Individual thrombin generation and spontaneous bleeding rate during personalized prophylaxis with Nuwiq® (human-cl rhFVIII) in previously treated patients with severe haemophilia A.

INTRODUCTION: For individuals with haemophilia A, prophylaxis with factor VIII (FVIII) is typically directed towards trough activity >1 IU/dL; however, some patients still experience spontaneous bleeding events (sBEs). AIM: Aims were to evaluate relationships of endogenous thrombin potential (ETP) and FVIII:C with occurrence of clinical bleeding. METHODS: GENA-21 was a prospective, open-label, phase IIIb study investigating the safety and efficacy of Nuwiq® (human-cl rhFVIII) in previously treated adults with severe haemophilia A. The study included a 72-hour pharmacokinetic (PK) evaluation phase and a 6-month personalized prophylaxis phase in which treatment was guided by PK parameters. This subanalysis assessed FVIII:C by one-stage assay and ETP by thrombin generation assay in blood samples. RESULTS: Baseline mean ETP was lower in the 7 patients who experienced sBEs during personalized prophylaxis versus 25 who did not (n = 32 with data from PK phase and prophylaxis phase; P = .0002). During personalized prophylaxis (n = 49), only patients with lower median trough ETP experienced sBEs (8/49 patients; ROC AUC = 0.9421; P < .0001); there was no significant relationship for FVIII:C in predicting sBEs (ROC AUC = 0.5838; P = .4750). Directly following infusion of human-cl rhFVIII, ETP was lower in patients who experienced sBEs versus those who did not (P = .0002), whereas FVIII:C did not differ significantly between these groups. CONCLUSIONS: In adults with severe haemophilia A and reduced thrombin generation, increased frequency of spontaneous bleeding was observed irrespective of trough FVIII levels. Thus, personalized prophylaxis should take into account variables other than FVIII:C. Large prospective trials are needed to verify ETP as a marker for spontaneous bleeding.

Fifth Åland Island conference on von Willebrand disease.

The fifth Åland Island meeting on von Willebrand disease (VWD) was held on the Åland Islands, Finland, from 22 to 24 September 2016-90 years after the first case of VWD was diagnosed in a patient from the Åland Islands in 1926. This meeting brought together experts in the field of VWD to share knowledge and expertise on current trends and challenges in VWD. Topics included the storage and release of von Willebrand factor (VWF), epidemiology and diagnostics in VWD, treatment of VWD, angiogenesis and VWF inhibitors.

PK-guided personalized prophylaxis with Nuwiq® (human-cl rhFVIII) in adults with severe haemophilia A.

INTRODUCTION: Nuwiq® (human-cl rhFVIII) is a 4th generation recombinant human FVIII, without chemical modification or protein fusion, produced in a human cell-line. AIMS/METHODS: This study (NuPreviq) was a prospective, open-label, multicentre, phase IIIb study of the efficacy and safety of personalized prophylaxis with Nuwiq® in 66 previously treated adults with severe haemophilia A. NuPreviq had three phases: (i) a 72-h pharmacokinetic (PK) phase; (ii) a 1-3 month standard prophylaxis phase; and (iii) a 6-month personalized prophylaxis phase. The personalized prophylaxis regimen was based on individual PK modelling for each patient according to whether their PK profile most closely fitted a two- or one-compartment model (NuPreviq approach). In cases of uncertainty, a noncompartment model was applied. RESULTS: The median dosing interval during personalized prophylaxis was 3.5 days, with 57% of patients on ≤2 weekly dosing. Mean annualized bleeding rates during personalized prophylaxis were 1.45 (median [interquartile range, IQR]: 0 [0, 1.9]) for all bleeds, 0.79 (median [IQR]: 0 [0, 0]) for spontaneous bleeds, and 0.91 (median [IQR]: 0 [0, 0]) for joint bleeds. During personalized prophylaxis, 83.1% of patients were spontaneous bleed-free. Compared with standard prophylaxis, median weekly prophylaxis dose was reduced by 7.2% from 100.0 to 92.8 IU kg-1 during the last 2 months of personalized prophylaxis. There were no FVIII inhibitors or treatment-related serious or severe adverse events. CONCLUSION: PK-guided personalized prophylaxis with Nuwiq® provided bleeding protection and enabled the dosing interval to be extended to twice weekly or less in many patients and an overall dose reduction.

Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series.

BACKGROUND: Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development. METHODS: We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch). RESULTS: We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5-135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases. CONCLUSIONS: By studying the largest cohort of inhibitor development in PTPs assembled to date, we showed that inhibitor development in PTPs, is on average, a milder event than in PUPs.

Practical aspects of factor concentrate use in patients with von Willebrand disease undergoing invasive procedures: a European survey.

INTRODUCTION: The bleeding propensity in von Willebrand disease (VWD) is usually moderate or mild and patients with VWD do not need continuous treatment, but do require extra increased haemostatic cover when undergoing dental or surgical procedures. Desmopressin can be effective in certain patient groups and this has been considered in a previous publication. AIM: This paper now seeks to evaluate current knowledge and practice in the use of factor concentrate in the management of VWD patients undergoing invasive procedures. METHODS: A literature search was performed on the use of factor concentrates to cover invasive procedures and a survey of current practice in a number of specialist haematology centres across Europe represented by the European Haemophilia Strategy Board was conducted. RESULTS: Our review of the literature and the results of the survey showed considerable heterogeneity in treatment regimens, and a lack of consistency in reporting of the variables that determine factor concentrate dosing and monitoring. CONCLUSION: By analysing the literature, examining guidelines and using consensus deliberation, this survey allowed the group to develop recommendations for management of VWD patients undergoing invasive procedures.

Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme.

INTRODUCTION: BAY 81-8973 is a recombinant factor VIII (rFVIII) with the same amino acid sequence as Bayer's sucrose-formulated rFVIII (rFVIII-FS) but manufactured with certain more advanced technologies. AIM: To describe surgery outcomes with BAY 81-8973 in the LEOPOLD trials. METHODS: Male patients with severe haemophilia A and no inhibitors aged 12-65 years with ≥150 exposure days (EDs) to FVIII (LEOPOLD I and II), or aged ≤12 years with ≥50 EDs to FVIII (LEOPOLD Kids), received BAY 81-8973 based on dosing recommendations for rFVIII-FS according to surgical requirements. Haemostasis-related complications, investigator/surgeon assessment of haemostasis, blood loss, need for transfusion and use of BAY 81-8973 were determined. RESULTS: In LEOPOLD I and II, 11 patients (mean age, 35.3 years) underwent 13 major surgeries. In LEOPOLD Kids, one patient (aged 6 years) underwent one major surgery. Thirty-two adult and paediatric patients underwent 46 minor surgeries. Haemostasis was rated good or excellent in all major and minor surgeries. Blood loss during surgery did not exceed expected amounts; blood transfusions were required in three of the 14 major surgeries. For major surgeries in LEOPOLD I and II, patients received a presurgical 50-IU kg(-1) dose of BAY 81-8973; median nominal dose on day of surgery was 7000 IU (107.5 IU kg(-1) ). Total BAY 81-8973 dose was 2500 IU (108.7 IU kg(-1) ) on the day of the only major surgery in LEOPOLD Kids. No haemostasis-related complications were reported. CONCLUSIONS: Haemostatic control with BAY 81-8973 during all surgeries in the LEOPOLD trials was good or excellent, with no haemostasis-related complications.

Practical aspects of DDAVP use in patients with von Willebrand Disease undergoing invasive procedures: a European survey.

INTRODUCTION: Desamino D-arginine vasopressin (DDAVP or desmopressin) is a useful and effective haemostatic treatment for patients with von Willebrand Disease (VWD). However, there are still issues regarding in which subtypes of VWD DDAVP is appropriate and little consensus on its use in different surgical settings. We also lack information concerning the appropriate laboratory parameters that should be monitored. AIM: The European Haemophilia Therapy Strategy Board (EHTSB) wished to investigate published information and clinical use of DDAVP in VWD patients. METHODS: We conducted a literature survey on management of VWD during surgical interventions and undertook a survey of specialist haematologist centres across Europe to assess current management of VWD patients. RESULTS: DDAVP is ineffective in type 3 VWD and its use in type 2B remains controversial due to the possibility of thrombocytopenia. It can, however, be used effectively to cover minor surgery and dental procedures in most other VWD patients. For major surgery there is wider use of factor concentrate in preference to DDAVP depending on the subtype of VWD. We give consensus recommendations on the use of DDAVP for surgical interventions in VWD including laboratory parameters that denote an adequate response and contraindications to its use. CONCLUSIONS: DDAVP can be recommended to cover invasive procedure in selected patients with VWD, however, we need more information and systematic recording of adverse events associated with DDAVP use in VWD. A companion paper will be published covering the use of factor concentrates in VWD patients.

Correlation between endogenous VWF:Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three-times-weekly prophylaxis with rFVIII-FS.

Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg(-1)) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII-FS; 25 IU kg(-1)). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13-64 years; BAY 79-4980, n = 63; rFVIII-FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUC(norm) and T1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII-FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.

Improvement in health-related quality of life with recombinant factor IX prophylaxis in severe or moderately severe haemophilia B patients: results from the BAX326 Pivotal Study.

Little is known about the health-related quality of life (HRQoL) burden of haemophilia B. The aim of this study was to assess HRQoL burden of haemophilia B, the benefit of recombinant factor IX (rFIX) prophylaxis and the HRQoL benefit of achieving a zero annual bleed rate. Subjects receiving rFIX (BAX326) prophylaxis or on-demand completed the SF-36 survey. Baseline SF-36 scores were compared to the general US population scores to understand the HRQoL burden. Changes in SF-36 scores between baseline and follow-up were tested using t-tests. Subgroup analysis was conducted to examine SF-36 change among subjects who switched to BAX326 prophylaxis. SF-36 scores were also compared between those with zero bleeds and those who bled during the study. Compared to the US norms, subjects reported lower average scores in all physical and several mental HRQoL domains. At follow-up, prophylaxis subjects reported statistically significant and clinically meaningful improvements in overall physical HRQoL, as measured by the Physical Component Score (PCS) (mean change 2.60, P = 0.019), Bodily Pain (BP) (3.45, P = 0.015) and Role Physical (RP) domains (3.47, P = 0.016). Subjects who switched to prophylaxis from intermittent prophylaxis or on-demand experienced more pronounced improvements not only in the PCS (3.21, P = 0.014), BP (3.71, P = 0.026), RP (4.43, P = 0.008) but also in Vitality (3.71, P = 0.04), Social Functioning (5.06, P = 0.002) and General Health domains (3.40, P = 0.009). Subjects achieving zero bleeds reported lower BP (P = 0.038). Prophylaxis with BAX326 significantly improved HRQoL in patients with moderately severe or severe haemophilia B by reducing bleeds.

Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study.

Haemostatic management of haemophilia B patients undergoing surgery is critical to patient safety. The aim of this ongoing prospective trial was to investigate the haemostatic efficacy and safety of a recombinant factor IX (rFIX) (Bax326) in previously treated subjects (12-65 years, without history of FIX inhibitors) with severe or moderately severe haemophilia B, undergoing surgical, dental or other invasive procedures. Haemostatic efficacy was assessed according to a predefined scale. Blood loss was compared to the average and maximum blood loss predicted preoperatively. Haemostatic FIX levels were achieved peri- and postoperatively in 100% of subjects (n = 14). Haemostasis was 'excellent' intraoperatively in all patients and postoperatively in those without a drain, and 'excellent' or 'good' at the time of drain removal and day of discharge in those with a drain employed. Following the initial dose, the mean FIX activity level rose from 6.55% to 107.58% for major surgeries and from 3.60% to 81.4% for minor surgeries. Actual vs. predicted blood loss matched predicted intraoperative blood loss but was equal to or higher than (but less than 150%) the maximum predicted postoperative blood loss reflecting the severity of procedure and FIX requirements. There were no related adverse events, severe allergic reactions or thrombotic events. There was no evidence that BAX326 increased the risk of inhibitor or binding antibody development to FIX. BAX326 was safe and effective for peri-operative management of 14 subjects with severe and moderately severe haemophilia B.

Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B.

BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12-65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC(0-72) h per dose. Twice-weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg(-1) per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.

Management of factor VII-deficient patients undergoing joint surgeries--preliminary results of locally developed treatment regimen.

Inherited factor VII (FVII) deficiency is a rare coagulation disorder with variable haemorrhagic manifestations. In severely affected cases spontaneous haemarthroses leading to advanced arthropathy have been observed. Such cases may require surgery. Therapeutic options for bleeding prevention in FVII deficient patients undergoing surgery comprise various FVII preparations but the use of recombinant activated factor VII (rFVIIa) seems to be the treatment of choice. To present the outcome of orthopaedic surgery under haemostatic coverage of rFVIIa administered according to the locally established treatment regimen in five adult patients with FVII baseline plasma levels below 10 IU dL(-1). Two patients required total hip replacement (THR); three had various arthroscopic procedures. Recombinant activated factor VII was administered every 8 h on day of surgery (D0) followed by every 12-24 h for the subsequent 9-14 days, depending on the type of surgery. Factor VII plasma coagulation activity (FVII:C) was determined daily with no predefined therapeutic target levels. Doses of rFVIIa on D0 ranged from 18 to 37 µg kg(-1) b.w. and on the subsequent days--from 13 to 30 µg kg(-1) b.w. Total rFVIIa dose per procedure ranged from 16 to 37.5 mg, and the total number of doses per procedure was 16-31. None of our patients developed excessive bleeding including those in whom FVII:C trough levels returned nearly to the baseline level on the first post-op day. Preliminary results demonstrate that rFVIIa administered according to our treatment regimen is an effective and safe haemostatic agent for hypoproconvertinaemia patients undergoing orthopaedic surgery.

Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study.

Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF)-36 Health Survey and the EQ-5D questionnaire in subjects ≥ 14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing ≥ 50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role - physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment.

Recommendations for assessment, monitoring and follow-up of patients with haemophilia.

Over the last few decades, clinical follow-up of patients with haemophilia has become more complex as a result of the introduction of new treatment strategies, the presence of comorbidities related to haemophilia or ageing, as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia. This publication describes the parameters and information that should be documented and the tests, examinations and interventions required for optimal follow-up of a patient with haemophilia. In the absence of formal studies, the present recommendations have been established as result of a series of consensus meetings in the frame of the European Haemophilia Therapy Standardization Board (EHTSB). The following 11 domains were identified: Baseline information, Current status, Treatment, Inhibitor status, Bleeding, Joint status and pain, Comorbidities, Dental care, Physical activities, Social participation and Quality of life. For each domain, details are proposed for the relevant parameters to be captured and monitored as well as the relevant tools that facilitate data collection. Adopting these recommendations should help the individual care of patients and, even though this is not the primary objective of this article, it should also help at national and international level to shape a new approach to haemophilia by working towards a more standardized outcome assessment. Greater standardization should have implications for data collection, improvements in treatment evaluation and optimizing resources.

von Willebrand's disease: a report from a meeting in the Åland islands.

von Willebrand's disease (VWD) is probably the most common bleeding disorder, with some studies indicating that up to 1% of the population may have the condition. Over recent years interest in VWD has fallen compared to that of haemophilia, partly the result of focus on blood-borne diseases such as HIV and hepatitis. Now the time has come to revisit VWD, and in view of this some 60 international physicians with clinical and scientific interest in VWD met over 4 days in 2010 in the Åland islands to discuss state-of-the-art issues in the disease. The Åland islands are where Erik von Willebrand had first observed a bleeding disorder in a number of members of a family from Föglö, and 2010 was also the 140th anniversary of his birth. This report summarizes the main papers presented at the symposium; topics ranged from genetics and biochemistry through to classification of VWD, pharmacokinetics and laboratory assays used in the diagnosis of the disease, inhibitors, treatment guidelines in different age groups including the elderly who often have comorbid conditions that present challenges, and prophylaxis. Other topics included managing surgeries in patients with VWD and the role of FVIII in VWF replacement, a controversial subject.

Registry of inherited bleeding disorders in Poland--current status and potential role of the HemoRec database.

We present data collected in HemoRec, an Internet-based platform implemented in 2006 in 15 haemophilia treatment centres in Poland and compare them with the national registry of inherited bleeding disorders established since 1991 at the Institute of Haematology and Blood Transfusion in Warsaw. We also analyse the current status of haemophilia treatment in Poland as well as future perspectives. Data on 1102 patients registered in HemoRec were analysed and compared with 4294 patients in the national registry (status as at 17.08.2009). The number of patients with severe haemophilia, mild/moderate haemophilia and von Willebrand in HemoRec is 530, 328 and 54 (respectively), compared with 1199, 1167 and 1128 in the national registry. The mean age of all haemophilic patients registered in HemoRec is 26.2 years, compared with 37.3 years in the general Polish male population in 2008. The number of haemophilic patients with inhibitor registered in HemoRec is 102 compared with 155 in the national registry (resulting in a prevalence of 14.9% of all severe haemophilia A and 1.6% of all severe haemophilia B patients). HemoRec includes data on a representative group of Polish haemophilic patients, mostly with haemophilia and haemophilia with inhibitor. von Willebrand's disease is largely under-registered in Poland. The survival of Polish haemophilic patients is shorter than that in the general population. The number of inhibitor patients in Poland is relatively large and should be decreased by wider availability of immunotolerance induction in 2010.

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies.

Nonafact(®), an ultrapure, monoclonal antibody-purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half-life, in vivo response and recovery of Nonafact(®) were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL(-1) per IU kg(-1) b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high-risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow-up study, 26 previously treated patients (PTP) were included with a median follow-up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow-up studies the investigators rated the effect of Nonafact(®) as excellent/good in 95% of major bleedings. Surgeries for which Nonafact(®) was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact(®) were used during almost 120 person-years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact(®) is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact(®) is cost saving compared to other FIX products.

BDDrFVIII (Moroctocog alfa [AF-CC]) for surgical haemostasis in patients with haemophilia A: results of a pivotal study.

SUMMARY: Moroctocog alfa (AF-CC) (Xyntha, BDDrFVIII) is manufactured by a process designed to enhance the theoretical viral safety profile relative to ReFacto, its predecessor, and to provide alignment with clinical monitoring by the one-stage clotting assay. To evaluate the efficacy and safety of B-domain-deleted recombinant factor VIII (BDDrFVIII) was given as bolus injection (BI) or continuous infusion (CI) in haemophilia patients undergoing major surgery. BDDrFVIII was administered by BI or CI per investigator discretion peri-operatively for at least 6 days. Thirty patients enrolled and were treated with at least one dose of BDDrFVIII. Twenty-five patients were evaluable for efficacy. Outcomes were favourable against a background of multiple major surgical procedures. All haemostatic efficacy ratings were 'excellent' or 'good'. End-of-surgery haemostasis ratings, the primary efficacy endpoint, were excellent for 72% (18/25) and good for 28% (7/25) of patients. Haemostasis ratings following the initial postoperative period were excellent for 92% (23/25) and good for 8% (2/25) of patients. Intra-operative blood loss was rated as normal in all patients. Thirteen patients had postoperative blood loss; in 10, this was rated as normal. A low frequency of transfusion was reported in both the intra-operative and postoperative settings. Adverse events (AEs) were consistent with surgery; three were considered related to BDDrFVIII. One patient had a related AE of postoperative haemorrhage. A clinically silent low-titre inhibitor was detected in one patient, and one patient had a false-positive inhibitor titre. This study demonstrates that BDDrFVIII is safe and efficacious for surgical prophylaxis in haemophilia A patients undergoing major surgery.

Modulation of factor VIII-specific memory B cells.

The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in patients with haemophilia A who are treated with FVIII products. Memory B cells play an essential role in maintaining established antibody responses. Upon re-exposure to the same antigen, they are rapidly re-stimulated to proliferate and differentiate into antibody-secreting plasma cells (ASC) that secrete high-affinity antibodies. It is, therefore, reasonable to believe that memory B cells have to be eradicated or inactivated for immune tolerance induction therapy to be successful in patients with haemophilia A and FVIII inhibitors. The aim of our studies was the development of strategies to prevent FVIII-specific memory B cells from becoming re-stimulated. We established a 6-day in vitro culture system that enabled us to study the regulation of FVIII-specific murine memory-B-cell re-stimulation. We tested the impact of the blockade of co-stimulatory interactions, of different concentrations of FVIII and of ligands for toll-like receptors (TLR). The blockade of B7-CD28 and CD40-CD40 ligand interactions prevented FVIII-specific murine memory B cells from becoming re-stimulated by FVIII in vitro and in vivo. Furthermore, high concentrations of FVIII blocked re-stimulation of FVIII-specific murine memory B cells. Triggering of TLR7 amplified re-stimulation by low concentrations of FVIII and prevented blockade by high concentrations of FVIII. We conclude that we defined modulators that either amplify or inhibit the re-stimulation of FVIII-specific murine memory B cells. Currently, we are investigating whether the same modulators operate in patients with haemophilia A and FVIII inhibitors.