ИСТИНА

Background: It is widely reported that TF-rich circulating microparticles have increased concentration in bloodstream in various pathological conditions such as sepsis, cancer, etc. On the surface of such vesicles TF and FVIIa could assemble into the enzyme - extrinsic tenase. Its substrate, factor X, can reversibly bind to negatively charged phospholipid membrane. Thus circulating microparticle makes a potential constant source of active factor Xa in the bloodstream. To analyze the role of the stream in the activation of blood coagulation by circulating microparticles the diffusion of factors, their mixing and their distribution between the membrane and solution have to be taken into account. Aims: Construction of a comprehensive computational model of factor X activation on the surface of a 3D microparticle moving in a bloodstream. Methods: The model was a set of partial differential equations in three dimensions based on a scheme of reactions including extrinsic tenase formation and factor X delivery via two-dimensional diffusion on the membrane. Results: The model was validated using reported experimental data (Hathcock et al. Biochemistry, 2005). It was found that apparent equilibrium dissociation constant (Kd) for interaction of FX/FXa with phospholipid membrane of microparticles in bloodstream rises with the vesicle radius. In the approximation of collision limit theory (Abbott et al. Biochemistry, 1987) the apparent association constant is inversely proportional to the vesicle radius, so Kd could rise with the vesicle radius. As a result the factor X activation is faster on smaller vesicles than on the large ones while keeping the total lipid concentration constant (many small vesicles or a few large vesicles). Conclusions: The binding of FX/FXa is better for smaller vesicles than for larger ones. Thus the big population of 30nm-diameter TFcontaining circulating microparticles would lead to 25% faster FX activation than small population of large vesicles.