Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity.
Activated factor XII (FXIIa) has plasminogen activator capacity but its relative contribution to fibrinolysis is considered marginal compared with 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. PolyP70stimulated the autoactivation of FXII and subsequent plasminogen activation, indicating that once activated, αFXIIa remains bound to polyP70Indeed, complex formation between polyP70and αFXIIa provides protection against autodegradation. Plasminogen activation by βFXIIa was minimal and not enhanced by polyP70, highlighting the importance of the anion binding site. PolyP70did not modulate plasmin activity but stimulated activation of Glu and Lys forms of plasminogen by αFXIIa. Accordingly, polyP70was found to bind to FXII, αFXIIa, and plasminogen, but not βFXIIa. Fibrin and polyP70acted synergistically to enhance αFXIIa-mediated plasminogen activation. The plasminogen activator activity of the αFXIIa-polyP70complex was modulated by C1 inhibitor and histidine-rich glycoprotein, but not plasminogen activator inhibitors 1 and 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 are the first to document a profibrinolytic function of platelet polyP.
Institute of Medical Sciences, School of Medicine, Medical Sciences, and Nutrition, University of Aberdeen, Aberdeen, United Kingdom; and.
Joanne L
0000-0001-8762-4542
JL
Mitchell
Institute of Medical Sciences, School of Medicine, Medical Sciences, and Nutrition, University of Aberdeen, Aberdeen, United Kingdom; and.
Ausra S
AS
Lionikiene
Institute of Medical Sciences, School of Medicine, Medical Sciences, and Nutrition, University of Aberdeen, Aberdeen, United Kingdom; and.
Georgi
G
Georgiev
Institute of Medical Sciences, School of Medicine, Medical Sciences, and Nutrition, University of Aberdeen, Aberdeen, United Kingdom; and.
Anja
A
Klemmer
Institute of Medical Sciences, School of Medicine, Medical Sciences, and Nutrition, University of Aberdeen, Aberdeen, United Kingdom; and.
Chelsea
C
Brain
Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada.
Paul Y
PY
Kim
Institute of Medical Sciences, School of Medicine, Medical Sciences, and Nutrition, University of Aberdeen, Aberdeen, United Kingdom; and.
Nicola J
0000-0002-7452-0813
NJ
Mutch
D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D050718:Complement C1 Inhibitor Protein / Q000494:pharmacology; D005174:Factor XII / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism*; D018698:Glutamic Acid / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism*; D011122:Polyphosphates / Q000378:metabolism*; D011506:Proteins / Q000494:pharmacology; D000099053:Histidine-Rich Glycoprotein
D050718:Complement C1 Inhibitor Protein; D011122:Polyphosphates; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D018698:Glutamic Acid; D005174:Factor XII; D005337:Fibrin; D010958:Plasminogen; D008239:Lysine
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