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

C. Puy, Erik Tucker, Z. C. Wong, D. Gailani, S. A. Smith, S. H. Choi, J. H. Morrissey, Andras Gruber, Owen McCarty

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1341-1352
Number of pages12
JournalJournal of Thrombosis and Haemostasis
Volume11
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

Factor XI
Factor XII
Polyphosphates
Prekallikrein
Thrombosis
Factor XIIa
Polyps
Neutralizing Antibodies
Thrombin
Virulence

Keywords

  • Factor XI
  • Factor XII
  • Polyphosphate
  • Thrombin generation
  • Thrombosis

ASJC Scopus subject areas

  • Hematology

Cite this

Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates. / Puy, C.; Tucker, Erik; Wong, Z. C.; Gailani, D.; Smith, S. A.; Choi, S. H.; Morrissey, J. H.; Gruber, Andras; McCarty, Owen.

In: Journal of Thrombosis and Haemostasis, Vol. 11, No. 7, 07.2013, p. 1341-1352.

Research output: Contribution to journalArticle

Puy, C. ; Tucker, Erik ; Wong, Z. C. ; Gailani, D. ; Smith, S. A. ; Choi, S. H. ; Morrissey, J. H. ; Gruber, Andras ; McCarty, Owen. / Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates. In: Journal of Thrombosis and Haemostasis. 2013 ; Vol. 11, No. 7. pp. 1341-1352.
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title = "Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates",
abstract = "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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T1 - Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates

AU - Puy, C.

AU - Tucker, Erik

AU - Wong, Z. C.

AU - Gailani, D.

AU - Smith, S. A.

AU - Choi, S. H.

AU - Morrissey, J. H.

AU - Gruber, Andras

AU - McCarty, Owen

PY - 2013/7

Y1 - 2013/7

N2 - 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.

AB - 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.

KW - Factor XI

KW - Factor XII

KW - Polyphosphate

KW - Thrombin generation

KW - Thrombosis

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