Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI
October
Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI
Cristina Puy 0 1 2
Erik I. Tucker 0 1 2
Ivan S. Ivanov 0 2
David Gailani 0 2
Stephanie A. Smith 0 2
James H. Morrissey 0 2
Andra s Gruber 0 1 2
Owen J. T. McCarty 0 1 2
0 the National Institutes of Health (R01HL101972 , R44HL106919, R01GM116184, R01HL047014). O.J.T. McCarty is an American Heart Association (AHA) Established Investigator (13EIA12630000). C. Puy is an AHA Fellow (14POST18180011). A. Gruber, E.I. Tucker, and Oregon Health & Science University have a significant financial interest in Aronora Inc, a company that may have a commercial interest in the result of this research , USA
1 Departments of Biomedical Engineering Oregon Health & Science University , Portland, Oregon , United States of America, 2 Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University , Portland, Oregon , United States of America , 3 Aronora , Inc , Portland, Oregon , United States of America, 4 Departments of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America, 5 Biochemistry Department, University of Illinois, Urbana, Illinois, United States of America, 6 Department of Cell, Developmental and Cancer Biology Oregon Health & Science University , Portland, Oregon , United States of America
2 Editor: Christian Schulz, Ludwig-Maximilians- Universitat Munchen , GERMANY
Factor (F) XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa) promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIα), in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP) derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIα, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIα by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin. rate of inactivation of TFPIα by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIα by
Data Availability Statement; All relevant data are within the paper
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FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma.
Conclusions
let-derived SCP.
Our data suggest that SCP is a cofactor for TFPIα inactivation by FXIa, thus, expanding the
range of hemostatic FXIa substrates that may be affected by the cofactor functions of
platebut did not have any additional role in the study
design, data collection and analysis, decision to
publish, or preparation of the manuscript. The
specific roles of these authors are articulated in the
`author contributions' section. This potential
conflict of interest has been reviewed and managed
by the Oregon Health & Science University Conflict
of Interest in Research Committee. J. Morrissey
and S. Smith have a patent:
Polyphosphatefunctionalized inorganic nanoparticles as
hemostatic compositions and methods of use
(9,186,417). These do not alter our adherence to
PLOS ONE policies on sharing data and materials.
The remaining authors declare no competing
financial interests.
Competing Interests: A. Gruber, E.I. Tucker, and
Oregon Health & Science University have a
significant financial interest in Aronora Inc., a
company that may have a commercial interest in
the results of this research. This potential conflict
of interest has been reviewed and managed by the
Oregon Health & Science University Conflict of
Interest in Research Committee. J. Morrissey and
S. Smith have a patent:
Polyphosphatefunctionalized inorganic nanoparticles as
hemostatic compositions and methods of use
(9,186,417). These do not alter our adherence to
PLOS ONE policies on sharing data and materials.
The remaining authors declare no competing
financial interests.
Introduction
Factor (F) XI was originally described in the waterfall model of coagulation as part of the
intrinsic or contact pathway, but it appears to be the only contact factor that contributes to
hemostasis. Congenital deficiency of FXI is occasionally associated with trauma-associated
abnormal bleeding, especially in tissues with increased fibrinolytic activity [
1
]. Since FXII,
prekallikrein and high molecular weight kininogen deficiencies do not affect hemostasis, the
hemostatic function of FXI may well be manifested through feedback activation by thrombin
generated by exposure of blood to tissue factor (TF) [
2,3
]. FXIa can also promote thrombin
generation through direct activation of FX, FV and FVIII [
4–6
]. Additionally, activated
platelets release polyp (...truncated)