The expanding role of prophylaxis with recombinant activated factor VII.

Recombinant activated coagulation factor VII (rFVIIa) (Novo-Seven, Novo Nordisk, Denmark) is a coagulation protein that induces haemostasis through direct activation of factor X, thus enhancing the rate of thrombin generation on thrombin-activated platelet surfaces and providing the thrombin necessary for the formation of a stable fibrin haemostatic plug1. The use of rFVIIa has been approved for the treatment of bleeding in patients with haemophilia A and B and inhibitor antibodies, acquired haemophilia, factor VII deficiency, or Glanzmann’s thrombasthenia (GT) refractory to platelet administration2–4. Besides its use for the management of acute bleeding in haemophilia patients with inhibitor, rFVIIa has also been used extensively for many years, both intra-operatively and post-operatively, for prevention of bleeding in inhibitor patients undergoing various types of surgical interventions4. In addition, over the last few years there has been an increasing number of case reports and small case series on the ability of this agent to prevent joint and other bleeds in such patients5,7. The first indication that rFVIIa may have a prophylactic effect in reducing the number of bleeds came from Brackmann and colleagues8 who described the successful use of rFVIIa in association with immune tolerance treatment (ITT) in four patients ranging in age from 0.5 to 26 years and with a dosage regimen varying from 90 μg/kg twice daily to 2–3 times a week. The duration of prophylaxis ranged from 2 to 27 months. No adverse events were reported. Subsequently, Saxon and colleagues9 reported on a boy with severe haemophilia A and high titre inhibitors who received secondary prophylaxis with rFVIIa (90 μg/kg daily) for a target ankle joint. Prior to prophylaxis, the patient had experienced 2.1 bleeds per week in his right ankle while during the prophylaxis period (21 weeks) the patient experienced a mean of 0.4 bleeds per week. No adverse events were reported. Young and colleagues10 reported the successful prophylactic use of rFVIIa in two haemophiliacs with high titre inhibitors: the first patient was treated as a result of development of a target joint, while the second patient suffered from multiple severe bleeds requiring frequent admissions to hospital. Morfini and colleagues11 retrospectively surveyed 13 patients with inhibitors treated prophylactically in different European centres with rFVIIa using various regimens that ranged from 220 μg/kg daily to 200–250 μg/kg/week administered for 4 months to 4 years. Twelve of the 13 patients had a reduction in bleeding frequency from a mean of 0.37–8.33 bleeds per month before prophylaxis to 0–2.25 bleeds per month during prophylaxis. Eight of nine patients were satisfied or very satisfied with rFVIIa treatment, and in cases reporting subjective quality of life, all were improved, much improved or significantly improved. The authors concluded that rFVIIa prophylaxis dramatically reduced the number of bleeding episodes with good patient compliance and improved quality of life. The only prospective study published so far on this topic is that by Konkle and colleagues12, who conducted a randomised, double-blind 3-month trial of two dosing regimens of rFVIIa (standard dose of 90 μg/kg/day and high dose of 270 μg/kg/day) in 22 inhibitor patients. The frequency of bleeding in both the standard- and high-dose groups was decreased by 45% and 59%, respectively, during short-term prophylaxis, and by 27% and 50%, respectively, during 3 months of post-treatment follow-up. No thromboembolic events were reported during prophylaxis. The authors concluded that clinically relevant reductions in bleeding frequency as compared with conventional on-demand therapy were achieved during prophylaxis without raising safety concerns and provided further evidence for the benefit of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds. In a further analysis of this trial, Hoots and colleagues13 showed that prophylaxis with rFVIIa improves quality of life of inhibitor patients who already have some level of arthropathy. In a recent review by Franchini and colleagues14, a total of 48 cases were collected from the literature, suggesting the benefit of rFVIIa as prophylaxis in haemophilia patients with inhibitors. A prospective, randomised, international study (ENJOIH), evaluating the safety and efficacy of primary prophylaxis with rFVIIa in children with haemophilia A with high titre inhibitors, is currently ongoing. However, given the positive results in congenital haemophilia inhibitor patients, a role of prophylaxis with rFVIIa also in patients with other rare inherited haemorrhagic disorders refractory to standard therapy could be hypothesised. This is the case of the interesting case-report published by Giordano and colleagues15 in this issue of Blood Transfusion. Indeed, the authors, for the first time, translated their personal experience on the prophylactic use of rFVIIa in haemophilia patients with inhibitors to prevent joint damage in a boy with Glanzmann’s thrombasthenia. The patient, who suffered for traumatic ankle haemarthrosis, received a prophylactic protocol with rFVIIa (90 μg/Kg immediately before joint mobilisations) during physical therapy. Recombinant FVIIa effectively and safely prevented recurrence of bleeding at early mobilisation of the limb and was thus an important therapeutic component in the complex management of this patient. In conclusion, we are sure that there are other GT patients with clinical conditions resembling that of the patient described by Giordano and colleagues15 who could benefit from a similar treatment regimen. We, therefore, think that this case-report is very important as it paves the way for the application by other physicians of this therapeutic approach, aimed at improving the clinical management and, ultimately, the quality of life of patients with GT.