Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates

Authors

  • C. Puy,

    Corresponding author
    1. Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR, USA
    • Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
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  • E. I. Tucker,

    1. Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
    2. Aronora, Inc, Portland, OR, USA
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  • Z. C. Wong,

    1. Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
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  • D. Gailani,

    1. Department of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
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  • S. A. Smith,

    1. Biochemistry Department, University of Illinois, Urban, IL, USA
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  • S. H. Choi,

    1. Biochemistry Department, University of Illinois, Urban, IL, USA
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  • J. H. Morrissey,

    1. Biochemistry Department, University of Illinois, Urban, IL, USA
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  • A. Gruber,

    1. Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
    2. Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR, USA
    3. Aronora, Inc, Portland, OR, USA
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  • O. J. T. McCarty

    1. Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
    2. Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR, USA
    3. Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA
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  • Manuscript handled by: D. Monroe

  • Final decision: D. Lane, 11 April 2013

Correspondence: Cristina Puy, Department of Biomedical Engineering, Oregon Health & Science University, CHH-13B, 3303 SW Bond Ave, Portland, OR 97239, USA

Tel.: +1 503 418 9307; fax: +1 503 418 9311.

E-mail: puygarci@ohsu.edu

Summary

Background

Inorganic polyphosphates (polyP), which are secreted by activated platelets (short-chain polyP) and accumulate in some bacteria (long-chain polyP), support the contact activation of factor XII (FXII) and accelerate the activation of FXI.

Objectives

The aim of the present study was to evaluate the role of FXI in polyP-mediated coagulation activation and experimental thrombus formation.

Methods and Results

Pretreatment of plasma with antibodies that selectively inhibit FXI activation by activated FXII (FXIIa) or FIX) activation by activated FXI (FXIa) were not able to inhibit the procoagulant effect of long or short-chain polyP in plasma. In contrast, the FXIIa inhibitor, corn trypsin inhibitor, blocked the procoagulant effect of long and short polyP in plasma. In a purified system, long polyP significantly enhanced the rate of FXII and prekallikrein activation and the activation of FXI by thrombin but not by FXIIa. In FXI-deficient plasma, long polyP promoted clotting of plasma in an FIX-dependent manner. In a purified system, the activation of FXII and prekallikrein by long polyP promoted FIX activation and prothombin activation. In an ex vivo model of occlusive thrombus formation, inhibition of FXIIa with corn trypsin inhibitor but not of FXI with a neutralizing antibodies abolished the prothrombotic effect of long polyP.

Conclusions

We propose that long polyP promotes FXII-mediated blood coagulation bypassing FXI. Accordingly, some polyp-containing pathogens may have evolved strategies to exploit polyP-initiated FXII activation for virulence, and selective inhibition of FXII may improve the host response to pathogens.

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