Polyphosphate co-localizes with factor XII on plateletbound fibrin and augments its plasminogen activator activity

Joanne L Mitchell, Ausra S. Lionikiene, Georgi Georgiev, Anja Klemmer, Chelsea Brain, Paul Y Kim, Nicola J. Mutch

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Abstract

Activated factor XII (FXIIa) has plasminogen activator capacity but its relative contribution to fibrinolysis is considered marginal compared to urokinase and tissue plasminogen activator. Polyphosphate (polyP) is released from activated platelets and mediates FXII activation. Here we investigate the contribution of polyP to the plasminogen activator function of αFXIIa. We show that both polyP70, of the chain length found in platelets (60-100-mer) and platelet-derived polyP, significantly augment the plasminogen activation capacity of αFXIIa. PolyP70 stimulated autoactivation of FXII and subsequent plasminogen activation, indicating that once activated, αFXIIa remains bound to polyP70. Indeed, complex formation between
polyP70 and αFXIIa provides protection against autodegradation. Plasminogen activation by βFXIIa was minimal and was not enhanced by polyP70; highlighting the importance of the anion binding site. PolyP70 did not modulate plasmin activity but stimulated activation of Glu- and Lys- forms of plasminogen by αFXIIa. Accordingly, polyP70 was found to bind to FXII, αFXIIa and plasminogen, but not βFXIIa. Fibrin and polyP70 acted synergistically to enhance αFXIIa-mediated plasminogen activation. The plasminogen activator activity of the αFXIIa-polyP70 complex was modulated by C1 inhibitor and histidine rich glycoprotein, but not plasminogen activator inhibitors (PAI-1 and PAI-2). Platelet polyP and FXII were found to colocalize on the activated platelet membrane in a fibrin-dependent manner and decorated fibrin strands extending from platelet aggregates. We show that in the presence of platelet polyP and the downstream substrate fibrin, αFXIIa is a highly efficient and favorable plasminogen activator. Our data is the first to document aprofibrinolytic function of platelet polyP.
Original languageEnglish
Pages (from-to)2834-2845
Number of pages12
JournalBlood
Volume128
Issue number24
Early online date30 Sep 2016
DOIs
Publication statusPublished - 15 Dec 2016

Keywords

  • plasminogen
  • factor XII
  • polyphosphate
  • fibrinolysis
  • fibrin
  • platelets

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    Iain Fraser Cytometry Centre

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