Treatment Of Acute Bleeding Episodes Research Articles

Musculoskeletal treatment in haemophilia.

Haemophilia is a group of coagulation disorders inherited in an X-linked recessive pattern.Nearly three-quarters of all haemorrhages in haemophilia occur in the musculoskeletal system, usually in the large muscles and joints of the lower extremity.While prevention of bleeding with active prophylaxis is the recommended optimal therapy for severe haemophilia, there are many patients suffering from musculoskeletal system complications subsequent to uncontrolled bleeding.Recombinant clotting factor concentrates led to home treatment of acute bleeding episodes as well as allowing for minor and major surgical interventions.Avoiding of further complications by radiosynoviorthesis is the first-line recommendation, and arthroplasty is regarded as the effective salvage procedure for patients presenting with severe disability.Physiotherapy and rehabilitation in haemophilia patients are important to return the normal status of joint motion, to regain the muscle strength, to obtain the optimal functional levels and to improve patients’ quality of life.Cite this article: EFORT Open Rev 2019;4 DOI: 10.1302/2058-5241.4.180068

Safety and efficacy of recombinant activated coagulation factor VII in congenital hemophilia with inhibitors in the home treatment setting: A review of clinical studies and registries.

Self-administration of factor and bypassing agents by persons with hemophilia in the home setting is recommended to facilitate earlier intervention after bleeding episodes. The objective of this review was to summarize recombinant activated coagulation factor VII (rFVIIa) safety and efficacy data from clinical trials and patient registries documenting use in the home treatment setting in people with congenital hemophilia with inhibitors (CHwI). A total of 16 studies and registries were identified for inclusion; 14 evaluated on-demand treatment of acute bleeding episodes (865 patients, 9024 bleeding episodes) and 2 evaluated use for secondary prophylaxis (108 patients, 42,861 prophylaxis days). In the on-demand studies, efficacy was consistently high (81%-96%), and thrombotic events were uncommon (n = 3). In the secondary prophylaxis studies, rFVIIa was associated with a 45% to 59% reduction in bleeding episodes and no thrombotic events. These data support the clinical practice of administering rFVIIa in patients in the home treatment setting after initiation under a physician's care.

Biochemical characterization of LR769, a new recombinant factor VIIa bypassing agent produced in the milk of transgenic rabbits.

The bypassing agent factor VII (FVIIa) is a first-line therapy for the treatment of acute bleeding episodes in patients with haemophilia and high-titre inhibitors. FVIIa is a highly post-translationally modified protein that requires eukaryotic expression systems to produce a fully active molecule. A recombinant FVIIa was produced in the milk of transgenic rabbits to increase expression and provide an efficient, safe and affordable product after purification to homogeneity (LR769). To present the biochemical and functional in vitro characteristics of LR769. Mass spectrometric analyses of the intact protein and of heavy and light chains revealed a fully activated, mature and properly post-translationally modified protein notably regarding N/O-glycosylations and γ-carboxylation. Primary structure analysis, performed by peptide mapping, confirmed 100% of the sequence and the low level or absence of product-derived impurities such as oxidized, deamidated and glycated forms. Low levels of aggregates and fragments were observed by different chromatographic methods. Higher order structure investigated by circular dichroism showed appropriate secondary/tertiary structures and conformational change in the presence of Ca2+ ions. Finally, activated partial thromboplastin time and thrombin generation assays showed the ability of LR769 to decrease coagulation time and to generate thrombin in haemophiliac-A-plasmas, even in the presence of inhibitors. The innovative expression system used to produce LR769 yields a new safe and effective rhFVIIa for the treatment of haemophilia A or B patients with inhibitors.

Treatment of bleeding episodes with recombinant factor VIII Fc fusion protein in A‐LONG study subjects with severe haemophilia A

The Phase 3 A-LONG study demonstrated the safety and efficacy of rFVIIIFc for the control and prevention of bleeding episodes in severe haemophilia A. To describe the treatment of bleeding episodes with rFVIIIFc in the A-LONG study. A-LONG subjects (<1 IU dL-1 endogenous FVIII) were treated with individualized prophylaxis (Arm 1), weekly prophylaxis (Arm 2) or episodic treatment (Arm 3). Information recorded for each bleeding episode included type, location and dose to treat the episode. During A-LONG, 757 bleeding episodes occurred during the efficacy period; the majority [456 (60%)] occurred in Arm 3 (episodic treatment). Of 93 subjects in the prophylaxis arms who entered the study with target joints, 43 (60%) in Arm 1 and 11 (52%) in Arm 2 did not experience a target joint bleed. Overall, 98% of bleeding episodes (and 98% of bleeds involving a target joint) resolved with one or two infusions; the median dose per infusion to treat a bleed was 27 IU kg-1 (27 IU kg-1 for target joints). Using population pharmacokinetic simulations, FVIII activity levels were predicted to be below the upper limit of normal (150 IU dL-1 ) in most patients in the event that rFVIIIFc is used to treat a bleeding episode in close proximity to a prophylactic dose. These findings demonstrate the efficacy of rFVIIIFc for the treatment of acute bleeding episodes in subjects with severe haemophilia A, regardless of treatment regimen.

Efmoroctocog Alfa: A Review in Haemophilia A.

Efmoroctocog alfa (Elocta(®), Eloctate(®), Eloctate™), a first-in-class recombinant factor VIII-Fc fusion protein (rFVIIIFc), has an extended half-life compared with conventional factor VIII (FVIII) preparations, including recombinant FVIII (rFVIII) products. It is approved for the treatment and prophylaxis of bleeding in patients with haemophilia A in multiple countries worldwide. Data accumulated from pivotal phase III studies (A-LONG in adults and adolescents aged ≥12years; Kids A-LONG in children aged <12years) and their ongoing extension study (ASPIRE) have demonstrated the long-term effectiveness of efmoroctocog alfa for the treatment of acute bleeding episodes, perioperative management and routine prophylaxis in previously treated males with severe haemophilia A. Among patients on individualized efmoroctocog alfa prophylaxis who had previously received FVIII prophylaxis, all but one of those aged ≥12years and three-quarters of those aged <12years reduced their injection frequency compared with their pre-study regimen. FVIII replacement therapy with efmoroctocog alfa was generally well tolerated in previously treated patients, with no evidence of increased immunogenicity. The safety and efficacy of FVIII replacement therapy with efmoroctocog alfa in previously untreated males aged <6years with severe haemophilia A are currently being evaluated. Although there are no direct, head-to-head studies, the available clinical trial evidence indicates that efmoroctocog alfa provides an effective alternative to conventional FVIII preparations (including rFVIIIs) for the management of haemophilia A. Moreover, by reducing the frequency of injections required, it has the potential to reduce treatment burden, and hence improve adherence to prophylaxis.

Eptacog alfa activated: a recombinant product to treat rare congenital bleeding disorders

Glanzmann's thrombasthenia (GT) and congenital factor VII deficiency (FVII CD) are rare autosomal recessive bleeding disorders: GT is the most frequent congenital platelet function disorder, and FVII CD is the most common factor-deficiency disease after haemophilia. The frequency of these disorders in the general population ranges from 1:500,000 to 1:2,000,000. Because GT and FVII CD are both rare, registries are the only approach possible to allow the collection and analysis of sufficient observational data. Recombinant activated factor VII (rFVIIa, eptacog alfa activated) is indicated for the treatment of acute bleeding episodes and for surgery coverage in patients with GT who are refractory to platelets and have antiplatelet or anti-human leukocyte antigen (HLA) antibodies, and for the prevention and treatment of bleeding in patients with FVII CD. This article summarises published data on the mechanism of action and use of rFVIIa in these disorders from two international, prospective, observational registries: the Glanzmann's Thrombasthenia Registry (GTR) for GT; and the Seven Treatment Evaluation Registry (STER) for FVII CD. Haemostatic effectiveness rates with rFVIIa were high across all patients with GT and those with FVII CD, and treatment with rFVIIa in the GTR and STER registries was well tolerated. The GTR and the STER are the largest collections of data in GT and FVII CD, respectively, and have expanded our knowledge of the management of these two rare bleeding disorders.

Pharmacokinetic and pharmacodynamic properties of plasma‐derived vs. recombinant factor IX in patients with hemophilia B: a prospective crossover study

Effective treatment of acute bleeding episodes in patients with hemophilia B relies on factor IX recovery, with higher levels being more desirable, whereas prevention of bleeds with a prophylactic regimen depends on the half-life of the product. Lower recovery values have been reported following administration of recombinant FIX (rFIX) than following administration of plasma-derived FIX (pdFIX). To compare the pharmacokinetic and pharmacodynamic properties of rFIX and pdFIX in patients with hemophilia B. A prospective crossover study of nine patients with moderate to severe hemophilia B was performed. Following a washout period, 50 U kg(-1) FIX was administered, and blood samples were taken as per protocol up to 48 h postinfusion. Paired data were analyzed with the Wilcoxon signed rank test. Mean peak recovery at 10 min postinfusion was 62.14 IU dL(-1) with pdFIX and 52.7 IU dL(-1) with rFIX (P = 0.08). Mean half-life was 16.6 h with pdFIX and 17.5 h with rFIX (P = 0.55). Maximum peak thrombin generation (PTG) was 35.9 nm with pdFIX and 28.9 nm with rFIX (P = 0.21). Administration of rFIX resulted in early PTG, whereas administration of pdFIX resulted in slightly later and sustained PTG. At 48 h, PTG was similar with pdFIX (19.0 nm) and rFIX (19.4 nm) (P = 0.91). Patients experienced better recovery with pdFIX than with rFIX. pdFIX and rFIX had similar half-lives. Maximum PTG was higher for pdFIX; however, this difference did not reach statistical significance. The clinical impact of the slightly increased, delayed and sustained PTG with pdFIX requires further investigation.

Results of the WIRK prospective, non‐interventional observational study of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors and other bleeding disorders

Recombinant activated factor VII (rFVIIa) has been available for the treatment of acute bleeding and for prevention of bleeding during surgery and invasive procedures in patients with congenital haemophilia with inhibitors (CHwI) and acquired haemophilia since 1996. The study objective was to assess the efficacy and safety of rFVIIa in patients with CHwI, acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia, in a real-life clinical setting. There were no specific inclusion or exclusion criteria; participation was offered to all German haemophilia centres known to use rFVIIa to treat patients with the above indications. Data on rFVIIa use and efficacy for the treatment of acute bleeding episodes and invasive procedures were recorded. Adverse drug reactions and recurrent bleeding episodes were also monitored. In total, 64 patients (50.0% women) received rFVIIa treatment. Patients experienced 281 evaluable bleeding episodes and underwent 44 invasive procedures. In 252 of 281 (89.7%) bleeding episodes, a stop (66.5%) or a significant reduction (23.1%) in bleeding was observed. No bleeding complications were reported for 42 of 44 (95.5%) invasive procedures covered with rFVIIa. A clear positive association was observed between early initiation of rFVIIa treatment for acute bleeding and efficacy. The total cumulative dose and number of injections were 468.3 ± 545.8 μg kg(-1) and 3.6 ± 4.6 respectively. No drug-related adverse events were reported. rFVIIa use in Germany provided effective haemostatic cover without associated adverse events in the management of acute bleeds and invasive procedures across a range of bleeding disorders.

インヒビター保有先天性血友病患者の出血エピソードにおける遺伝子組換え活性型血液凝固第VII因子製剤（ノボセブン&lt;sup&gt;Ⓡ&lt;/sup&gt;）の有効性および長期的安全性：10年間の市販後調査解析報告

インヒビターを保有する先天性血友病患者の出血エピソードにおける遺伝子組換え活性型血液凝固第VII因子製剤（rFVIIa）の10年間の使用成績調査をもとに，その有効性と安全性を解析した．有効性評価が可能な先天性血友病患者142例1,718出血エピソードについて解析した結果，rFVIIa投与から12時間以内に止血効果が認められた割合は65％，最終的に止血効果が認められた割合は88％であった．rFVIIa単独治療群の1回投与量，投与回数，投与日数の中央値はそれぞれ103μg/kg，3.0回，1.0日であった．出血部位は関節内出血が63％と最も多く，次いで筋肉内出血が14％，皮下出血が9％であった．頭蓋内出血，消化管出血，血尿では投与日数が有意に長かった．また安全性については，144例，8,097出血エピソード，全24,778回の投与に対して，4例5件の血栓塞栓性事象が報告された．

Intra-Patient Variability in Recombinant Activated FVII (rFVIIa) Dosing Over 3 to 8 Year Periods in Patients with Congential Hemophilia with Inhibitors Experiencing Frequent Acute Bleeding Episodes: Analysis From the Hemostasis and Thrombosis Research Society (HTRS) Registry,

Abstract 3314 BACKGROUND:For congenital hemophilia patients who develop inhibitors to factors VIII or IX, the management of bleeding episodes can be complex, and often requires use of bypassing agents (BPA) such as rFVIIa (NovoSeven® RT). While some have reported on the variability in responsiveness to BPAs between patients, with the implication that some patients are more or less responsive to particular agents, few trial or registry data sets have sufficient long-term data to capture the intra-patient variability in dosing for specific bleed types or locations to identify if treatment is individualized on a patient basis or instead on a bleed-by-bleed basis by the hematologist and patient/caregiver. The HTRS Registry is a multi-center, longitudinal database of bleeding episodes and treatment patterns for bleeding disorder patients, with a particular focus on the treatment of acute bleeding episodes in inhibitor patients. METHODS:The HTRS registry recorded data between January 2004-March 2011 for 2,053 bleeding episodes in 134 inhibitor patients. From these data, we identified US patients with 75 or more rFVIIa-treated bleeding episodes and analyzed for intra-patient variability using descriptive statistics and graphical representations. RESULTS:5 patients (3 hemophilia A from 2 centers, 2 hemophilia B from 1 center) were identified with 568 rFVIIa-treated bleeds (28% of total recorded). Patients were White and Non-Hispanic, and ranged in age from 2.2 to 13.7 years old at the time of first reported bleed (2000–2005) and from 6.2 to 17.6 years old at the time of last reported bleed (2004–2008). Patients had 95–162 documented bleeds (mean 113.6) over 38–98 months (mean 62.5), with between 1 and 2.7 bleeds per month (mean 2.0). Median total dose per bleeding episode and interquartile ranges (IQR, 25%-75%) are shown below.Patient numberrFVIIa Trx BleedsStatisticTotal rFVIIa Dose Per Episode (mcg/kg)All BleedsTraumaticSpontaneousJointMuscleA162Median663.5816640640692IQR480–940524–1000469–906480–940465–927B106Median640595640600745IQR470–1000427.5–867480–1000414–820540–1140C103Median630855630675790IQR370–1109483–1363400–900450–1131485–1095D102Median570600600600540IQR360–960360–990424 –960480–960360–1485E95Median711474724.5774430IQR273–840354–592.5297–840492–840258–765Median total dose per episode for all bleeds varied from 570 to 711 mcg/kg, with the minimum reported dose of 50 mcg/kg and maximum of 43,200 mcg/kg. There was some variability but no consistent pattern across patients when comparing median doses for traumatic, spontaneous, joint, muscle and mucosal bleeds. The ratios of IQR/median and range/median total dose were also variable across patients and often across types within patients.The variability in total dose across bleed types/locations can also be demonstrated graphically as in the figures below (patient A, IQR - shaded, median – dotted line). Furthermore, initial doses were consistently above US package insert recommendations of 90 mcg/kg and high initial doses (>250 mcg/kg) were seen throughout 2002–2006. [Display omitted] [Display omitted] CONCLUSIONS:While registry data are subject to a variety of biases, they are able to capture real world data across patient populations that allows for assessment of variability between patients. In the case of the longstanding HTRS registry, we have the ability to also examine in a limited way differences in dosing within 5 individual patients across a 3–8 year period of childhood and adolescence. Surprisingly, or perhaps not so surprisingly, these exploratory analyses seem to indicate that treatment may be individualized by the hematologist (and hemophilia treatment center) and patient/caregiver for every bleed, and that even in individuals with many spontaneous, traumatic, or joint bleeds, treatment varies between mild bleeds treated with as little as one dose and severe bleeds or surgeries requiring prolonged treatment. Given the challenges of documentation of home treatment within medical records and consequently limited information available for assessment in registries, further analysis of co-variates that can account for these intra-patient variations (e.g. increasing frequency of target joint bleeds, extent of trauma, concurrent activities/sports/camp) will require prospective observational diary or registry studies that can capture additional information. Disclosures:Neufeld:Novo Nordisk Inc.: Consultancy, Research Funding. Off Label Use: rFVIIa (NovoSeven) is approved for the treatment of bleeding episodes in congenital hemophilia with inhibitors; doses shown in this abstract might differ from the US prescribing information. Cooper:Novo Nordisk Inc.: Employment.

Recombinant Factor VIIa Concentrate versus Plasma-derived Concentrates for the Treatment of Acute Bleeding Episodes in Persons with Haemophilia and Inhibitors

The development of inhibitors remains the most challenging complication of treatment in persons with haemophilia, resulting in increased morbidity and a significant economic burden. The ultimate goal of treatment in patients with inhibitors is immune tolerance induction (ITI) therapy; however, during the induction phase of ITI, when ITI fails and where ITI is not affordable, the treatment of bleeding becomes a crucial issue. Recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) have been developed to bypass the inhibitor antibody effect and have been tested in several randomised controlled trials, including two crossover head-to-head comparisons. Two systematic reviews of the literature have appraised and synthesised the available evidence. The recombinant drug seems to provide a more favourable benefit–risk ratio and may be easily administered as a single front-loaded bolus, making it a good candidate for the role of first-line treatment for bleeding in patients with inhibitors. Aggressive treatment of acute bleeds should be considered, including the use of higher and repeated-dose regimens until complete resolution of the bleed.

A Protease Resistant Factor VIII Analog for Blockade of Inhibitory Antibodies

AbstractAbstract 3361High titer inhibitory antibodies (Abs) to Factor VIII (FVIII) generated in response to FVIII replacement therapy can render the therapy ineffective in hemophilia A (HA) patients. Abs to FVIII contain serine protease-like nucleophilic sites that react covalently with electrophilic phosphonate diester groups placed on the Lys side chains of FVIII (E-FVIII), resulting in restoration of the ability of exogenous FVIII to act as a cofactor for blood coagulation (Planque et al, J Biol Chem 2008; 283, p11876-11886). Irreversible inactivation of Abs by E-FVIII could potentially permit administration of FVIII for treatment of acute bleeding episodes in HA patients with high titer inhibitory antibodies. Another favorable effect of E-FVIII is its ability to block the production of anti-E-FVIII Abs by cultured memory B cells (Smith et al., J Thromb Haemost 2007; 5 Supplement 2: O-M-063). Here we report the resistance of E-FVIII to proteolytic clearance, a property predicted to enable prolonged blockade of pathogenic anti-FVIII immunity. E-FVIII was degraded by the serine proteases thrombin, trypsin and chymotrypsin at rates 100, 29 and 23-fold less rapidly, respectively, compared to FVIII, determined by electrophoretic generation of protein fragments. The effect of E-FVIII on thrombin catalyzed VAL-PRO-ARG-aminomethylcoumarinamide hydrolysis followed classical irreversible inhibitory kinetics, consistent with covalent bonding of the phosphonate group to the thrombin active site. Thrombin affinity (Ki) for E-FVIII and the rate of covalent bond formation (k2), respectively, were 1331 nM and 1.8 min-1. E-FVIII resistance to thrombin should reduce its consumption in the coagulation pathway, increasing its availability for the reaction with anti-FVIII Abs. FXa, an enzyme that contributes in the metabolic clearance of FVIII from blood, also degraded E-FVIII more slowly compared to FVIII. The half-life of E-FVIII in human serum and human plasma in vitro was substantially superior to that of FVIII. Only weak binding of E-FVIII to human von Willebrand Factor (VWF) was detected, suggesting that stabilizing interactions with VWF are not the reason for increased E-FVIII resistance to the proteases. E-FVIII did not prolong the time to clot formation determined by the APTT test and did not inhibit FXa generation in the chromogenic Coamatic test. Therefore, E-FVIII does not cause a global inhibition of the serine protease pathways required for blood coagulation. The reaction model entails covalent bonding of the E-FVIII phosphonate if productive noncovalent contact with the enzyme is established. As the E-FVIII is present at limiting concentrations (<Ki), generalized protease inhibition does not occur. These data suggest that clearance of E-FVIII in vivo by blood-borne proteases should be limited, potentially affording a longer half-life and prolonged blockade of pathogenic antibody effects. Reduced E-FVIII digestion by intracellular proteases may also attenuate the presentation of pathogenic FVIII antigenic epitopes to T cells, thereby, reducing the production of inhibitory anti-FVIII antibodies. Disclosures:Planque:Covalent Immunology Products: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Escobar:Covalent Immunology Products: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Nishiyama:Covalent Immunology Products: Consultancy, Equity Ownership, Patents & Royalties. Paul:Covalent Immunology Products: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Management of Varices and Variceal Hemorrhage in Cirrhosis

Gastroesophageal varices are present at diagnosis in almost half of patients with cirrhosis, and variceal hemorrhage continues to be a lethal complication of cirrhosis. This review explains the three main challenges in clinical management: primary prophylaxis to prevent a first episode of hemorrhage, the treatment of acute bleeding episodes, and secondary prophylaxis to prevent recurrence of variceal hemorrhage.

Acquired haemophilia syndrome: Pathophysiology and therapy

Acquired inhibitors against coagulation factor VIII (FVIII), also termed acquired haemophilia A, neutralize its procoagulant function and result in severe or often life-threatening bleeding. The antibodies arise in individuals with no prior history of clinical bleeding. Acquired haemophilia occurs rarely with the incidence of approximately 1 to 4 per million/year, with severe bleeds in up to 90% of affected patients, and high mortality between 8-22%. About 50% of diagnosed patients were previously healthy, while the remaining cases may be associated with postpartum period, autoimmune diseases, malignancy, infections, or medications. Most patients have spontaneous haemorrhages into the skin, muscles or soft tissues, and mucous membranes, or after trauma and surgery, whereas haemarthroses are uncommon. The diagnosis of acquired haemophilia A based on the prolongation of activated partial thromboplastin time which does not normalize after the addition of normal plasma, reduced FVIII, with evidence of FVIII inhibitor measured by the Bethesda assay (Nijmegen modification). The treatment of acute bleeding episodes and the long-term eradication of the autoantibodies in acquired haemophilia are the main therapeutic strategy. Two options are currently available for acute bleeding control: the use rFVIIa or FEIBA in patients with higher inhibitor titer (> 5 BU), or to raise the level of FVIII by administration of DDAVP or concentrates of FVIII in patients with low level of inhibitors (< 5 BU). Treatment with FEIBA (50-100 IU/ kg every 8-12 hours) has shown good haemostatic response in 76-89% of the bleeding episodes. Patients treated with rFVIIa (90 microg/kg every 2-6 hours) have achieved good response in 95-100% as a first-line, and 75-80% as a salvage therapy. Patients with low inhibitor titer and lower response can be treated with concentrate of FVIII in the recommended dose of 40 IU/kg plus 20 IU/kg for each BU of inhibitor. The treatment of non-life-threatening haemorrhages with desmopressin (DDAVP 0.3 microg/kg) may increase both FVIII and vWF. Sometimes inhibitors disappear spontaneously, but long-term management is necessary for eradication of inhibitors by immunosuppression (prednisone 1 mg/kg 3 weeks alone or in combination cyclophosphamide 2 mg/kg), immunomodulation, intravenous immunoglobulin (HD IgG 2 g/kg 2 or 5 d), physical removal of antibodies (plasmapheresis or immunoadsorption), or various combinations. Recently, a therapy with rituximab, an anti-CD20 monoclonal antibody, has shown to be effective in acquired haemophilia.

Postpartum-acquired haemophilia A: a description of three cases and literature review

Postpartum-acquired haemophilia A is a rare but potentially severe complication of pregnancy. Although the natural history of the disease is usually benign, with a high percentage of spontaneous remissions and a low mortality, its quick recognition is important to control bleeding episodes. The therapeutic strategies in these patients are the treatment of acute bleeding episodes and the long-term eradication of the autoantibody. We report three different cases of postpartum-acquired haemophilia demonstrating the broad heterogeneity of the clinical presentation and of therapeutic necessity of this condition. Finally, we present a review of the literature on the current therapeutic management of this haemorrhagic disorder.

Paediatric haemophilia with inhibitors: existing management options, treatment gaps and unmet needs

Development of inhibitors is a severe complication of haemophilia posing many management challenges. While a long-term goal in inhibitor patients is eradication of inhibitors through immune tolerance induction, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) are essential for control of bleeding episodes. Paediatric patients with haemophilia and inhibitors are at particular risk of recurrent haemarthroses, and management of these patients should seek to avoid joint damage and support the child's full social and physical development. Current options for management of bleeding complications include on-demand treatment of acute bleeding episodes, secondary prophylaxis to avoid recurrent bleeds and surgery to treat affected joints. There is also a rationale for adopting prophylactic approaches to prevent bleeding in inhibitor patients, allowing this group similar opportunities for protection against arthropathy development as are given to non-inhibitor patients. This paper, based on a roundtable meeting of haematology experts at the first Zürich Haemophilia Forum in May 2008, reviews the current evidence supporting more intense and prophylactic approaches to manage bleeding risk in paediatric haemophilia patients with inhibitors, and highlights the need for investigations of primary prophylaxis in this vulnerable patient group, to support best long-term outcome.

FEIBA®in treatment of acute bleeding episodes in patients with haemophilia A and factor VIII inhibitors: a retrospective survey in regional haemophilia centre

FEIBA (factor eight inhibitor by-passing activity) is used to achieve haemostasis in haemophiliacs with inhibitor. The aim of this study was to evaluate efficacy and consumption of the product in treatment of haemorrhages in haemophiliacs with factor VIII inhibitor, and determine factors that can influence the results of treatment. We used data from our haemophilia centre from years 2000-2008. Six haemophiliacs with factor VIII inhibitor were treated on demand with FEIBA for 61 bleeding episodes (45 haemarthroses, six muscle bleeds, six other sites bleeds and four multiple sites bleeds). The median cumulative dose of FEIBA per bleeding episode was 205 U kg(-1). Bleeding was stopped in 96.7% (59 of 61) of events but re-bleeding occurred in 3 events (4.9%) within 48 h after cessation of bleeding. In home treatment (20 of 61) bleeding stopped in 90% (18 of 20) without recurrence and the median consumption per event was reduced to 153 U kg(-1). Without the use of home treatment the median consumption was 250 U kg(-1) per event and bleeding ceased definitely in 92.7% (38 of 41) of cases. The cumulative dose of FEIBA was lower for three episodes with re-bleeding: median 96 U kg(-1) but not in the two cases of ineffective treatment: 361 U kg(-1). FEIBA in management of bleeding episodes completely resolved the haemorrhage in 91.8% of events and in a further 4.9% if treatment was restarted. Using home treatment saved expenditure due to the lower cumulative dose needed for treatment of haemorrhage.

Use of Single Dose of rFVIIa in Congenital Hemophilia: Analysis of Data Capture from the Hemophilia and Thrombosis Research Society Registry (2004–2008)

The recommended dose of recombinant factor VIIa (rFVIIa, NovoSeven®) is 90 mcg/kg every 2–3 hours. The Home Treatment Study demonstrated an average of 2.2 doses of 90 mcg/kg were required to treat mild to moderate bleeds. Since it is recognized that a single dose administered shortly after a bleed, if equally effective, would be more convenient and possibly could reduce bleeding morbidity, this study examined the experience registered with the use of single rFVIIa doses in the United States.The HTRS database contains patient data relating to hemophilia treatment and related disorders, and in particular the treatment of acute bleeding episodes in individuals with hemophilia complicated by anti-factor VIII (FVIII) or IX (FIX) alloantibody inhibitors. Between January 2004 and March 2008, the database contained information on over 5,000 bleeding episodes. The data for patients receiving only a single bolus intravenous dose of rFVIIa and no additional treatment were evaluated. The parameters assessed included patient demographics, bleed location, bleed type (specifically joint and muscle bleeds), and dose.Of 2,532 patients who received rFVIIa, 70 with congenital hemophilia A (n=63) or B (n=7) and inhibitors experienced 508 bleeding episodes that were treated solely with a single dose of rFVIIa. The mean (median, range) age at the time of bleed was 12.7 years (8.2, 0.6–60.4). Mean titers for anti-FVIII and anti-FIX were 62.2 BU (15.0, 0–1408) and 6.8 BU (1.3, 0–31.7), respectively. The bleed sites recorded were joints (271 bleeds [53%], including 55 in target joints [20.2% of joint bleeds]), muscle (78, 15%), mucosal (45, 9%), intracranial (25, 5%), and subcutaneous (21, 4%). Joint bleeds occurred primarily in the ankles (124 bleeds), elbows (61 bleeds) and knees (53 bleeds).For 508 bleeds treated with a single dose of rFVIIa, the mean (median, range) dose was 119.5 mcg/kg (100, 25–500) with 20 of those doses ≥270 mcg/kg. Patients with joint bleeds were treated with 123.1 mcg/kg (100, 25–500), target joint bleeds with 155.3 (140, 50–393), and those with the muscle bleeds received 120.1 mcg/kg (100, 50–500). The most common single dose regimen overall and for the joint and muscle bleeds was 90 mcg/kg rFVIIa.The majority of bleeds (424, 82.7%) were treated at home, but bleeds were also treated at Hemophilia Treatment Centers (61, 12.0%) and in the emergency room (15, 3.0%). Overall, physician reported “bleeding stopped” in 97% of the 494 bleeds, 97% of hemarthroses, 96% of target joint hemarthroses and 96% of muscle bleeds. For the remaining 14 episodes, although documentation did not indicate “bleeding stopped”, no other medications were recorded.There were no serious adverse drug reactions.Registry data can only demonstrate the treatment reported in selected bleeds captured, and the analysis here specifically examined bleeds treated with only a single dose either because of bleed resolution or by physician/patient choice. The data analyzed here demonstrate single doses of rFVIIa of up to 500 mcg/kg (mean 119 mcg/kg) for mild to moderate bleeds effectively resolved bleeds in 97%, including hemarthrosis, target joints hemarthrosis, and muscle bleeds. These data support the possibility that rFVIIa can be administered in a single bolus dose with equivalent or superior efficacy as multiple lower doses for bleeding episodes treated as part of a home therapy regimen. While 3 randomized trials have examined the equivalence of a single dose of 270 mcg/kg with 3 doses of 90 mcg/kg, these data suggest that single doses of rFVIIa therapy in the real world often were empirically titrated on a patient specific basis, according to the severity and site of the bleeding episode. These registry data provide justification for prospective, randomized, single dose titration trials of rFVIIa or future analogues.

Use of rFVIIa in Individuals with Congenital Hemophilia B Complicated by Alloantibody Inhibitors to Factor IX: Analysis of Data Capture from the Hemophilia and Thrombosis Research Society (HTRS) Registry (2004–2008)

Congential hemophilia B (HemB) is one fifth as common as hemophilia A. The development of inhibitors in Hem B is also less common (3–5%) than observed with hemophilia A and is associated with the absence of factor IX (FIX) antigen caused by large or complete deletions or major derangements of the FIX gene. These mutations have been linked to severe anaphylactic reactions upon re-exposure to factor IX (FIX). This has compromised attempts at immune tolerance induction with FIX products and has also been associated with the onset of nephrotic syndrome. The presence of FIX within activated prothrombin complex concentrates, precludes the use of these agents in this unique patient population. Thus, patients with HemB and inhibitors (HemBwI) are managed with recombinant VIIa (rVIIa, NovoSeven®), some for close to a decade since its original FDA approval. The rFVIIa dosing typically used is less well understood, as is the relationship between anaphylaxis to FIX exposure and rFVIIa dosing.The HTRS registry records data regarding the treatment of acute bleeding episodes in those with hemophilia A or B and related hemorrhagic disorders, with focus on congenital hemophilia complicated by inhibitors. From data collected between January 2004 and March 2008, all patients with HemBwI that were treated at least in part with rFVIIa for acute bleeds were examined for their initial and total dose, number of doses, and number of days on rFVIIa therapy. Due to significant outlier bleeds, median values and interquartile ranges (IQR) are reported for many parameters.There were 287 patients with HemB and 33 with HemBwI. Of over 2,532 bleeds treated with rFVIIa, 353 bleeds were reported in 12 individuals with HemBwI treated with 4,254 doses of rFVIIa. One patient had 102 bleeds recorded. The mean age was 13.2 years (range 0.6–55.9 years). Mean titers of anti-FIX alloantibodies were 11.8 BU (median, 4.3; range, 0–55.5).Bleeding SitesN (%)Treatment LocationN (%)Joint234 (66%)Home306 (87%)Target joint70 (20%)Hospital, inpatient25 (7%)Muscle67 (19%)Hospital, ER8 (2%)Mucosal12 (3%)HTC8 (2%)Subcutaneous11 (3%)Head4 (1%)Bleeding TypeN (%)Spontaneous243 (69%)Traumatic84 (24%)Mean (Median)IQRRangeTotal dose (mcg/kg)1,514 (720)360–160054–43,200Initial dose (mcg/kg)142.8 (120)99–18053–400# Doses12 (6)3–111–480JointTarget JointMuscleInitial dose - mean (median)145.1 (120)121.6 (120)143.9 (120)Total dose - mean (median)1306 (840)953 (840)2510 (480)Overall efficacy as assessed by physician report of “bleeding stopped” was 82% (joint, 84%; target joint, 91%; muscle, 73%). Most other bleeds were categorized as “bleeding slowed” (53 of 62, 18%) and “no improvement” (9 of 53, 3%), however none of those patients switched medications and treatment was self-limited suggesting all patients ultimately had resolution of their bleeds. There were 44 single dose treatments including 31 joint bleeds. Mean (median, range) dose was 142.8 mcg/kg (120, 53–400). Physicians reported “bleeding stopped” in 43 (98%).There were no serious adverse drug reactions or thromboembolic events related to rFVIIa associated with the bleeding episodes analyzed.While registries admittedly only capture those data reported in a selected and potentially biased manner, the 2004–2008 data from HTRS provide the largest single source of data on the real world dosing, safety and efficacy of rFVIIa in HemBwI in a predominantly home setting. Dosing was similar between joint, target joint and muscle bleeds, and similar to reported dosing in HemAwI. Clinical efficacy appeared greatest for target joint bleeds, although no patients switched to other medications to control bleeding. Further analysis on HemBwI patients to assess differences in dosing for patients with history of anaphylactic responses to FIX will be important to understand this patient group better.

Use of Higher Doses of rFVIIa in Individuals with Congenital Hemophilia Complicated by Alloantibody Inhibitors: Analysis of Data Capture from the Hemophilia and Thrombosis Research Society (HTRS) Registry (2004–2008)

In 1999, recombinant factor VIIa (rFVIIa, NovoSeven®) received FDA approval with recommended dosing of 90 mcg/kg every 2 hours. Individual case reports and small series have described the use of rFVIIa at doses ≥ 270 mcg/kg and 3 randomized trials have suggested that one bolus dose of rFVIIa at 270 mcg/kg provides equivalent efficacy and safety when compared to the conventional regimen of three doses of 90 mcg/kg over 6 hrs. The extent to which higher doses of rFVIIa have been used in clinical practice in the US is unknown.The HTRS registry records data regarding the treatment of acute bleeding episodes in those with hemophilia A or B and related hemorrhagic disorders with special emphasis on outcomes in individuals with congenital hemophilia complicated by alloantibody inhibitors; From over 5,000 evaluable bleeding episodes reported between January 2004 and March 2008, all episodes treated with at least one dose of ≥ 250 mcg/kg rFVIIa were examined for their initial and total dose, number of doses, and number of days on rFVIIa therapy. The efficacy of two treatment regimens was assessed:an initial high dose ≥250 mcg/kg followed by “as needed” lower doses; some of these only required a single high dose; andinitial smaller doses of rFVIIa or aPCC followed by a≥250 mcg/kg dose for salvage.Of 2,532 bleeds treated with rFVIIa, 153 bleeds treated with at least one dose ≥ 250 mcg/kg were reported in 21 individuals with either congenital hemophilia A (n=17) or B (n=4) with alloantibody inhibitors. These 153 bleeding episodes required 1642 doses of rFVIIa of which 358 doses were ≥ 250 mcg/kg. The mean patient age was 12.6 years (0.9– 41.7 years). Mean titers of anti-FVIII and anti-FIX alloantibodies were 104.6 BU (0–683) and 0.9 BU (0–5.6), respectively. Bleed sites were in joints (102 bleeds, 67%), muscles (31 bleeds, 20%), mucosal surfaces (7 bleeds, 5%), and subcutaneous areas (6 bleeds, 4%). Bleeds were treated mainly in the home (78%).Of 153 bleeding episodes treated with at least one dose ≥ 250 mcg/kg rFVIIa, 80 had at least one dose ≥ 270 mcg/kg, and 49 had at least one dose ≥ 300 mcg/kg. For the whole group, mean (median, range) total dose was 1835 (867, 250–27323) mcg/kg with 10.4 (4, 1–201) doses over 3.8 (2.0, 1–79) days. Half of the doses received for these bleeds were ≥ 250 mcg/kg, and 79.1% had an initial dose of ≥ 250 mcg/kg. For those receiving a dose of ≥250 mcg/kg, there were 14.5 (4, 1–157) doses prior to the dose of ≥ 250 mcg/kg. Efficacy was 90% in 147 bleeds where rFVIIa was used as primary treatment and 100% in 6 bleeds where rFVIIa was used after a mean 154 U/kg (2.0 doses) of aPCC. Efficacy was 90% for joint bleeds and 94% for muscle bleeds. There were 15 episodes of presumed efficacy where documentation did not indicate bleeding stopped, but no other medications were recorded, resulting in adjusted overall efficacy of 100%.There were 9 patients with 23 bleeding episodes treated with a single dose of ≥ 250 mcg/kg, including mostly joint bleeds (10 spontaneous, 7 traumatic), and mostly home treatment (21). Dosing was 307 ± 62.1 (300, 250–500) mcg/kg and in 91% physicians reported “bleeding stopped” (remaining 2 had no other doses or medications). Cumulative exposure in this group was 157 doses of 250–269 mcg/kg, 70 doses of 270–299 mcg/kg, and 131 of 300–500 mcg/kg. There were no serious adverse drug related events or thrombotic complications reported after treatment of these bleeding episodes.The 2004–2008 data from HTRS provides the largest single source of data on the safety and efficacy of higher doses of rFVIIa administered to reverse moderate to severe bleeds in a broad cohort of inhibitor patients with hemophilia. Efficacy was consistent for both intra-articular or muscle bleeds in a home setting and rFVIIa was an effective single hemostatic agent in this context so the administration of additional replacement products was unnecessary. Importantly, rFVIIa ≥250 mcg/kg was not associated with any serious adverse drug reactions or thrombogenicity. These data support the feasibility of an initial high dose of rFVIIa for treatment of bleeds in inhibitor patients and justifies the conduct of a prospective, randomized clinical trial to confirm these observations.