Factor XI anion-binding sites are required for productive interactions with polyphosphate

Y. Geng, I. M. Verhamme, S. A. Smith, Q. Cheng, M. Sun, J. P. Sheehan, J. H. Morrissey, D. Gailani

Research output: Contribution to journalArticlepeer-review

Abstract

Summary: Background: Conversion of factor XI (FXI) to FXIa is enhanced by polymers of inorganic phosphate (polyP). This process requires FXI to bind to polyP. Each FXIa subunit contains anion-binding sites (ABSs) on the apple 3 (A3) and catalytic domains that are required for normal heparin-mediated enhancement of FXIa inhibition by antithrombin. Aims: To determine the importance of FXI ABSs to polyP enhancement of FXI activation. Methods: Recombinant FXI variants lacking one or both ABSs were tested in polyP-dependent purified protein systems, plasma clotting assays, and a murine thrombosis model. Results: In the presence of polyP, 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, polyP binding to FXIa did not enhance inhibition by antithrombin and did not interfere with FXIa activation of FIX. FXI lacking one or both ABSs 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 ABSs was inferior to wild-type FXI in supporting arterial thrombus formation. Conclusions: The ABSs on FXIa 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.

Original languageEnglish (US)
Pages (from-to)2020-2028
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume11
Issue number11
DOIs
StatePublished - Nov 2013

Keywords

  • Blood coagulation
  • Factor XI
  • Factor XIa
  • Heparin
  • PolyPhosphates

ASJC Scopus subject areas

  • Hematology

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