title: Antithrombin affects hemostatic response to recombinant activated factor VII in factor VIII deficient plasma.
abstract: BACKGROUND
  Thromboembolic complications can occur with recombinant activated factor VII (rFVIIa) treatment in trauma and surgical patients but they are infrequent in hemophiliacs. Bleeding diathesis in these conditions is often attributed to reduced thrombin generation, which may be improved with rFVIIa. Normally, thrombin that diffuses from local vascular injury sites is quickly inactivated by antithrombin (AT). Evaluating the influence of AT levels on thrombin generation in hypocoagulable FVIII-deficient plasma would be a simple approach to better understand how procoagulant stimuli, such as rFVIIa, might result in postoperative thrombotic complications. We hypothesize that reduced AT concentrations would increase the procoagulant effects of rFVIIa in FVIII-deficient plasma.
  
  
  METHODS
  Thrombin generation was evaluated in vitro in FVIII-deficient and AT/FVIII-deficient plasma using thrombelastography and a thrombin generation assay (Thrombinoscope). The effect of added rFVIIa on these variables was evaluated.
  
  
  RESULTS
  Delayed thrombus formation based on thrombelastography in FVIII-deficient plasma was predictably reversed by rFVIIa. Improved thrombus formation and responses to rFVIIa were observed when AT levels were 20%-50% of normal. Thrombin generation in FVIII-deficient plasma increased in an inverse relationship to AT levels. Supplemental rFVIIa decreased the lag time of thrombin generation but not the amount of thrombin generated.
  
  
  CONCLUSIONS
  Using FVIII-deficient plasma as a model of reduced thrombin generation, we demonstrate that low AT levels enhance in vitro hemostatic responses to rFVIIa. Reduced AT levels in trauma and surgical patients with normal or increased FVIII levels may be considered potentially prothrombotic. Monitoring of AT levels during rFVIIa therapy may thus reduce thrombotic complications in nonhemophiliacs.
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, 1364 Clifton Rd., NE, Atlanta, GA 30322, USA.
authors.forename: Fania
authors.initials: F
authors.lastname: Szlam
authors.forename: Taro
authors.initials: T
authors.lastname: Taketomi
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Sheppard
authors.forename: Christine L
authors.initials: CL
authors.lastname: Kempton
authors.forename: Jerrold H
authors.initials: JH
authors.lastname: Levy
authors.forename: Kenichi A
authors.initials: KA
authors.lastname: Tanaka
mesh_terms: D000991:Antithrombins / Q000172:deficiency*; D001780:Blood Coagulation Tests; D003029:Coagulants / Q000494:pharmacology*; D015942:Factor VIIa / Q000494:pharmacology*; D006467:Hemophilia A / Q000097:blood*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D011994:Recombinant Proteins / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000991:Antithrombins; D003029:Coagulants; D011994:Recombinant Proteins; D015942:Factor VIIa; D013917:Thrombin