的不敏感性。该传播波的参数受磷脂或血小板的可用性控制，并且在缺乏因子 VIII 和 XI 的血友病 A 或 C 患者的血浆中不会形成波，因子 VIII 和 XI 是凝血的两个主要正反馈的介质。用血栓调节蛋白刺激蛋白 C 途径的负反馈会产生波形成的非稳态模式，随后减速和消失。这表明血液可以作为传导凝血传播波的可兴奋介质。
