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Factor XI anion‐binding sites are required for productive interactions with polyphosphate
Author(s) -
Geng Y.,
Verhamme I. M.,
Smith S. A.,
Cheng Q.,
Sun M.,
Sheehan J. P.,
Morrissey J. H.,
Gailani D.
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.12414
Subject(s) - antithrombin , chemistry , factor ix , antithrombins , coagulation , prekallikrein , heparin , biochemistry , factor xi , enzyme , medicine , kallikrein
Summary Background Conversion of factor XI ( FXI ) to FXI a is enhanced by polymers of inorganic phosphate (poly P ). This process requires FXI to bind to poly P . Each FXI a subunit contains anion‐binding sites ( ABS s) on the apple 3 ( A 3) and catalytic domains that are required for normal heparin‐mediated enhancement of FXI a inhibition by antithrombin. Aims To determine the importance of FXI ABS s to polyP enhancement of FXI activation. Methods Recombinant FXI variants lacking one or both ABS s were tested in poly P ‐dependent purified protein systems, plasma clotting assays, and a murine thrombosis model. Results In the presence of poly P , activation rates for FXI lacking either ABS were reduced compared with wild‐type FXI , and FXI lacking both sites had an even greater defect. In contrast to heparin, poly P binding to FXI a did not enhance inhibition by antithrombin and did not interfere with FXI a activation of FIX . FXI lacking one or both ABS s does not reconstitute FXI ‐deficient plasma as well as wild‐type FXI when polyP was used to initiate coagulation. In FXI ‐deficient mice, FXI lacking one or more ABS s was inferior to wild‐type FXI in supporting arterial thrombus formation. Conclusions The ABS s on FXI a that are required for expression of heparin's cofactor activity during protease inhibition by antithrombin are also required for expression of polyP cofactor activity during FXI activation. These sites may contribute to FXI ‐dependent thrombotic processes.