Polyphosphate (polyP) is a biomolecule comprised of repeating units of inorganic phosphate residues linked by energy-rich phosphoanhydride bonds. PolyP is highly conserved throughout evolution and plays a vital role in the survival of prokaryotes and single-cell eukaryotes1 by functioning in processes such as motility, virulence and stress. Its role in mammalian systems was less well defined, however, identification of polyP in the dense granules of human platelets2 prompted analysis of the function of polyP in hemostasis. Stimulation of platelets by conventional agonists such as ADP, thrombin and collagen induces release of polyP, and promotes coagulation by acting at several points in the cascade3. These include 1) providing a surface for activation of the contact pathway protein factor XII, 2) augmenting conversion of factor V to factor Va which participates in the prothrombinase complex and 3) accelerating thrombin-mediated activation of factor XI4. The net outcome is a reduction in the lag time to thrombin formation thereby driving clot formation. The effect of polyP on thrombin generation has down-stream repercussions in terms of clot breakdown, as it augments the early activation of thrombin activatable fibrinolysis inhibitor (TAFI). There has been a degree of uncertainty and debate over whether polyP is capable of reaching adequate concentrations within the plasma milieu to elicit these profound effects on haemostasis. However, the observations that polyP can bind directly to fibrin5, allowing it to be incorporated into the forming clot, localise the biomolecule to its site of action. In addition, binding alters the structure of the fibrin clot altering its susceptibility to degradation by fibrinolytic enzymes6. These observations led to the hypothesis that polyP operates as a timed switch, being released from platelets upon activation thereby allowing rapid repair of an injury while simultaneously preventing clot breakdown until sufficient wound healing has occurred3. The ability of polyP to promote FXII-dependent coagulation has been reported in several studies but has been contested, as shorter soluble polymers, such as those found in platelets, are relatively inefficient in this process. Recent work from our group7 and others8 documents the retention of polyP on the surface of degranulated platelets. This pool of polyP is of longer chain length than the soluble secreted form and is complexed to divalent metal ions8 thereby augmenting its ability to stimulate factor XII activation. These studies highlight the potential that polyP may exert its biological cofactor activity when anchored to a surface such as platelets, fibrin and potentially other blood cells. Many questions remain as to how this polymer regulates its plethora of functions and whether the binding surface impacts on the target reaction and the half-life of the polymer. However, taken together these in vitro and in vivo studies have delineated a role for polyP in hemostasis and highlight the requirement for more efficient tools to quantify this interesting biomolecule in subsets of patients.
References
Kornberg A. Inorganic polyphosphate: a molecule of many functions. Prog Mol Subcell Biol. 1999;23:1-18. Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem. 2004;279(43):44250-44257. Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A. 2006;103(4):903-908. Choi SH, Smith SA, Morrissey JH. Polyphosphate is a cofactor for the activation of factor XI by thrombin. Blood. 2011;118(26):6963-6970. Whyte CS, Chernysh IN, Domingues MM, Connell S, Weisel JW, Ariens RA, Mutch NJ. Polyphosphate delays fibrin polymerisation and alters the mechanical properties of the fibrin network. Thromb Haemost. 2016;116(5):897-903. Mutch NJ, Engel R, Uitte de Willige S, Philippou H, Ariens RA. Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin. Blood. 2010;115(19):3980-3988. Mitchell JL, Lionikiene AS, Georgiev G, Klemmer A, Brain C, Kim PY, Mutch NJ. Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity. Blood. 2016;128(24):2834-2845. Verhoef JJ, Barendrecht AD, Nickel KF, Dijkxhoorn K, Kenne E, Labberton L, McCarty OJ, Schiffelers R, Heijnen HF, Hendrickx AP, Schellekens H, Fens MH, de Maat S, Renne T, Maas C. Polyphosphate nanoparticles on the platelet surface trigger contact system activation. Blood. 2017;129(12):1707-1717.
Disclosures
No relevant conflicts of interest to declare.
Are Bleeding Scores Predicting Severity and Outcome in Hemophilia and Rare Bleeding Disorders?
