Clinical use and the Italian demand for activated prothrombin complex and activated recombinant factor VII concentrates.

Abstract

The activated prothrombin complex concentrate (aPCC, Factor Eight Inhibitor Bypassing Activity, FEIBA, Baxter, Deerfield, IL, USA) and the recombinant activated factor VII concentrate (rFVIIa, NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) are the so-called “by-passing agents”, i.e. products able to promote haemostasis through mechanisms alternative to the physiological tenase complex, in which a phospholipid-dependent reaction occurs with factor (F) X as the substrate, activated (a) FIX as the enzyme and FVIIIa as a cofactor1. The mechanism(s) of action of these agents are still not completely elucidated. The aPCC, which contains activated FII, FIX, FX and small amounts of FVII, is thought to facilitate thrombin generation on the platelet surface. This product was first introduced in clinical practice in 1975, as a therapeutic agent for haemophilia B when specific FIX concentrates were not available, and in the current vapour-heated formulation in 19852. The rFVIIa concentrate was specifically developed to provide a therapeutic approach in haemophilia with inhibitors, being able at high concentrations to enhance platelet-surface FXa generation, irrespective of the presence of FVIII or FIX3. The first use of rFVIIa was reported in 1988, and the product was registered in Europe in 1996 and in the United States in 1999. aPCC and rFVIIa are the mainstay of treatment of patients with congenital and acquired haemophilia (AH) with inhibitors4–6, in whom efficacy and safety of such agents have been documented over more than three and two decades of clinical use, respectively. As a specific replacement agent, rFVIIa is indicated in patients with factor VII deficiency7 and, as an alternative haemostatic agent, in patients with Glanzmann’s thrombasthenia (GT) and alloantibodies and/or platelet transfusion refractoriness8. Because of the rarity of the other recognised indications for treatment, most clinical and literature data regarding bypassing agents have been generated in the setting of congenital haemophilia with inhibitors. Before presenting the Italian demand for aPCC and rFVIIa in this 5-yr analysis, the clinical use of bypassing agents in the management of patients with bleeding disorders, in particular in those with congenital haemophilia and inhibitors, with the numerous challenges and open issues, will be concisely reviewed.