title: Evidence for factor IX-independent roles for factor XIa in blood coagulation.
abstract: BACKGROUND
  Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates.
  
  
  OBJECTIVE
  To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI-deficiency produces an antithrombotic effect in mice independently of FIX.
  
  
  METHODS
  FXIa, FXIa variants and anti-FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model.
  
  
  RESULTS
  In FIX-deficient plasma, FXIa induced thrombin generation, and anti-FXIa antibodies prolonged clotting times. This process involved FXIa-mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium-dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride-induced carotid artery occlusion than FXI-deficient or FIX-deficient mice.
  
  
  CONCLUSIONS
  In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA; Department of Bioengineering and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Matafonov
authors.forename: Q
authors.initials: Q
authors.lastname: Cheng
authors.forename: Y
authors.initials: Y
authors.lastname: Geng
authors.forename: I M
authors.initials: IM
authors.lastname: Verhamme
authors.forename: O
authors.initials: O
authors.lastname: Umunakwe
authors.forename: E I
authors.initials: EI
authors.lastname: Tucker
authors.forename: M-F
authors.initials: MF
authors.lastname: Sun
authors.forename: V
authors.initials: V
authors.lastname: Serebrov
authors.forename: A
authors.initials: A
authors.lastname: Gruber
authors.forename: D
authors.initials: D
authors.lastname: Gailani
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D005164:Factor IX / Q000276:immunology / Q000502:physiology*; D015945:Factor XIa / Q000276:immunology / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D059748:Proteolysis
chemical_list: D005164:Factor IX; D015945:Factor XIa
keywords: factor IX; factor V; factor X; factor XI; factor XIa