Polyphosphate as modulator of hemostasis, thrombosis, and inflammation

Abstract

Inorganic polyphosphate (polyP), a linear polymer of phosphates, is present in many infectious microorganisms and is secreted by mast cells and platelets. PolyP has recently been shown to accelerate blood clotting and slow fibrinolysis, in a manner that is highly dependent on polymer length. Very long-chain polyP (of the type present in microorganisms) is an especially potent trigger of the contact pathway, enhances the proinflammatory activity of histones, and may participate in host responses to pathogens. PolyP also inhibits complement, providing another link between polyP and inflammation/innate immunity. Platelet-size polyP (which is considerably shorter) accelerates factor V activation, opposes the anticoagulant action of tissue factor pathway inhibitor, modulates fibrin clot structure, and promotes factor XI activation. PolyP may have utility in treating bleeding. It is also a potential target for the development of antithrombotic drugs with a novel mechanism of action and potentially fewer bleeding side effects compared with conventional anticoagulants.

Keywords: blood coagulation; coagulation factor XI; inflammation; kallikrein‐kinin system; platelets; polyphosphates.

Figure 1

Structure of inorganic polyphosphate (polyP). PolyP is a linear, negatively charged polymer of phosphates held together by high-energy phosphoanhydride bonds. Microbial polyP ranges in size from tens of phosphates to thousands of phosphates long [3, 63], while polyP secreted from human platelets and mast cells is shorter and much less heterodisperse — approximately 60 to 100 phosphate units long [7, 8, 15, 34].

Figure 2

PolyP modulates blood clotting at the indicated points. (1) Very long-chain polyP (of the type found in microbes) is a potent trigger of the contact pathway of blood clotting, leading to generation of factor XIIa and release the inflammatory mediator, bradykinin, via proteolysis from high molecular weight kininogen (HK); (2) PolyP accelerates factor V activation; (3) PolyP enhances fibrin clot structure and renders clots resistant to fibrinolysis; and (4) PolyP greatly accelerates factor XI activation by thrombin. (Not shown is the ability of polyP to antagonise the anticoagulant activity of TFPI, nor the ability of polyP to stimulate factor XI autoactivation.) While efficient triggering of the contact pathway requires very long-chain polyP (step 1), the other three reactions are also promoted by polyP of the size secreted by activated platelets (about 60 to100 phosphates long).