Inorganic polyphosphate in blood coagulation

Polyphosphate (polyP) was recently discovered to be stored in a subset of the secretory granules of human platelets (the blood cell that supports formation of clots) and to be secreted upon activation of these cells. It is also present in other human cell types and is present in infectious microorganisms. Work from our laboratory and others has now shown that polyphosphate is a novel, potent modulator of blood clotting that likely plays roles in hemostasis, thrombosis, infl ammation, and the host response to pathogens. Polyphosphate acts at multiple points in the coagulation cascade, providing a template for initiation of the contact pathway of clotting, enhancing the activation of factor V (a critical cofactor in clotting whose accelerated activation results in an earlier thrombin burst), and markedly enhancing the rate of activation of factor XI by thrombin (resulting in marked amplifi cation of thrombin generation). Polyphosphate also acts on the formation and degradation of fi brin by becoming incorporated into polymerizing fi brin fi brils (rendering them thicker and obscuring the binding sites for fi brinolytic proteins, which in turn delays clot degradation). Therapeutic agents targeting polyphosphate may have the potential to limit thrombosis with fewer hemorrhagic complications than conventional anticoagulant drugs that target essential proteases of the blood-clotting cascade.