Polyphosphate exerts differential effects on blood clotting, depending on polymer size.
Polyphosphate, a linear polymer of inorganic phosphate, is secreted by activated platelets and accumulates in many infectious microorganisms. We recently showed that polyphosphate modulates the blood coagulation cascade at 3 steps: it triggers the contact pathway, it accelerates factor V activation, and it enhances fibrin polymerization. We now report that polyphosphate exerts differential effects on blood clotting, depending on polymer length. Very long polymers (≥ 500mers, such as those present in microorganisms) were required for optimal activation of the contact pathway, while shorter polymers (∼ 100mers, similar to the polymer lengths released by platelets) were sufficient to accelerate factor V activation and abrogate the anticoagulant function of the tissue factor pathway inhibitor. Optimal enhancement of fibrin clot turbidity by polyphosphate required ≥ 250mers. Pyrophosphate, which is also secreted by activated platelets, potently blocked polyphosphate-mediated enhancement of fibrin clot structure, suggesting that pyrophosphate is a novel regulator of fibrin function. In conclusion, polyphosphate of the size secreted by platelets is very efficient at accelerating blood clotting reactions but is less efficient at initiating them or at modulating clot structure. Microbial polyphosphate, which is highly procoagulant, may function in host responses to pathogens.
Smith
Stephanie A
SA
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Choi
Sharon H
SH
Davis-Harrison
Rebecca
R
Huyck
Jillian
J
Boettcher
John
J
Rienstra
Chad M
CM
Reinstra
Chad M
CM
Morrissey
James H
JH
D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D005591:Chemical Fractionation; D015951:Factor Xa / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009391:Nephelometry and Turbidimetry; D010316:Particle Size; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology*; D011122:Polyphosphates / Q000737:chemistry* / Q000494:pharmacology*
D000925:Anticoagulants; D008074:Lipoproteins; D011108:Polymers; D011122:Polyphosphates; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; D015951:Factor Xa