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Summary: Haemophilia is a serious inherited bleeding disorder resulting from a deficiency of coagulation factor VIII (haemophilia A) or coagulation factor IX (haemophilia B). While effective therapies have been developed to replace the missing factor and restore normal coagulation, they can lead to the development of neutralizing anti‐drug antibodies, termed inhibitors, which significantly worsen morbidity and quality of life. While advancements have been made to improve the management of patients, and particularly for this review, children with inhibitors, there remain significant unmet needs including inhibitor prevention, inhibitor eradication and, when those fail, more effective bleed prevention and a reduction in the treatment burden. This review will discuss current treatment options including the recently licensed bispecific antibody, emicizumab, and provide insights into how I treat children with inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: As a result of the new treatment paradigm that the haemophilia community will face with the availability of novel (non‐factor) therapies, an updated consensus on ITI recommendations and inhibitor management strategies is needed. Aim: The Future of Immunotolerance Treatment (FIT) group was established to contemplate, determine and recommend the best management options for patients with haemophilia A and inhibitors. Discussion and Conclusions: Despite the considerable success of emicizumab in the management of inhibitor patients, the FIT group still sees the importance of eradicating inhibitors. However, the availability of emicizumab and other non‐factor therapies in the future might impact greatly on how ITI is undertaken. Theoretically, concomitant use of emicizumab and FVIII might allow emicizumab to effectively prevent bleeding with lower dose ITI regimens. This might allow for the greater adoption of low‐dose/low‐frequency FVIII ITI regimens, which may result in a reduced need for central venous access devices while still maintaining a reasonable likelihood of ITI success. The FIT group proposes a new management algorithm for current ITI (without emicizumab) and a hypothetical new approach with the availability of emicizumab. As there are no published data regarding the concomitant use of emicizumab and FVIII for ITI, the FIT Expert group encourages the undertaking of properly conducted prospective studies to explore these approaches further. [ABSTRACT FROM AUTHOR]

Highlights from the article: The other seven patients had at least one bleed treated with 2 or more doses of Rebleeding) and the second bleed was treated with 6 doses, Bleeds, the ability to treat most bleeds with 1 dose with Table 1 OD treatment of bleeds by the number of N9-GP doses.

The incidence of pediatric venous thromboembolism (VTE) has been increasing significantly over the past decade in part as a result of increased recognition of this serious disorder but more so because of the increased use of central venous catheters and other technological advancements involved in the care of ill children. Management of pediatric VTE is a complex undertaking, considering that the vast majority of children who develop this complication have serious underlying medical disorders. Although the incidence is rising, in comparison with adults, this remains a relatively rare disorder, and as such, large-scale clinical trials have not been completed, rendering management decisions to be based on extrapolation from adult data and the experience of the treating physician. Clearly, both are fraught with problems. Thus, day-to-day management remains more art than science until such time that the results from clinical trials (many of which are under way) become available. This edition of "How I Treat" describes the author's experience in managing 3 common scenarios that one may encounter in pediatric thrombosis and suggests a logical approach to such situations. Furthermore, the author provides 3 algorithms to help guide management decisions. [ABSTRACT FROM AUTHOR]

Thrombotic complications are increasing at a steady and significant rate in children resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the standard agents (heparin, low molecular weight heparin, and vitamin K antagonists) and alternative agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the standard and alternative anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. Clearly, the standard anticoagulants all have significant shortcomings including variable pharmacokinetics, issues with therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The alternative anticoagulants have properties which overcome these shortcomings and prospective clinical trial data are presented supporting the current and future use of these agents in place of the standard anticoagulants. [ABSTRACT FROM AUTHOR]

Introduction Paradigm™4 was an international extension trial investigating the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in haemophilia B patients (FIX activity ≤ 2%; aged 13–70 years) who had previously participated in phase III pivotal (paradigm™2) or surgery (paradigm™3) trials. Methods Patients chose to continue treatment with nonacog beta pegol in either one of two once-weekly prophylaxis arms (10 IU/kg or 40 IU/kg), or an on-demand arm (40 IU/kg for mild/moderate bleeds; 80 IU/kg for severe bleeds). The primary objective was to evaluate immunogenicity; key secondary objectives included assessing safety and haemostatic efficacy in the treatment and prevention of bleeds. Results Seventy-one patients received prophylaxis or on-demand treatment. No patient developed an inhibitor and no safety concerns were identified. The success rate for the treatment of reported bleeds was 94.6%; most (87.9%) resolved with one injection. The median annualised bleeding rate for patients on prophylaxis was 1.36 (interquartile range [IQR] 0.00–2.23) and 1.00 (IQR 0.00–2.03) for the 10 and 40 IU/kg treatment arms, respectively. The mean FIX activity trough achieved for 10 and 40 IU once weekly was 9.8% and 21.3%, respectively. Fourteen patients on prophylaxis underwent 23 minor surgical procedures; haemostatic perioperative outcomes for all of those evaluated were ‘excellent’ or ‘good’. Conclusions Nonacog beta pegol showed a favourable tolerability profile (with no safety issues identified) with good prophylactic protection and control of bleeding in previously treated adult and adolescent haemophilia B patients. [ABSTRACT FROM AUTHOR]

. Haemostasis management in people with haemophilia can present a range of challenges to physicians. Specific challenges that may be encountered relate to regimens for immune tolerance induction, use of central venous access devices, optimizing care of paediatric patients with inhibitors and improving outcomes in acquired haemophilia. There are also challenges related to performing surgery, and the establishment of specialist centres is valuable with regard to this. These challenges are considered in the light of available data, and with perspectives gained from the experience of experts treating patients around the world. Sharing this knowledge may help to improve patient management. [ABSTRACT FROM AUTHOR]

The most serious current complication of factor replacement therapy for hemophilia patients is the development of neutralizing antibodies to the factor termed inhibitors. Patients with high-titer inhibitors frequently develop serious bleeding complications which do not respond to standard factor replacement therapy. Therefore, they must be treated with the so-called bypassing agents, recombinant factor VIIa and activated prothrombin complex concentrates, neither of which is as effective as standard factor replacement in patients without inhibitors. Immune tolerance therapy aimed at eradicating inhibitors is successful in a majority of patients; however, a sizable minority will have life-long inhibitors and often develop debilitating joint disease. The ultimate goal is to develop strategies aimed at preventing inhibitor development though these have not been realized yet. Until this is achieved, additional novel approaches are needed to improve the treatment of bleeding episodes and to better treat arthropathy once it develops. Finally, there is no laboratory monitoring device which can predict the clinical response of patients to bypassing agents. Thus another goal of current research is to develop such a tool which will enable the individualization of bypassing agent. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily. Methods: EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18 years. A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months. Conclusions: EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials. Trial registration: Clinicaltrials.gov NCT02234843, registered on 9 September 2014. [ABSTRACT FROM AUTHOR]

Background: The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. Methods: This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows. Results: Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study. Conclusions: Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children. Trial registration: ClinicalTrials.gov number, NCT01145859. [ABSTRACT FROM AUTHOR]

Background Pediatric hospital-acquired venous thromboembolism (HA-VTE) rates have increased dramatically. To achieve generalizable knowledge in the derivation and validation of HA-VTE risk factors and risk prediction models and inform future risk-stratified prevention strategies, multi-institutional studies are needed. Objectives This paper presents an investigator-initiated, multicenter pediatric case-cohort study designed to identify risk factors for HA-VTE to create a HA-VTE risk prediction model. Methods A registry, which houses pertinent variables from HA-VTE subjects and non-HA-VTE controls, was created for the Children's Hospital-Acquired Thrombosis (CHAT) study. Specific variables from the registry associated with HA-VTE risk will be identified using multivariable regression to create a pediatric HA-VTE risk prediction model to be prospectively validated. Results Seven large pediatric institutions have entered over 600 HA-VTE subjects aged 0–21 years of age into the registry. Subjects showed a male predominance (57%), a median age of three years (IQR 0.3–13) and were most likely admitted to an intensive care unit (57%) at VTE diagnosis. Median time to HA-VTE was 10 days after admission. The most prevalent risk factors include central venous catheters (80%), surgery (43%), systemic steroids (31%), congenital heart disease (27%), infection (14%) and cancer (13%). Conclusions CHAT, with its creation of a risk prediction model with prospective validation using the CHAT registry, is a novel study design and will be the first step in identifying safe and effective strategies to decrease HA-VTE in children by helping define the highest risk population for initial, or more aggressive, thromboprophylaxis efforts. [ABSTRACT FROM AUTHOR]

Background: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors.Methods: We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C.Results: A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.Conclusions: Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .). [ABSTRACT FROM AUTHOR]