Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin

Activated platelets secrete a negatively charged polymer, polyphosphate (polyP). Here, we explore the interactions of polyP with fibrin(ogen) and its effect on fibrin structure and fibrinolysis. Electrophoretic mobility and binding assays indicate that polyP interacts with fibrinogen and soluble fib...

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Bibliographic Details
Published in:Blood 2010-05, Vol.115 (19), p.3980-3988
Main Authors: Mutch, Nicola J., Engel, Ruchira, Uitte de Willige, Shirley, Philippou, Helen, Ariëns, Robert A.S.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Down-Regulation - drug effects
Electrophoretic Mobility Shift Assay
Fibrin - metabolism
Fibrinolysin - metabolism
Fibrinolysis - drug effects
Hematologic and hematopoietic diseases
Humans
Medical sciences
Plasminogen - metabolism
Polyphosphates - pharmacology
Surface Plasmon Resonance
Tissue Plasminogen Activator - metabolism
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Summary:Activated platelets secrete a negatively charged polymer, polyphosphate (polyP). Here, we explore the interactions of polyP with fibrin(ogen) and its effect on fibrin structure and fibrinolysis. Electrophoretic mobility and binding assays indicate that polyP interacts with fibrinogen and soluble fibrin. Clots formed in the presence of polyP exhibited reduced turbidity and permeability indicative of a tighter fibrin network, but these changes were not related to cross-linking or fibrinopeptide release. Microscopy showed a change in fibrin distribution in clots formed with polyP; with formation of tight aggregates of fibrin fibers interspaced with large pores in contrast to homogenous fiber distribution in control clots. Lysis by tissue plasminogen activator (tPA) and plasminogen or plasmin was delayed in clots formed with polyP and depended on both the activator and polyP concentration. Adding polyP to the clot after fibrin formation or to repolymerizing soluble fibrin did not affect lysis, indicating changes induced by polyP occur at the level of conversion of fibrinogen to fibrin. Surface plasmon resonance showed that the presence of polyP reduced the binding of both plasminogen and tPA to partially lysed fibrin surfaces. These data show that polyP directly influences fibrin architecture and attenuates fibrinolysis through reduced binding of fibrinolytic proteins.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2009-11-254029