Treatment of Deep Vein Thrombosis with Continuous IV Infusion of LMWH: A Retrospective Study in 32 Children

Thirty-two consecutive children aged 0–18 years with VTE treated with LMWH administered as a continuous infusion (CI) were identified at the Children's University Hospital Brno. The treatment led to at least partial resolution of the thrombus within two weeks in 85% of patients. There were no adverse events or increased bleeding reported in any patients. No recurrences were observed during a followup period of 6 months. Although continuous infusion should not replace subcutaneous (SC) administration of LMWH, CI appeared to be safe and efficient and may provide an alternate method of administering LMWH in a subset of the paediatric population where SC administration may not be feasible. Further prospective studies are needed to support the promising findings of our pilot clinical observation

Estimating and interpreting individual patients' pharmacokinetic profiles in persons with Hemophilia A or B using a population pharmacokinetic approach: communication from the SSC of the ISTH

The ISTH SSC on Factor VIII/IX has previously issued guidelines for studies assessing the pharmacokinetics (PK) of factor concentrates [1,2]. They suggested drawing 10 or 11 blood samples over a period of 32-48h or 50-72h, after infusing 25-50 or 50-75 IU/kg, respectively for factor VIII (FVIII) or factor IX (FIX), in cohorts of 12-15 patients with a crossover design. Such PK studies are not ideal for tailoring the treatment of individual patients, mostly for the requirement of several blood samples. Due to broad inter-individual variation, the individual disposition of FVIII and FIX cannot be predicted from morphometric characteristics and average PK parameters, but requires empirical assessment in each individual [3–6]. Previous guidance of this ISTH SSC described the PK methodology for the prediction of individual trough levels of FVIII [7]. The present communication, building on recent advancements in the population PK (PopPK) of FVIII and FIX [8], adds to the former documents

Dilemmas on emicizumab in children with haemophilia A: A survey of strategies from PedNet centres.

INTRODUCTION Haemophilia A care has changed with the introduction of emicizumab. Experience on the youngest children is still scarce and clinical practice varies between haemophilia treatment centres. AIM We aimed to assess the current clinical practice on emicizumab prophylaxis within PedNet, a collaborative research platform for paediatricians treating children with haemophilia. METHODS An electronic survey was sent to all PedNet members (n = 32) between October 2022 and February 2023. The survey included questions on the availability of emicizumab, on the practice of initiating prophylaxis in previously untreated or minimally treated patients (PUPs or MTPs) and emicizumab use in patients with or without inhibitors. RESULTS All but four centres (28/32; 88%) responded. Emicizumab was available in clinical practice in 25/28 centres (89%), and in 3/28 for selected patients only (e.g. with inhibitors). Emicizumab was the preferred choice for prophylaxis in PUPs or MTPs in 20/25 centres; most (85%) started emicizumab prophylaxis before 1 year of age (30% before 6 months of age) and without concomitant FVIII (16/20; 80%). After the loading dose, 13/28 centres administered the recommended dosing, while the others adjusted the interval of injections to give whole vials. In inhibitor patients, the use of emicizumab during ITI was common, with low-dose ITI being the preferred protocol. CONCLUSION Most centres choose to initiate prophylaxis with emicizumab before 12 months of age and without concomitant FVIII. In inhibitor patients, ITI is mostly given in addition to emicizumab, but there was no common practice on how to proceed after successful ITI

Prophylaxis in children with haemophilia in an evolving treatment landscape

Introduction For children with haemophilia, early initiation of prophylaxis is crucial to prevent life-threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half-life coagulation factor products to include other haemostasis products, such as the non-replacement therapy emicizumab. Aim To review key factors that determine the choice of prophylaxis in young children. Methods Key clinical questions on the implementation of prophylaxis for haemophilia in children were identified and PubMed was searched for evidence supporting guidance on the implementation of prophylaxis. Results The results of the literature search and the practical experience of the authors were used to build consensus on when to start prophylaxis, the pros and cons of the products available to guide the choice of product, and practical aspects of starting prophylaxis to guide the choice of regimen. Conclusions In this era of increasing therapeutic choices, available information about the range of treatment options must be considered when initiating prophylaxis in young children. Parents or care givers must be sufficiently informed to allow informed shared decision making. Although plentiful data and clinical experience have been gathered on prophylaxis with clotting factor replacement therapy, its use in young children brings practical challenges, such as the need for intravenous administration. In contrast, our relatively brief experience and limited data with subcutaneously administered non-replacement therapy (i.e., emicizumab) in this patient group imply that starting emicizumab prophylaxis in young children requires careful consideration, despite the more convenient route of administration.TakedaThis article was written on behalf the European Collaborative Haemophilia Network (ECHN). ECHN is supported by an Independent Educational Grant from Takeda. Medical writing assistance was provided by Janet R. Davies, PhD, ELS, and Kim Grootscholten, MSc, of COR2ED, Basel, Switzerland

Postauthorization safety surveillance study of antihaemophilic factor (recombinant) reconstituted in 2 mL sterile water for injection in children with haemophilia A

International audienceIntroduction - Antihaemophilic factor (recombinant) (rAHF; ADVATE ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. Aim - To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII < 1%) or moderately severe (FVIII 1%-2%) haemophilia A. Methods - This was a prospective, non-interventional, postauthorization safety surveillance study (NCT02093741). Eligible patients were previously treated with rAHF and had a negative inhibitor test result during ≤10 exposure days prior to study entry. Results - Of 65 patients enrolled (0-11 years of age), 54 and 11 had severe and moderately severe haemophilia A, respectively; 56 patients received prophylaxis, and 11 had ≤50 exposure days, of which 4 had ≤4 exposure days. No patients reported local hypersensitivity reactions, treatment-related adverse events or developed inhibitors. Investigators rated overall effectiveness of rAHF 2 mL prophylaxis as excellent or good. Ninety-four bleeding events in 34 patients were treated. Haemostatic effectiveness was rated as excellent or good for 75.8% of bleeds; 86.2% of bleeds required 1 or 2 infusions. Conclusion - In children with severe/moderately severe haemophilia A, no hypersensitivity reactions were reported with rAHF 2 mL treatment, and the safety and effectiveness are consistent with data previously reported for rAHF 5 mL

Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: Rationale and general considerations

Objectives: In a separate document, we have provided specific guidance on performing individual pharmacokinetic (PK) studies using limited samples in persons with hemophilia with the goal to optimize prophylaxis with clotting factor concentrates. This paper, intended for clinicians, aims to describe how to interpret and apply PK properties obtained in persons with hemophilia. Methods: The members of the Working Party on population PK (PopPK) of the ISTH SSC Subcommittee on Factor VIII and IX and rare bleeding disorders, together with additional hemophilia and PK experts, completed a survey and ranking exercise whereby key areas of interest in the field were identified. The group had regular web conferences to refine the manuscript’s scope and structure, taking into account comments from the external feedback to the earlier document. Results: Many clinical decisions in hemophilia are based on some form of explicit or implicit PK assessment. Individual patient PK profiles can be analyzed through traditional or PopPK methods, with the latter providing the advantage of fewer samples needing to be collected on any prophylaxis regimen, and without the need the for a washout period. The most useful presentation of PK results for clinical decision making are a curve of the factor activity level over time, the time to achieve a certain activity level, or related parameters like half-life or exposure (AUC). Software platforms have been developed to deliver this information to clinicians at the point of care. Key characteristics of studies measuring average PK parameters were reviewed, outlining what makes a credible head-to-head comparison among different concentrates. Large data collections of PK and treatment outcomes currently ongoing will advance care in the future. Conclusions: Traditionally used to compare different concentrates, PK can support tailoring of hemophilia treatment by individual profiling, which is greatly simplified by adopting a PopPK/Bayesian method and limited sampling protocol