title: Effects of recombinant activated factor VII on thrombin-mediated feedback activation of coagulation.
abstract: Thrombin is a key hemostatic enzyme, which propagates its own generation by activating factors V, VIII, and XI. Sustained thrombin generation also activates thrombin-activatable fibrinolysis inhibitor (TAFI), which stabilizes fibrin clot against fibrinolysis. Recombinant activated factor VII (rFVIIa) is considered a novel hemostatic intervention for refractory bleeding, but rebleeding episodes related to fibrinolysis still occur. The present study aimed to investigate the antifibrinolytic effects of rFVIIa in relation to thrombin generation. Using thrombelastography, the effects of rFVIIa on thrombin-activated fibrin formation and on fibrinolysis induced by tissue plasminogen activator were evaluated in various factor-deficient plasma samples. A Thrombinoscope was used to quantitate thrombin generation. Thrombin increased antifibrinolytic activity in a concentration-dependent manner as demonstrated by a longer clot lysis time. In plasma deficient in factors V, VIII, IX, X, or XI, clot lysis occurred early (< 20 min), and rFVIIa addition had minimal effect, except for improved antifibrinolytic effect in factor-XI-deficient plasma. A normal clot lysis time was observed in factor-XIII-deficient or dual antithrombin/factor-VIII-deficient plasma. Inhibition of TAFI increased the rate of fibrinolysis. Thrombin generation was delayed or decreased in single factor-deficient plasma except for factor XIII deficiency. After rFVIIa addition, the peak thrombin generation reached over 100 nmol/l in factor-XI-deficient plasma, but not in plasma deficient in factors V, VIII, IX, or X. Thrombin generation and subsequent activation of TAFI were important for clot stability. We conclude that rFVIIa therapy does not compensate for increased susceptibility to fibrinolysis due to lack of factor(s) necessary for the formation of tenase and prothrombinase.
authors.affiliation: Division of Cardiothoracic Anesthesia, Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Taro
authors.initials: T
authors.lastname: Taketomi
authors.forename: Fania
authors.initials: F
authors.lastname: Szlam
authors.forename: Stephen O
authors.initials: SO
authors.lastname: Bader
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Sheppard
authors.forename: Jerrold H
authors.initials: JH
authors.lastname: Levy
authors.forename: Kenichi A
authors.initials: KA
authors.lastname: Tanaka
mesh_terms: D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D025901:Carboxypeptidase B2 / Q000502:physiology; D015942:Factor VIIa / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D011994:Recombinant Proteins / Q000494:pharmacology; D013916:Thrombelastography; D013917:Thrombin / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000502:physiology
chemical_list: D000933:Antifibrinolytic Agents; D011994:Recombinant Proteins; C103587:recombinant FVIIa; D025901:Carboxypeptidase B2; D015942:Factor VIIa; D013917:Thrombin; D010959:Tissue Plasminogen Activator