Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo

By F. Mueller, N. Mutch, W. Schenk, Stephanie A. Smith, Lucie Esterl, H. Spronk, Stefan Schmidbauer, W. Gahl, J. Morrissey, T. Renné. Cell, 2009

853 citations recorded by the source corpus.

Summary Platelets play a central role in thrombosis, hemostasis, and inflammation. We show that activated platelets release inorganic polyphosphate (polyP), a polymer of 60-100 phosphate residues that directly bound to and activated the plasma protease factor XII. PolyP-driven factor XII-activation triggered release of the inflammatory mediator bradykinin by plasma kallikrein-mediated kininogen processing. PolyP increased vascular permeability and induced fluid extravasation in skin microvessels of mice. Mice deficient in factor XII or bradykinin receptors were resistant to polyP-induced leakage. PolyP initiated clotting of plasma via the contact pathway. Ablation of intrinsic coagulation pathway proteases factor XII and factor XI protected mice from polyP-triggered lethal pulmonary embolism. Targeting polyP with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Infusion of polyP restored defective plasma clotting of Hermansky-Pudlak Syndrome patients, which lack platelet polyP. The data identify polyP as a new class of mediator having fundamental roles in platelet-driven proinflammatory and procoagulant disorders.

Subfields: Cardiology and Cardiovascular Medicine, Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/d91aae3d93443f0bce56a589d1217f18f2b82165

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cardiology and Cardiovascular Medicine

1. M. Levi
2. S. Jackson

In Genetics

1. H. Versteeg
2. Pieter H. Reitsma
3. J. Heemskerk
4. M. Levi
5. S. Jackson
6. H. Eltzschig
7. T. Eckle

In Hematology

1. H. Versteeg
2. Pieter H. Reitsma
3. J. Heemskerk
4. M. Levi
5. S. Jackson

Citations in the corpus

• Arterial thrombosis—insidious, unpredictable and deadly (2011, background): “, although recent studies have suggested a major role for inorganic polyphosphates in this proces”
• New fundamentals in hemostasis. (2013, background): “Cell- and platelet-derived polyphosphates bind to and activate FXII, thereby leading to the subsequent activation of plasma kallikrein, FIX, and further downstream coagulation factors (184).”
• Ischemia and reperfusion—from mechanism to translation (2011, background): “Other studies have shown that platelets release inorganic polyphosphates, polymers of 60–100 phosphate residues that directly activate plasma protease factor XII and thereby function as proinflammatory and procoagulant mediators in vivo”
• Platelet secretion: From haemostasis to wound healing and beyond (2015, neutral): “The putativemechanism involves direct polyP binding to Factor XII, thus triggering coagulation by the tissue factor-independent, contact activation pathway [24,25].”
• Extracellular DNA traps promote thrombosis (2010, background): “Given the procoagulant activity of nucleic acids (28) and polyphosphates (29), future studies should address whether NETs promote coagulation, how NETs affect the mechanical properties of fibrin (2), and the susceptibility of clots to thrombolysis.”