Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): A cross-reactive material positive variant defective in factor IX activation

A. Zivelin, T. Ogawa, S. Bulvik, M. Landau, J. R. Toomey, J. Lane, U. Seligsohn, David Gailani

Research output: Contribution to journalArticlepeer-review

Abstract

During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N-terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI-Glu555 is activated normally by FXIIa and thrombin, and FXIa-Glu555 binds activated factor IX similarly to wild type FXIa (FXIaWT). When compared with FXIaWT, FXIa-Glu555 activates factor IX at a greatly reduced rate (∼400-fold), and is resistant to inhibition by antithrombin. Interestingly, FXIaWT and FXIa-Glu555 cleave the small tripeptide substrate S-2366 with comparable kcats. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2′ site and the P2′ residues on factor IX and antithrombin. FXI-Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.

Original languageEnglish
Pages (from-to)1782-1789
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume2
Issue number10
DOIs
StatePublished - Oct 2004

Keywords

  • Bleeding disorder
  • Factor IX
  • Factor XIa

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