Systematic Analysis of the Design, Methodology and Patient Population Characteristics of the Pediatric Direct Oral Anticoagulant (DOAC) Trials of Venous Thromboembolism Treatment.

Introduction: The pediatric direct oral anticoagulation (DOAC) trials provide an opportunity to evaluate and characterize challenges in their design and execution to inform future antithrombotic trials.

Objective: To perform a systematic review of pediatric DOAC trials for the treatment of venous thromboembolism to critically appraise their methodology and understand the feasibility and challenges.

Methods: Systematic search of MEDLINE, EMBASE, the Cochrane Library and ClinicalTrials.

Contrasting Approaches in the Implementation of GRADE Methodology in Guidelines for Haemophilia and Von Willebrand Disease.

Introduction: The 2024 ISTH clinical practice guideline (CPG) for treatment of congenital haemophilia, the NBDF-McMaster Guideline on Care Models for Haemophilia Management, and ASH ISTH NBDF WFH guidelines on the diagnosis and management of VWD all utilised GRADE methodology.

Aim: Discuss missed opportunities and the methodological approach of the ISTH Guideline in contrast to how GRADE was previously applied in rare diseases.

Methods: Critically analyse the methodology of each guideline along with best practices in the use of GRADE.

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.

Clinical impact of circulating biomarkers in prediction of adverse cardiac events in patients with congenital heart disease. A systematic review.

Introduction: Patients with congenital heart disease (ConHD) are at increased risk for adverse cardiac events. Predicting long-term outcomes and guidance of patient management might benefit from a range of (new) biomarkers. This is a rapidly evolving field with potentially large consequences for clinical decision making.

Safety and Efficacy of Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Previously Untreated Patients with Hemophilia B.

 Recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) has been shown to be an effective, well-tolerated treatment for patients with severe hemophilia B who had previously received factor replacement therapy. This study investigated the safety and efficacy of rIX-FP in previously untreated patients (PUPs).  Patients with moderately severe/severe hemophilia B (≤2% FIX) previously untreated with FIX replacement products received rIX-FP (25-75 IU/kg) prophylaxis weekly or on-demand treatment over ≥50 exposure days (EDs).

Influence of Age, Heart Failure and ACE Inhibitor Treatment on Plasma Renin Activity in Children: Insights from a Systematic Review and the European LENA Project.

Background: Plasma renin activity (PRA) has gained relevance as prognostic marker in adults with heart failure. The use of PRA as a clinically meaningful parameter in children and children with heart failure requires a thorough knowledge of the factors that influence PRA to correctly assess PRA levels. We aim to evaluate the influence of age, heart failure and angiotensin-converting enzyme inhibitor (ACEi) on PRA levels in children.

Apixaban for Prevention of Thromboembolism in Pediatric Heart Disease.

Background: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages.

Objectives: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease.

Persistent Hydrocephalus, Shunt, and Subglottic Stenosis in a Newborn with Plasminogen Deficiency due to Delayed Treatment with Plasminogen Concentrates: A Case Report.

Introduction: Here we present the case of a newborn baby boy with severe plasminogen deficiency causing occlusive hydrocephalus and ligneous conjunctivitis.

Case Presentation: Shortly after birth, the hydrocephalus was treated with a ventriculoperitoneal shunt implantation. However, the child had to be readmitted soon afterward because of shunt obstruction.

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.

The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results.

Background: The pathfinder6 (NCT02137850) international phase 3 trial examined immunogenicity, safety, and efficacy of the extended half-life factor VIII (FVIII) replacement product N8-GP (turoctocog alfa pegol; Esperoct) in previously untreated patients (PUPs) with hemophilia A.

Objectives: We present end-of trial results for extended PUP N8-GP treatment for up to a median (range) 2.5 (0.

Corrigendum to 'The Hemophilia Joint Health Score version 2.1 Validation in Adult Patients Study: A multicenter international study' [Research and Practice in Thrombosis and Haemostasis, 6/2, (2022) e12690].

[This corrects the article DOI: 10.1002/rth2.12690.

What did we learn (and did not learn) from the pediatric direct oral anticoagulant trials, and how might we better design pediatric anticoagulant trials in the future?

A State of the Art lecture titled "What the direct oral anticoagulants (DOACs) trials did and didn't tell us" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. The use of DOACs in children is of particular interest as they exhibit several advantages over conventional anticoagulation agents most commonly used in pediatrics. To date, several DOAC pediatric investigational programs (PIPs) have been completed, and although they have provided some of the best quality of evidence in pediatric anticoagulation therapy, the data generated by these trials remain limited.

Guiding future paediatric drug studies based on existing pharmacokinetic and efficacy data: Cardiovascular drugs as a proof of concept.

Introduction: Off-label drug use in the paediatric population is common, and the lack of high-quality efficacy studies poses patients at risk for failing pharmacotherapy. Next to efficacy studies, pharmacokinetic (PK) studies are increasingly used to inform paediatric dose selection. As resources for paediatric trials are limited, we aimed to summarize existing PK and efficacy studies to identify knowledge gaps in available evidence supporting paediatric dosing recommendations, thereby taking paediatric cardiovascular drugs as proof of concept.

Updated guidance for efficacy and safety outcomes for clinical trials in venous thromboembolism in children: communication from the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis.

Despite the growing number of pediatric antithrombotic clinical trials, standardized safety and efficacy outcome definitions for pediatric venous thromboembolism (VTE) clinical trials have not been updated since 2011. Many recent trials have adapted the recommended definitions, leading to heterogeneity in outcomes and limiting our ability to compare studies. The International Society on Thrombosis and Haemostasis Scientific and Standardization Subcommittee (SSC) on Pediatric and Neonatal Thrombosis and Hemostasis organized a Task Force to update the efficacy and safety outcome definitions for pediatric VTE clinical trials.

Impact of SERPINC1 mutation on thrombotic phenotype in children with congenital antithrombin deficiency-first analysis of the International Society on Thrombosis and Haemostasis pediatric antithrombin deficiency database and biorepository.

Background: The natural history and genotype-phenotype correlation of congenital antithrombin (AT) deficiency in children are unknown.

Objectives: To describe the clinical presentation of congenital AT deficiency in children and evaluate its correlation to specific mutations in SERPINC1.

Methods: In 2017, a prospective pediatric database and DNA biorepository for congenital AT deficiency was established.