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.
  
  
  OBJECTIVE
  The aim of the present study was to evaluate the role of FXI in polyP-mediated coagulation activation and experimental thrombus formation.
  
  
  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.
authors: Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA. puygarci@ohsu.edu
authors: C
authors: C
authors: Puy
authors: E I
authors: EI
authors: Tucker
authors: Z C
authors: ZC
authors: Wong
authors: D
authors: D
authors: Gailani
authors: S A
authors: SA
authors: Smith
authors: S H
authors: SH
authors: Choi
authors: J H
authors: JH
authors: Morrissey
authors: A
authors: A
authors: Gruber
authors: O J T
authors: OJ
authors: McCarty
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D005172:Factor XI / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005173:Factor XI Deficiency / Q000097:blood; D005174:Factor XII / Q000378:metabolism*; D015956:Factor XIIa / Q000037:antagonists & inhibitors / Q000378:metabolism; D015945:Factor XIa / Q000378:metabolism; D006801:Humans; D010940:Plant Proteins / Q000494:pharmacology; D011122:Polyphosphates / Q000097:blood*; D011516:Prothrombin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control; D013997:Time Factors
chemical_list: D057134:Antibodies, Neutralizing; D010940:Plant Proteins; D011122:Polyphosphates; C052160:trypsin inhibitor, Zea mays; D011516:Prothrombin; D005174:Factor XII; D005172:Factor XI; D015945:Factor XIa; D015956:Factor XIIa; D013917:Thrombin
keywords: factor XI; factor XII; polyphosphate; thrombin generation; thrombosis
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