In-vivo functions and regulation of polyphosphate in the vascular system

Polyphosphate, an inorganic polymer consisting of linearly linked phosphate subunits, is ubiquitously found in living organisms. Functions and regulation of the polymer have been analyzed in plants, bacteria and yeast; however, the roles of polyphosphate in mammals are still emerging.

In contrast to synthetic polyphosphate that has been extensively utilized in ex-vivo studies, natural polyphosphate is complexed with bivalent cations (mostly Ca 2+ ) and regardless of chain length, forms microparticles that are retained on the surface of procoagulant platelets, platelet-derived microparticles and cancer extracellular vesicles. On cell surfaces, these Ca 2+ /polyphosphate aggregates initiate the factor XII-driven contact system, triggering proinflammatory and procoagulant reactions through the kallikrein kinin system and intrinsic pathway of coagulation, respectively. Polyphosphate inhibitors interfere with thrombosis while sparing hemostasis, replicating the effect of factor XII neutralizing agents. Furthermore, polyphosphate binds to platelet factor 4, which has implications for autoimmune thrombotic diseases, such as heparin-induced thrombocytopenia (HIT) and vaccine-induced thrombotic thrombocytopenia (VITT), potentially contributing to their pathogenesis. The metabolism and organ-specific distribution of the polymer remain incompletely defined and is the topic of ongoing research.

Polyphosphate acts as a procoagulant and proinflammatory mediator. Neutralizing polyphosphate provides well tolerated thromboprotection, mimicking the effects of factor XII deficiency.