Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

Abstract

Inorganic polyphosphate is widespread in biology and exhibits striking prohemostatic, prothrombotic, and proinflammatory effects in vivo. Long-chain polyphosphate (of the size present in infectious microorganisms) is a potent, natural pathophysiologic activator of the contact pathway of blood clotting. Medium-chain polyphosphate (of the size secreted from activated human platelets) accelerates factor V activation, completely abrogates the anticoagulant function of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. Polyphosphate may have utility as a hemostatic agent, whereas antagonists of polyphosphate may function as novel antithrombotic/anti-inflammatory agents. The detailed molecular mechanisms by which polyphosphate modulates blood clotting reactions remain to be elucidated.

Figure 1

Structure of inorganic polyP. Inorganic polyphosphate (polyP) is a linear, highly anionic polymer of phosphates held together by high-energy phosphoanhydride bonds. Platelet polyP is approximately 60 to 100 phosphate units long,^,, whereas microbial polyP can range up to thousands of phosphate units long.^,

Figure 2

The roles of polyP in blood clotting vary depending on polymer length. (A) Microbial long-chain polyP (ranging from less than a hundred phosphates to several thousand phosphate units long) acts at 4 points in the clotting cascade, indicated in red: 1 initiates the contact pathway of blood clotting^,,; 2, accelerates factor V activation and abrogates TFPI function (the latter not shown explicitly)^,; 3, enhances fibrin polymerization^,,; and 4, accelerates factor XI back-activation by thrombin. (B) Platelet-size polyP (∼ 60 to ∼ 100 phosphate units long) acts most potently at 3 points in the clotting cascade, indicated in red: 2 indicates abrogates TFPI function (and overlaps the minimal size necessary to accelerate factor V activation)^,; 3, overlaps the minimal size necessary to enhance fibrin polymerization^,,; and 4, accelerates factor XI back-activation by thrombin. Reproduced from Choi et al with permission.²⁹

Figure 3

The various effects of PolyP on blood clotting are strikingly dependent on polymer length. Specific activities of polyP are plotted versus polyP polymer lengths, normalized in each case to 100% maximal activity. The data are replotted from Smith et al (but on linear axes) for: (A) triggering of plasma clotting via the contact pathway, (B) modulating fibrin clot turbidity, (C) accelerating factor V activation, and (D) abrogating TFPI anticoagulant function; and from Choi et al for (E) promoting factor XI back-activation by thrombin. (E) polyP longer than 350 mers was not tested. In each panel, the pink bar represents the approximate size of polyP secreted from activated human platelets (∼ 60 to ∼ 100 mers),^,, and yellow rectangle, the approximate size of microbial polyphosphate (ranging from < 100 mers to > 1500 mers).