Major Surgery in Haemophilic Patients with Inhibitors Using Recombinant Factor VIla

Abstract

In the haemophilic patient, development of antibodies that inhibit the function of the missing coagulation factor causes several delicate problems. Most importantly, antibodies will block the function of the specific coagulation factor, and often the antibody activity is so fierce that effective substitution therapy is outruled. In consequence, alternative measures must be adopted to control bleeding. Amongst those most commonly employed, like factor IX concentrates, activated prothrombin complex concentrates, and factor VIII of porcine origin, a new recombinant activated factor VII molecule has been evaluated clinically for some years with promising results. The aim of the present paper was to present a series of patients suffering from haemophilia A or B in whom inhibitors have complicated the clinical picture, and in whom a surgical procedure was indicated. As part of a compassionate use program devised by the producer of this genetically engineered factor VIla, 12 patients underwent life-saving or essential surgery where the recombinant factor VIla product was used to promote haemostasis in 13 surgical procedures. Due to a short in vivo half-life of activated factor VIla, frequent administration was scheduled, injecting factor VIla every 2-3 h for up to 2 days after which dosage intervals were prolonged. In one case, a global evaluation of the end treatment result was not reported, but in all of the other 12 cases the end result were considered excellent (n = 11) or efficient (n = 1). In none of the cases was other types of coagulation factor treatment modalities necessary. In conclusion, recombinant factor VIla seems a tempting alternative to traditional treatment of the haemophilic patient with inhibitors, in whom surgery is called for. With other types of haemostatic agents, surgery in haemophilic inhibitor patients has only been studied rarely, and operations have generally been restricted to life-threatening situations.

Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality

“…The current approach to therapy is intravenous infusion of the missing or defective coagulation factor, but work by Hedner and colleagues has established that infusion of recombinant human activated Factor VII (rhFVIIa; NovoSeven), a critical protein in the extrinsic pathway, can restore hemostasis through rhFVIIa-catalyzed generation of thrombin in patients with antibodies to Factor VIII (FVIII) or Factor IX (FIX) (1)(2)(3). Based on the current understanding of the coagulation cascade, all patients with hemophilia could conceivably be treated with rhFVIIa, a protein to which all such patients have immunological tolerance.…”

Factor VIIa: Use in Patients With Hemophilia

“…Notwithstanding that most orthopedic procedures are major surgical events, an early multicenter publication on 13 major surgical procedures, including six orthopedic surgeries, reported excellent results using rFVIIa. 12 A series of treatment data from German patients summarizing the utilization of rFVIIa in the management of a wide range of hemophilic bleeds, including three orthopedic procedures, was published in 1999, also with favorable results. 13 In a more recent publication, the authors present an overview of orthopedic surgery based on a search of the literature.…”

Ham-Wasserman Lecture

“…36 Infused as bolus at the recommended doses of 90-120 µg/kg, to be repeated 2 to 4 times at 2-to 3-hour intervals, rFVIIa is claimed to stop approximately 80% of spontaneous hemorrhages and prevent excessive bleeding during major surgical procedures. [37][38][39] There are also experiences with continuous intravenous infusion, 40 which is particularly useful for prolonged treatments and surgery, 41 and with home therapy, which makes early intervention possible. 39 On the whole, it would appear from the published reports that rFVIIa is nearly as effective as factor concentrates in patients without inhibitors, with a success rate close to 80%.…”