Hemostasis and thrombosis beyond biochemistry: roles of geometry, flow and diffusion

An important trend in the modern concept of blood coagulation is the growing agreement that, in order to understand regulation of coagulation in vivo and disorders of its function, it is essential to take into account its spatial heterogeneity, diffusion, and flow. In a way, this suggests that the idea of the "coagulation cascade" itself becomes increasingly misleading because there is no such place in an organism where reactions of this cascade really co-exist: activation, propagation and termination of coagulation are regulated by different subsets of chemical reactions that have different spatial localization and depend on cofactors expressed by different cell types in different tissues, so that only diffusion and flow can link these distinct "compartments" together into the one functional system. Here we review the last two decades of evidence obtained from in vitro, in vivo and computational systems biology approaches. When combined, the data comprise into an adequately comprehensive picture of the spatial regulation and organization of blood coagulation. In addition to the basic insights into the regulatory mechanisms, these approaches provided interesting results in the fields of coagulation diagnostics and other applications. Finally, the remaining unresolved and conflicting issues in the spatiotemporal regulation of coagulation are discussed.