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PLoS One. 2016 Oct 20;11(10):e0165172. doi: 10.1371/journal.pone.0165172. eCollection 2016.

Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.

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Departments of Biomedical Engineering Oregon Health & Science University, Portland, Oregon, United States of America.
Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
Aronora, Inc, Portland, Oregon, United States of America.
Departments of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
Biochemistry Department, University of Illinois, Urbana, Illinois, United States of America.
Department of Cell, Developmental and Cancer Biology Oregon Health & Science University, Portland, Oregon, United States of America.



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.


Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPIα proteolysis was analyzed by western blot. TFPIα activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the 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 FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma.


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 platelet-derived SCP.

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Conflict of interest statement

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: Polyphosphate-functionalized 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.

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