36% were controlled with 1 infusion in 12?h, 42% by 1 infusions in 36?h and 14% in >36?h. difficulties remain Gemcabene calcium with NFTs, particularly regarding the potential for synergistic action on thrombin generation with concomitant use of other haemostatic agents, such as BPAs, for the treatment of breakthrough bleeds and in perioperative management. Concomitant use of NFTs with other haemostatic brokers could increase the risk of adverse events such as thromboembolic events or thrombotic microangiopathy. This review focuses on the origins, development and on-going role of aPCC in the evolving treatment scenery in the management of PwHI. Keywords: congenital haemophilia, inhibitors, bypassing brokers, FEIBA, aPCC Introduction Congenital haemophilia A (HA) and B (HB) are bleeding disorders characterised by a deficiency of blood clotting factor VIII (FVIII) or factor IX (FIX), respectively. 1 The type of FVIII/IX mutation present is usually a major determinant of severity and bleeding tendency. 1 Severe cases present with bleeding and joint bleeds from early child years, which, without appropriate treatment and prevention, can result in irreversible joint damage and chronic arthropathy. 2 Strides have been made in the management of congenital haemophilia over recent decades, including the introduction of plasma-derived and recombinant clotting factor products, use of prophylaxis as standard of care for bleeding prevention, and appropriate surgical Rabbit Polyclonal to SH3GLB2 management. 3 4 5 6 7 Such therapy has led to improvements in the health of patients with haemophilia by suppressing the onset of joint damage and arthropathy, Gemcabene calcium preventing life-threatening bleeds, and improving patient quality of life. 8 9 Nevertheless, treatment challenges remain. First, for patients receiving FVIII/IX products, intravenous infusion is required up to every 2 days for patients with severe HA and at least twice weekly for those with severe HB. 10 11 Although high infusion frequency can be reduced with the use of extended half-life products, the frequency can still be burdensome. 12 Second, treatment can be complicated by the development of alloantibodies (inhibitors) that bind to FVIII or FIX, preventing its haemostatic action. 13 Such antibodies can neutralise therapeutically administered factor alternative products, and occur in up to 25 to 40% of severe HA patients, 5 to 15% of moderate/moderate HA patients and 1 to 5% of patients with severe HB. 14 Anaphylactic reactions and nephrotic syndrome are also not uncommon in patients with HB and inhibitors. 15 16 The aetiology of inhibitor development is usually multifactorial, including both genetic and treatment-related risk factors. 17 18 19 20 Presence of inhibitors is usually associated with reduced treatment efficacy, increased occurrence of life-threatening bleeds and severe joint damage, which can lead to poor quality of life for patients, family and caregivers; higher morbidity and mortality rates; and increased healthcare costs. 21 22 23 Recommended treatment of patients with congenital haemophilia and inhibitors (PwHIs) has focused on eradicating inhibitors using immune tolerance induction (ITI) therapy. 3 4 5 6 7 24 25 ITI regimens vary and can be used with or without bypassing brokers (BPAs) for the treatment of breakthrough bleeding, surgical setting and prophylaxis. 7 BPAs were developed to bypass the factors blocked by inhibitors, and function by generating thrombin via pathways that do not require activation of FVIII or FIX. 26 Two BPAs are currently available: activated prothrombin complex concentrate (aPCC, FEIBA [factor eight inhibitor bypass activity]; Takeda, Lexington, Massachusetts, United States) and recombinant activated FVII (rFVIIa, NovoSeven; NovoNordisk, Bagsvaerd, Denmark). Both compounds have been approved for on-demand treatment and perioperative management for PwHIs, while aPCC is the only compound approved worldwide for prophylaxis in PwHI. 27 28 29 Both aPCC and rFVIIa have efficacy rates >80% in the control of acute bleeding events, with comparable tolerability and low rate of thrombotic complications, as concluded by a Cochrane systematic review. 30 The choice of BPA for on-demand treatment may be driven by several factors, including burden of the infusion due to volume and infusion time, experience of treater and/or patient preference. 26 Furthermore, individuals may show a better response to one agent Gemcabene calcium over another, as reflected in the FEIBA NovoSeven Comparative (FENOC) study, Gemcabene calcium 31 in which 32% of patients reported efficacy for either aPCC or rFVIIa at 6?hours post-treatment. 31 Achievement of good haemostatic efficacy within the first few hours of a bleed can reduce the risk of cartilage destruction; therefore, selection of the most.