Premium
Factor XII promotes blood coagulation independent of factor XI in the presence of long‐chain polyphosphates
Author(s) -
Puy C.,
Tucker E. I.,
Wong Z. C.,
Gailani D.,
Smith S. A.,
Choi S. H.,
Morrissey J. H.,
Gruber A.,
McCarty O. J. T.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12295
Subject(s) - factor xii , prekallikrein , chemistry , coagulation , factor ix , thrombus , platelet activation , kallikrein , platelet factor 4 , biochemistry , thrombin , platelet , heparin , medicine , immunology , enzyme , biology
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 ( FXII a) or FIX) activation by activated FXI ( FXI a) were not able to inhibit the procoagulant effect of long or short‐chain polyP in plasma. In contrast, the FXII a 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 FXII a. 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 FXII a 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.