International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Haemophilia-A Critical Appraisal.

Introduction: Evidence-based clinical practice guidelines drive optimal patient care and facilitate access to high-quality treatment. Creating guidelines for rare diseases such as haemophilia, where evidence does not often come from randomized controlled trials but from non-randomized and well-designed observational studies and real-world data, is challenging. The methodology used for assessing available evidence should consider this critical fact.

Expert Opinion for Defining a Severe Bleeding Phenotype to Guide Prophylaxis in Patients with Nonsevere Hemophilia.

Prophylaxis is the standard of care for patients with severe hemophilia, patients with moderate hemophilia, or those with another congenital bleeding disorder that is associated with a severe bleeding phenotype and/or a high risk of spontaneous life-threatening bleeding. Patients with nonsevere hemophilia (factor VIII [FVIII] ≥ 1%) may also have a bleeding phenotype that requires prophylaxis. To date, however, there are no clear criteria as to when prophylaxis is indicated in these patients.

Pharmacokinetic model-based assessment of factor IX prophylaxis treatment regimens in severe hemophilia B.

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed.

Reduced Volume and Faster Infusion Rate of Activated Prothrombin Complex Concentrate: A Phase 3b/4 Trial in Adults with Hemophilia A with Inhibitors.

 Activated prothrombin complex concentrate (aPCC) is indicated for bleed treatment and prevention in patients with hemophilia with inhibitors. The safety and tolerability of intravenous aPCC at a reduced volume and faster infusion rates were evaluated.  This multicenter, open-label trial (NCT02764489) enrolled adults with hemophilia A with inhibitors.

florio HAEMO: A Longitudinal Survey of Patient Preference, Adherence and Wearable Functionality in Central Europe.

Introduction: florio HAEMO is a hemophilia treatment monitoring application (app) offering activity tracking and wearable device connectivity. Its use might support everyday activities for people with hemophilia. The aim of this study was to evaluate user satisfaction, long-term usage and the impact on data entry when pairing a wearable with a hemophilia monitoring app.

Measurement of recombinant porcine factor VIII in patients with congenital haemophilia A and inhibitors in the presence of emicizumab.

Introduction: Recombinant porcine factor VIII (rpFVIII) is a treatment option for break-through bleeds in patients with congenital haemophilia A with inhibitors (CHAwI) on emicizumab. However, there are limited data about the measurement of rpFVIII in the presence of emicizumab.

Aim: To analyse whether rpFVIII can be measured with a chromogenic assay with bovine component (bCSA) in plasma from CHAwI on emicizumab treatment.

Real-world data in patients with congenital hemophilia and inhibitors: final data from the FEIBA Global Outcome (FEIBA GO) study.

Background: The bypassing agent, activated prothrombin complex concentrate [aPCC, FEIBA (factor VIII inhibitor bypass activity); Baxalta US Inc, a Takeda company, Lexington, MA, USA], is indicated for the treatment of bleeding episodes, perioperative management, and routine prophylaxis in patients with hemophilia A or B with inhibitors. In certain countries, aPCC is also indicated for the treatment of bleeding episodes and perioperative management in patients with acquired hemophilia A.

Objectives: To describe long-term, real-world effectiveness, safety, and quality-of-life outcomes for patients with congenital hemophilia A or B and high-responding inhibitors receiving aPCC treatment in routine clinical practice.

octanate: over 20 years of clinical experience in overcoming challenges in haemophilia A treatment.

Treatment of haemophilia A with FVIII replacement has evolved over the past decades to adapt to the needs of patients. octanate®, a plasma-derived, double virus-inactivated, von Willebrand factor (VWF)-containing FVIII concentrate, has been used in clinics worldwide for over 20 years. First licensed in 1998 in Germany, octanate® is approved in over 80 countries for the prevention and treatment of bleeding and for surgical prophylaxis in patients with haemophilia A, and in over 40 countries for immune tolerance induction (ITI).

New findings on inhibitor development: from registries to clinical studies.

The high incidence of inhibitors against factor VIII (FVIII) concentrates in patients with haemophilia A has encouraged debate as to whether product-type plays a role. There is debate in the literature as to whether rFVIII concentrates are associated with a higher incidence of inhibitors compared to pdFVIII products. The management of haemophilia in patients with inhibitors includes on-demand/prophylaxis treatment with bypassing agents, and/or immune tolerance induction (ITI).

Spotlight on the human factor: building a foundation for the future of haemophilia A management: report from a symposium on human recombinant FVIII at the World Federation of Hemophilia World Congress, Melbourne, Australia on 12 May 2014.

Inhibitor development is the most serious and challenging complication in the treatment of severe haemophilia A. Up to 38% of such patients develop inhibitors with current recombinant factor VIII (rFVIII) products produced in hamster cell lines. Human-cl rhFVIII is a new generation fully sulfated B-domain-deleted FVIII coagulant glycoprotein, which is generated from a human cell line.

Inhibitors in patients with haemophilia A.

Inhibitor development is the most problematic and costly complication of haemophilia treatment. Inhibitor development depends on a complex multifactorial immune response that is influenced by patient- and treatment-related factors. Considerable research is focussed on inhibitor development as well as the mechanism of eradication through immune tolerance induction (ITI).

Influence of factor 5 rs6025 and factor 2 rs1799963 mutation on inhibitor development in patients with hemophilia A--an Israeli-German multicenter database study.

Objective: The present cohort study was performed to investigate the impact of the factor 5 rs6025 [F5] and the factor 2 rs1799963 [F2] mutations on high-titer inhibitor development [HRI] in patients with severe/moderate-severe hemophilia A [HA].

Patients And Methods: 216 patients with F8<2% born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. The first HA patient per family who presented for diagnosis was included in the present study.

The immune tolerance induction (ITI) dose debate: does the International ITI Study provide a clearer picture?

Among the proposed predictors for immune tolerance induction (ITI) outcome, the therapeutic regimen - specifically the dose and frequency of administered factor VIII (FVIII) as well as FVIII product type - is intensely debated. Are there any advantages for low-dose regimens (50 IU FVIII kg(-1) three times a week) over high-dose regimens (200 IU FVIII kg day(-1)) or vice versa? Are von Willebrand factor (VWF)-containing plasma-derived concentrates superior to recombinant FVIII concentrates for tolerance induction? A review of the available literature indicates that patients with good prognostic factors can achieve success with either low-dose or high-dose ITI regimens. Retrospective data suggest that patient characteristics such as maximum historical inhibitor titres and pre-ITI inhibitor titres are better predictors of treatment success than dose.

Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review.

Background: Different rates of inhibitor development after either plasma-derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature.

Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics.

Early long-term FEIBA prophylaxis in haemophilia A patients with inhibitor after failing immune tolerance induction: A prospective clinical case series.

Persistent high-titre inhibitors after immune tolerance induction (ITI) increase the risks of haemorrhage and arthropathy, resulting in high morbidity and mortality. Long-term prophylaxis with bypassing agents may avert these risks. This study was performed to assess the effectiveness and safety of early prophylaxis with FEIBA in preventing bleeding and joint damage after failed ITI.

Effects of the factor V G1691A mutation and the factor II G20210A variant on the clinical expression of severe hemophilia A in children--results of a multicenter studys.

The present multicenter cohort study of 107 pediatric PUPs was performed to determine whether the concomitant inheritance of the factor (F) V G1691A or the F II G20210A mutation influences the clinical expression of severe hemophilia A (HA). Carriers of the FV and FII mutations had a significantly lower annual bleeding frequency (ABF) than non-carriers (p=0.012).

Recombinant vs. plasma-derived products, especially those with intact VWF, regarding inhibitor development.

The development of inhibitors in previously untreated patients (PUPs) with haemophilia A is correlated with a variety of endogenous and exogenous risk factors. It is still controversial whether recombinant factor VIII (rFVIII) products pose a higher risk for inhibitor development than plasma-derived (pd) FVIII concentrates, particularly with intact von Willebrand factor (VWF). A systematic review on the epidemiology of inhibitors in haemophilia A investigated the influence of different FVIII products on inhibitor formation.

Role of von Willebrand factor in immune tolerance induction.

Patients with hemophilia who develop inhibitors present a particular challenge in therapeutic management. Although such patients are at high risk for severe bleeding episodes, the optimal treatment approach--prophylaxis--is ineffective unless inhibitors are eliminated. Several protocols for immune tolerance induction have been used.

Long-term aspects of hemophilia B treatment: part I-role for prophylaxis.

This paper reviews hemophilia prophylaxis in terms of patient selection for this approach, when to start treatment, and choosing therapy. Both primary and secondary prophylaxis have been shown to reduce the frequency of joint bleeds and improve physical and social functioning for children and adults with hemophilia, although only primary prophylaxis has been shown effective in preventing progression of arthropathy. Limited data are available on hemophilia B prophylaxis; target outcomes have been poorly defined and quality-of-life information is lacking in these patients, partly due to the need for standardized assessment tools.

Epidemiology of inhibitors and current treatment strategies.

The development of inhibitors is currently one of the most serious complications in the treatment of hemophilic children. Prospective studies of previously untreated patients (PUP) showed that up to 52% of patients with severe hemophilia A developed inhibitors during the first 50 exposure days (ED) (>100 for outliers). Inhibitor development is influenced by the type of hemophilia, the severity and the type of mutation.

Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products.

In order to assess inhibitor development in previously untreated patients (PUPs) with severe (factor VIII [FVIII]<1%) and moderate (FVIII 1 to 5%) hemophilia A, a prospective study was initiated in 1976. During the 23-year study period, 72 hemophiliacs were frequently exposed prophylactically or on demand to plasma-derived (pd) (n = 51) or recombinant FVIII (rFVIII) (n = 21) concentrates (median 270 exposure days [ED]). Inhibitor testing was performed before the first exposure and at regular intervals thereafter.

Portal vein thrombosis in a patient with severe haemophilia A and F V G1691A mutation during continuous infusion of F VIII after intramural jejunal bleeding--successful thrombolysis under heparin therapy.

Unlabelled: We report on a 14-year-old boy with severe haemophilia A who developed a portal vein thrombosis during continuous infusion of F VIII. For treatment of a posttraumatic intramural jejunal haematoma with extension into the mesenterium the patient received continuous infusion (CI) of a high purity F VIII concentrate, starting with an initial bolus injection of 100 IU F VIII/kg bw and followed by 4-5 IU F VIII/kg bw/h i.v.