Polyphosphate as a Target for Interference With Inflammation and Thrombosis

Abstract

Activated platelets and mast cells expose the inorganic polymer, polyphosphate (polyP) on their surfaces. PolyP initiates procoagulant and proinflammatory reactions and the polymer has been recognized as a therapeutic target for interference with blood coagulation and vascular hyperpermeability. PolyP content and chain length depend on the specific cell type and energy status, which may affect cellular functions. PolyP metabolism has mainly been studied in bacteria and yeast, but its roles in eukaryotic cells and mammalian systems have remained enigmatic. In this review, we will present an overview of polyP functions, focusing on intra- and extracellular roles of the polymer and discuss open questions that emerge from the current knowledge on polyP regulation.

Understanding the Pathophysiology of COVID-19: Could the Contact System Be the Key?

“…Auto-activation of FXII to FXIIa by contact with a variety of artificial and biological negatively charged surfaces, including microorganisms, gives rise to CS cascade. Biological substances with the potential to support its activation include: DNA, RNA, polyphosphates retained on activated platelet surface, aggregated proteins, neutrophil extracellular traps (NETs) and ferritin (15)(16)(17)(18)(19). Kannemeier et al (20) presented evidence that different forms of eukaryotic and prokaryotic RNA serve as promoters of blood coagulation, enhancing auto-activation of proteases of the CS, such as FXII and FXI.…”

Platelet δ-Storage Pool Disease: An Update

“…Similar electron-dense nanoparticles have been synthesized in controlled precipitations of soluble polyphosphates with calcium ± magnesium [60]. Polyphosphates are essential calcium chelators and reservoirs of ATP in the presence of ADP and have a potential strong buffering capacity in the presence of serotonin [61]; their multiple roles in thrombosis, hemostasis, and inflammation have been extensively reviewed by Mailer et al [62] and illustrated by Baker et al [63]. By remaining firmly attached to the platelet after its release, a dense particle is able to activate the coagulation contact pathway, which is not the case for short platelet polyphosphate polymers in solution [64].…”

Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems

“…The prolonged occlusion time in bdkrb2 −/− mice is recapitulated in wild-type mice treated with HOE-140 [ 80 ], a BDKRB2 antagonist, indicating a mechanism involving defective bradykinin signaling. Although klkb1 −/− mice have expected attenuated plasma contact activation as indicated by prolonged activated partial thromboplastin time (aPTT), reduced thrombin generation induced by the contact pathway, and decreased edema in the lung upon collagen/epinephrine insult, these mice, unlike FXII deficient ( f12 −/− ) mice [ 81 , 82 ], do not have a survival advantage over wild-type mice when challenged on a pulmonary embolism model induced by collagen/epinephrine or long chain polyphosphate, potent activators of contact pathway [ 83 ]. In addition, reconstitution with purified prekallikrein in klkb1 −/− mice was unable to correct their thrombosis delay.…”