Clinical use of factor VIII and factor IX concentrates.

Factor VIII (FVIII) and factor IX (FIX) are the cofactor and the pro-enzyme, respectively, acting in the tenase complex, a key mechanism of physiological haemostasis in which a phospholipide-dependent reaction produces the activation of factor X1. Mutations in the genes encoding for coagulation FVIII or IX, both located in the X chromosome, are responsible for haemophilia A and haemophilia B, respectively. These congenital bleeding disorders occur overall in approximately 1 in 5,000 male live births without racial predilection. However, the prevalence of haemophilia A is estimated 4–6 times higher than haemophilia B2–3. According to the residual endogenous FVIII/FIX concentrations, individuals with plasma factor levels 5–40 IU/dL are defined as moderate and mild haemophiliacs4. Although the bleeding phenotype is recognised to be heterogeneous and affected by many genetic and environmental factors5–6, this classification reflects rather closely the severity of clinical symptoms. Thus, patients with mild haemophilia experience excessive bleeding in the large majority of cases in response to surgery, other invasive procedures or major injuries4,7. On the other hand, patients with moderate haemophilia experience excessive bleeding after relatively minor trauma and those with severe haemophilia bleed spontaneously or after trivial trauma4,8. In the latter, haemarthrosis, particularly into hinged joints (ankle, knee, elbow), is largely the most frequently reported bleeding symptom8,9. Recurrent joint bleeding is associated with progressive joint morbidity (haemophilic arthropathy), leading to chronic pain and disability, that often warrant orthopaedic surgery and joint replacement10. Soft-tissue haematomas, mucosal, parenchimal and delayed post-surgical bleeding are less common manifestations, including life-threatening intracranial, neck-throat and gastro-intestinal haemorrhages8,9,11. Replacement therapy with intravenously delivered plasma-derived or recombinant FVIII and FIX concentrates, aimed at correcting the coagulation factor deficiency in the case of, or in order to prevent, bleeding is the cornerstone of management of patients with haemophilia A and haemophilia B, respectively. Indeed, these specific and viral-inactivated products are the source of choice of the missing proteins, in preference to fresh frozen plasma (for both factors), cryoprecipitate (for FVIII) or prothrombin complex concentrates (for FIX)11. The two forms of haemophilia have been usually considered indistinguishable from a clinical point of view and, consequently, as regards patterns of treatment. In this respect, most literature data have been achieved in cohorts of patients with haemophilia A and extrapolated to those with haemophilia B. However, according to recent findings, the bleeding tendency associated with FIX deficiency is likely to be less severe, with possible better long-term outcomes12. Plasma-derived FVIII concentrates may also contain variable amounts of von Willebrand factor (VWF), therefore some products are used in the management of those patients with von Willebrand disease with severe VWF deficiencies, in whom response to endogenous release by desmopressin is impossible or insufficient13. After a historical overview of treatment of haemophilia, this article will report the current clinical use of FVIII and FIX concentrates, also with reference to the Italian clinical scenario.