A review. Congenital haemophilia occurs in approx. 1 in 10,000 births and affects an estimated 400,000 people worldwide, about 80% of whom have haemophilia A (deficiency of coagulation FVIII), whereas the remainder have haemophilia B (deficiency of FIX). Although life- and limb-threatening bleeding (for example, intracranial, iliopsoas and gastrointestinal hemorrhage) can occur in patients with congenital haemophilia, joint bleeding is its hallmark. Characterized by pain, swelling and stiffness (Fig. 1), haemarthroses account for more than 80% of all bleeding episodes in patients with severe haemophilia (defined as baseline FVIII or FIX activity <1% of normal). Even a single serious joint hemorrhage can cause irreversible intra-articular changes that progress and culminate in joint destruction (Fig. 2) and impaired health-related quality of life (HRQoL). In other words, the importance of every bleeding episode cannot be overstated. The development of factor concentrates, which first became com. available in the 1970s (Fig. 3), allowed rapid i.v. infusions of the deficient clotting factor to be administered 'on demand' when a bleeding episode occurred. Moreover, patients could infuse at home, thereby shortening the delay between the onset of bleeding and the initiation of treatment. Although this strategy has proved effective in controlling acute hemorrhage, it cannot halt the progressive damage caused by haemarthroses. In the early 1990s, following publication of two articles describing long-term prophylaxis - the routine scheduled replacement of the missing clotting factor - the management of congenital haemophilia began to shift from reactive to proactive in an effort to prevent joint and other bleeding events. These initial observations describing the benefits of prophylaxis were subsequently confirmed by five randomized clin. trials (RCTs) conducted over the next two decades. In 1995, the World Health Organization and World Federation of Hemophilia recommended prophylaxis as optimal therapy for patients with severe haemophilia A or B. These recommendations were later adopted by national haemophilia organizations. FVIII prophylaxis. Response to FVIII prophylaxis is influenced by factors that are both patient-related (i.e., haemophilia severity, FVIII genetics, bleeding phenotype, joint status, lifestyle and phys. activity) and treatment-related (i.e., dosing regimen, individual pharmacokinetics [PK] and adherence). Thus, a 'one size fits all' approach to bleeding prevention is not ideal and may lead to insufficient or inefficient dosing in some patients. Consequently, Baxter has focused on individualizing the prophylactic regimen by considering the patient's PK response to FVIII infusions as well as treatment outcome. In an RCT that enrolled 66 males aged 7 to 59 years with severe to moderately severe haemophilia A, PK-tailored rAHF-PFM prophylaxis administered every third day reduced joint and other bleeding from 44 events to 1 (median annualized bleed rate [ABR]), as compared with on-demand treatment. The treatment also had the advantage of decreasing the number of weekly prophylactic infusions by one-third compared with standard prophylaxis. Taking the concept of individualized treatment further, Baxter developed a new medical software device that calculates a patient's PK and an appropriate prophylactic dose using as few as two blood samples taken after rAHF-PFM infusion. It also provides information about FVIII levels between infusions. The device has received the CE mark from the European Economic Area, and clearance by the US Food and Drug Administration is pending. Its use is expected to eliminate the need for multiple blood samples and cumbersome calculations, both major impediments to implementing PK-guided dosing in routine clin. practice. FIX prophylaxis. Whereas prophylaxis is widely used in patients with haemophilia A, people with haemophilia B are less likely to receive such treatment, possibly owing to a relative paucity of data and/or the perception that bleeding episodes are not as severe in haemophilia B. The availability of addnl. recombinant FIX (rFIX) products may encourage more physicians to consider this treatment option. The pivotal clin. study that led to licensing of Baxter's rFIX concentrate in 2013 enrolled 73 males aged 12 to 65 years with severe or moderately severe haemophilia B. A subsequent study in 23 children reinforced the safety and efficacy results demonstrated in the pivotal study. In both studies, the median ABR was 2.0 for patients on prophylaxis. Prophylaxis for patients with inhibitors. Following exposure to clotting factor concentrate, up to 24% to 35% of patients with severe haemophilia A and 3% with severe haemophilia B develop inhibitors: alloantibodies that neutralize the activity of clotting factor concentrate The development of a high-titer (>5 Bethesda units) inhibitor complicates treatment and bleeding prevention because standard FVIII or FIX replacement is no longer effective. Consequently, patients with inhibitors are at increased risk for difficult-to-control hemorrhage and the development of complications. People with haemophilia who develop inhibitors and have a high anamnestic response (i.e., a marked increase in inhibitor titer on re-exposure to factor concentrate) have traditionally been managed with on-demand therapy using concentrates that bypass the need for FVIII or FIX. Two bypassing agents are currently available: activated prothrombin complex concentrate (aPCC) and recombinant activated FVII (rFVIIa). Over the past 3 years, however, two RCTs evaluating the prophylactic administration of aPCC have provided compelling evidence that the established benefits of FVIII and FIX prophylaxis can be extended to patients with inhibitors. Consequently, the indication for aPCC was expanded to include routine prophylaxis. The first of these RCTs enrolled 26 males (median age: 28.7 years) with haemophilia A and a history of high-responding inhibitors. aPCC prophylaxis administered thrice-weekly for 6 mo was associated with a 62% reduction in all bleeding episodes; a 61% reduction in joint bleeding; and a 72% reduction in bleeding into target joints, defined as ≥3 haemarthroses in a single joint during a 6-mo treatment period, as compared with on-demand aPCC treatment (P < 0.001). Similarly, in the second RCT, which enrolled 36 males (median age: 23.5 years) with haemophilia A or B and inhibitors, the ABR in patients receiving aPCC prophylaxis given every other day for 12 mo was 72.5% lower than with on-demand aPCC treatment (P = 0.0003). Both studies also showed that aPCC prophylaxis improved several dimensions of HRQoL. Most of the patients enrolled in both studies had long-standing inhibitors and evidence of arthropathy. Whether starting aPCC prophylaxis at a young age and before the development of repeated haemarthroses can provide joint-protective benefits similar to those provided by early FVIII or FIX prophylaxis is unclear. However, preliminary findings suggest that this may indeed be possible. After a median of 7 years of follow-up, seven children who began aPCC prophylaxis immediately after failing immune tolerance induction had a median ABR of 1.5, and none had major joint damage while receiving prophylactic aPCC infusions.