title: High dose factor VIIa improves clot structure and stability in a model of haemophilia B.
abstract: Factor IX (FIX) deficiency results in haemophilia B and high dose recombinant activated factor VII (rFVIIa) can decrease bleeding. Previously, we showed that FIX deficiency results in a reduced rate and peak of thrombin generation. We have now used plasma and an in vitro coagulation model to examine the effect of these changes in thrombin generation on fibrin clot structure and stability. Low FIX delayed the clot formation onset and reduced the fibrin polymerisation rate. Clots formed without FIX were composed of thicker fibrin fibres than normal. rFVIIa shortened the clot formation onset time and improved the fibre structure of haemophilic clots. We also examined clot formation in the presence of a fibrinolytic challenge by including tissue plasminogen activator or plasmin in the reaction milieu. In these assays, normal FIX levels supported clot formation; however, clots did not form in the absence of FIX. rFVIIa partially restored haemophilic clot formation. These results were independent of the effects of the thrombin-activatable fibrinolysis inhibitor. Our data suggest that rFVIIa enhances haemostasis in haemophiliacs by increasing the thrombin generation rate to both promote formation of a structurally normal clot and improve clot formation and stability at sites with high endogenous fibrinolytic activities.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC 27599-7525, USA. alisa_wolberg@med.unc.edu
authors.forename: Alisa S
authors.initials: AS
authors.lastname: Wolberg
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Allen
authors.forename: Dougald M
authors.initials: DM
authors.lastname: Monroe
authors.forename: Ulla
authors.initials: U
authors.lastname: Hedner
authors.forename: Harold R
authors.initials: HR
authors.lastname: Roberts
authors.forename: Maureane
authors.initials: M
authors.lastname: Hoffman
mesh_terms: D001777:Blood Coagulation; D018929:Cell Culture Techniques; D004334:Drug Administration Schedule; D005164:Factor IX / Q000008:administration & dosage / Q000627:therapeutic use; D015942:Factor VIIa / Q000008:administration & dosage* / Q000627:therapeutic use; D005337:Fibrin / Q000378:metabolism; D005341:Fibrinolysin / Q000494:pharmacology; D002836:Hemophilia B / Q000097:blood* / Q000188:drug therapy*; D006487:Hemostasis; D006490:Hemostatics / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008855:Microscopy, Electron, Scanning; D009391:Nephelometry and Turbidimetry; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013917:Thrombin / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D006490:Hemostatics; D011994:Recombinant Proteins; D005164:Factor IX; D005337:Fibrin; D015942:Factor VIIa; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin