Identification of the factors influencing anticoagulation response to warfarin in children

M.D.The requirement for anticoagulant therapy in children is increasing and warfarin remains the long-term anticoagulant agent of choice. However, little is known about the factors that influence inter-individual variability in response to warfarin among children. The aim of this MD was to gain a greater understanding of the factors that affect warfarin anticoagulant control and response in children. A retrospective study of a cohort of anticoagulated children identified factors contributing to poor anticoagulant control. It also highlighted the importance of the way in which anticoagulant control is assessed in children, with the study results showing that the use of a linear interpolation method may be more appropriate than the proportion of INRs within target range during intermittent periods of instability when INR measurements are carried out more frequently. A multi-centre, cross-sectional study of 120 children with stable anticoagulation with warfarin showed that 72% of the inter-individual variability in warfarin maintenance dose is accounted for by height, VKORC1 and CYP2C9 genotype, and indication for warfarin. The study results were used to develop a pharmacogenetics-based warfarin-dosing algorithm. The latter was demonstrated to have the power to accurately predict maintenance warfarin dose in an unrelated cohort of 23 children. Analysis of data for a subgroup of 51 children showed that VKORC1 and CYP2C9 genotype influence outcome variables during initiation of warfarin therapy, including peak INR response during week 1 and the proportion of supratherapeutic INRs during month 1 of therapy. The above findings have provided us with an insight into the factors influencing anticoagulant control and variability in response to warfarin in children. Application of a pharmacogenetics-based approach to initiation and maintenance warfarin therapy in children has the potential to improve efficacy and safety of warfarin therapy in this challenging patient population

Recombinant Activated Factor VII (rFVIIa) in the Management of Major Obstetric Haemorrhage: A Case Series and a Proposed Guideline for Use

Major obstetric haemorrhage remains a significant cause of maternal morbidity and mortality. Previous case reports suggest the potential benefit of recombinant activated factor VII (rFVIIa: NovoSevenR) as a haemostatic agent. We performed a retrospective review of the use of rVIIa in major obstetric haemorrhage in the Northern Region between July 2004 and February 2007. Fifteen women received rFVIIa. The median patient age was 34 years. Major haemorrhage occurred antepartum (5 patients), intrapartum (1), and postpartum (9). All women received an initial dose of 90 mcg/kg rFVIIa and one received 2 further doses. Bleeding stopped or decreased in 12 patients (80%). Additional measures included antifibrinolytic and uterotonic agents, Rusch balloon insertion, uterine curettage/packing, and vessel embolisation. Eight patients required hysterectomy. All women survived to discharge from hospital. No adverse events, including thrombosis, were recorded. This study provides further support for the safety and efficacy of rFVIIa as adjunct therapy in major obstetric haemorrhage

Apixaban overdose in children:case report and proposed management. A brief communication from the Pediatric and Neonatal Thrombosis and Hemostasis SSC of ISTH

Background: Direct oral anticoagulants are commonly prescribed for adults and increasingly also for children requiring anticoagulation therapy. While household medications should not be accessible to children, accidental, and intentional overdoses occur. Key Clinical Question: How should apixaban overdose in children be managed?. Clinical Approach: We present a case of an accidental overdose with the factor Xa antagonist apixaban in a young child and propose an approach to the management of cases of apixaban overdose in children. Conclusion: Given the increasing use of direct oral anticoagulants, it is important to have an approach to the management of overdose of these medications.</p

Identifying Children with HEreditary Coagulation disorders (iCHEC): A protocol for a prospective cohort study

Introduction It is challenging to obtain a reliable bleeding history in children who are referred for a suspected inherited bleeding disorder. Bleeding symptoms may be subtle as children face fewer haemostatic challenges compared with adults. In order to standardise bleeding histories, questionnaires have been developed, called bleeding assessment tools (BATs). Although it has been shown that high bleeding scores are associated with the presence of a mucocutaneous bleeding disorder, these BATs lack sensitivity, efficiency and flexibility in the paediatric setting. We developed a new BAT (the iCHEC (identifying Children with HEreditary Coagulation disorders) BAT) to improve on these characteristics. We aim to evaluate the diagnostic accuracy of the iCHEC BAT as a screening tool for children who are suspected for having a bleeding disorder. Methods and analysis This is a prospective cohort study. Children (age 0-18 years) suspected for a bleeding disorder who present at tertiary haematology clinics, and/or their parents/guardians, will be asked to complete the iCHEC BAT. Sensitivity was increased by inclusion of paediatric-specific bleeding symptoms and novel qualitative questions per bleeding symptom. Efficiency was improved by developing a self-administered (online) version of the questionnaire. Flexibility for changes in the bleeding phenotype of developing children was improved by including questions that define when the bleeding symptoms occurred in the past. The diagnostic accuracy of the specific bleeding items will be evaluated by receiver operator characteristic curves, using classification based on the results from laboratory assessment as the reference standard. Analysis of the discriminative power of individual bleeding symptoms will be assessed. Ethics and dissemination The study has been approved by the medical ethics committees of all participating centres in the Netherlands, Canada and the UK. All paediatric subjects and/or their parents/guardians will provide written informed consent. Study results will be submitted for publication in peer-reviewed journals

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility