High dose factor VIIa improves clot structure and stability in a model of haemophilia B

SummaryFactor IX (FIX) deficiency results in haemophilia B and high doserecombinant activated factor VII (rFVIIa) can decrease bleeding.Previously, we showed that FIX deficiency results in a reduced rate andpeak of thrombin generation. We have now used plasma and an in vitrocoagulation model to examine the effect of these changes in thrombingeneration on fibrin clot structure and stability. Low FIX delayed the clotformation onset and reduced the fibrin polymerisation rate. Clots formedwithout FIX were composed of thicker fibrin fibres than normal. rFVIIashortened the clot formation onset time and improved the fibre structure ofhaemophilic clots. We also examined clot formation in the presence of afibrinolytic challenge by including tissue plasminogen activator or plasmin inthe reaction milieu. In these assays, normal FIX levels supported clotformation; however, clots did not form in the absence of FIX. rFVIIa partiallyrestored haemophilic clot formation. These results were independent of theeffects of the thrombin-activatable fibrinolysis inhibitor. Our data suggestthat rFVIIa enhances haemostasis in haemophiliacs by increasing thethrombin generation rate to both promote formation of a structurallynormal clot and improve clot formation and stability at sites with highendogenous fibrinolytic activities.Keywords: clot, fibrin, fibrinolysis, haemophilia, recombinant factor VIIa,plasmin.