Sticky and promiscuous plasma proteins maintain the equilibrium between bleeding and thrombosis.

Abstract

A vascular fissure requires a patch that must be provided by constituents of the cellular and fluid phases of flowing blood. The principal components involved in primary haemostasis are platelets, collagen and von Willebrand factor (vWF). Platelets, the cellular elements of the patch, are inert until they encounter conditions that trigger their activation. Platelet adhesion and aggregation at the site of vascular injury lead to the formation of a platelet plug and to a local activation of the coagulation cascade. The resulting final product of blood coagulation is a fibrin network that stabilises the primary platelet plug. Most coagulation factors are zymogens of serine proteases. They are converted from an inactive form to an active enzyme by limited proteolytic cleavage of one or a few peptide bonds. The coagulation reactions must become extinguished as soon as the patch in the injured blood vessel has been established. Several inhibitors, present in excess in plasma, neutralise the surplus of remaining proteases, and the fibrinolytic system dissolves the plug after the surrounding tissue has been repaired. In fulfilling their function to control the fluidity and integrity of the vascular system, the plasmatic and cellular haemostatic players undergo multiple interactions of two kinds: they recognize and bind, often irreversibly, to several partners which are present in their immediate environment. On the other hand, some haemostatic factors, such as fibrinogen and von Willebrand factor, enhance their stickiness by polymerisation of identical subunits carrying multiple adhesive sites. Several haemostatic plasma proteins and their cellular surface receptors are involved in or may be affected by other homeostatic systems, such as immune response, complement activation, cytokine release, cell proliferation, growth and differentiation. These diverse functions are only possible because of the modular structure of participating proteins. In the process of evolution a series of structural modules have been incorporated into protein molecules as their integral domains by exon duplication and shuffling. Owing to variable conformations of the resulting multi-domain proteins, the same modules may perform different tasks and be recognized only by specific ligands, thus controlling the delicately balanced system of haemostasis.