title: Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex.
abstract: BACKGROUND
  Hemophilia is caused by deficiencies in coagulation factor VIII or IX, resulting in direct blockade of the intrinsic tenase complex and indirect blockade of the extrinsic tenase complex which is rapidly inhibited upon binding of factor Xa to tissue factor pathway inhibitor. We evaluated the ability of Gla-domainless factor Xa, a truncated form of factor Xa devoid of procoagulant properties, to bind to tissue factor pathway inhibitor and to alleviate the physiological inhibition of the extrinsic tenase.
  
  
  METHODS
  Using a thrombin generation assay triggered by a low concentration of tissue factor, we evaluated the ability of Gla-domainless factor Xa to restore blood coagulation in plasma from hemophilia A and B patients without and with inhibitors. We then compared its efficacy to generate thrombin to depletion of antithrombin or tissue factor pathway inhibitor by specific antibodies. Finally, we compared the kinetics of neutralization of factor Xa and Gla-domainless factor Xa by antithrombin and tissue factor pathway inhibitor.
  
  
  RESULTS
  Gla-domainless factor Xa was able to restore thrombin generation in plasma samples from hemophiliacs. This effect was observed for plasma from hemophilia A patients without or with inhibitors and for plasma from hemophilia B patients. Gla-domainless factor Xa had a lower affinity than factor Xa for tissue factor pathway inhibitor whereas the affinities of both proteins for antithrombin were similar. Finally, despite a short half-life in plasma, the effect of Gla-domainless factor Xa on thrombin generation was sustained for at least 1 hour.
  
  
  CONCLUSIONS
  As Gla-domainless factor Xa was able to restore thrombin generation in plasma from hemophilia patients, our results suggest that it may be an effective alternative to current treatments for hemophilia with or without an inhibitor.
authors.affiliation: Therex, TIMC-IMAG, CNRS Université Joseph Fourier, UMR 5525, Grenoble, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Marlu
authors.forename: Benoît
authors.initials: B
authors.lastname: Polack
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000991:Antithrombins / Q000276:immunology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism*; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000276:immunology / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000378:metabolism
chemical_list: D000906:Antibodies; D000991:Antithrombins; D008074:Lipoproteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; C051928:lipoprotein-associated coagulation inhibitor; D013917:Thrombin; D015951:Factor Xa; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant