Regulation of Coagulation by Polyphosphate
Authors: Mutch Nicola J. 
Published: November 2019

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
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Disclosures
No relevant conflicts of interest to declare.