Efficacy of recombinant factor VIIa administered by continuous infusion to haemophilia patients with inhibitors

Abstract

We have prospectively monitored treatment of haemophilia patients with inhibitors by recombinant factor VIIa (rFVIIa) administered by continuous infusion to obtain more insight in the underlying factors of the clinical efficacy of this administration method. At present, 43 treatment episodes of 14 different Dutch haemophilia inhibitor patients are included in the database. Analysis of the data showed a discrepancy between the efficacy of rFVIIa continuous infusion treatment of acute and surgical bleeds in the oral cavity [one (14%) effective, two (29%) partially effective, four (57%) not effective] and other parts of the body [29 (80%) effective, four (11%) partially effective, two (6%) not effective, one (3%) impossible to classify]. Patients who had acute or surgical oral cavity bleeds, uncontrolled by rFVIIa continuous infusion, reacted favourably to rFVIIa continuous infusion in other locations of the body. Acute bleeding episodes in the oral cavity, which could not be controlled by rFVIIa continuous infusion, stopped when the treatment regimen was switched to rFVIIa bolus injections. Finally, haemostatic control during dental extractions was excellent after the initial rFVIIa bolus injection preceding the continuous infusion, but rebleeds occurred in all patients within 48 h under rFVIIa continuous infusion coverage. These observations suggest that the efficacy of rFVIIa continuous infusion depends, at least in part, on the location of the body in which the bleeding occurs and that rFVIIa bolus injections are more effective than rFVIIa continuous infusion in the oral cavity. We hypothesize that the inability of rFVIIa continuous infusion treatment to sufficiently inhibit fibrinolysis is the underlying cause of the decreased efficacy of rFVIIa continuous infusion treatment in the oral cavity.

Mechanism of Action of Recombinant Activated Factor VII

“…The high thrombin concentration required for TAFI activation might also explain why continuous infusion of rFVIIa was inferior to bolus injections in bleedings in the oral cavity (in which a high fibrinolytic activity is present) since continuous infusion produces lower peak levels compared to a bolus regimen. 15 rFVIIa also enhanced TAFI activation in plasma from healthy volunteers who received the anticoagulant drug fondaparinux. 61 However, in plasma from patients with liver disease or undergoing liver transplantation, no antifibrinolytic effect of rFVIIa could be observed, most likely because TAFI activation is already optimal in these patients.…”

“…This method, however, seems to be less effective-at least in some cases. 14,15 Adjunctive therapy with antifibrinolytic agents such as tranexamic acid is used in some instances, but its contribution remains unclear. The recovery and clearance rate of rFVIIa may vary substantially from one patient to the next.…”

Factor VIIa: Use in Patients With Hemophilia

“…CI was also evaluated in various bleeding settings, with the administration of rFVIIa via this method shown to be unsuccessful in patients undergoing dental surgery. 36 In an Italian multicenter study reporting on the use of CI in 25 patients, 37 hemostasis was satisfactory in 30 of 35 procedures. In an attempt to determine a likely explanation for the hemostatic insufficiency observed in the other five procedures, the authors tested the circulating factor VII:C levels.…”

“…Favorable outcomes have been published as case reports from several centers, even with a very low rate of rFVIIa infusion. [28][29][30][31][32][33][34][35][36] However, in one study, hemostatic efficacy was regarded as insufficient in patients receiving 16.5 µg/kg/hr since four out of six major operations were complicated by excessive bleeding. 35 This rate of infusion roughly compares with the consumption of rFVIIa by bolus injections at a rate of 100 µg/kg every six hours.…”

FVIIa corrects the coagulopathy of fulminant hepatic failure but may be associated with thrombosis: A report of four cases

“…There are conflicting results regarding the effectiveness of a continuous infusion as it may not be efficacious to inhibit fibrinolysis. 17 Several studies have shown that surgery in hemophilia patients with high titre of inhibitors can be performed safely using rFVIIa.…”