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

\ua9 2024 The Authors. 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

Positive Clinical Neuroscience: Explorations in Positive Neurology

Disorders of the brain and its sensory organs have traditionally been associated with deficits in movement, perception, cognition, emotion, and behavior. It is increasingly evident, however, that positive phenomena may also occur in such conditions, with implications for the individual, science, medicine, and for society. This article provides a selective review of such positive phenomena – enhanced function after brain lesions, better-than-normal performance in people with sensory loss, creativity associated with neurological disease, and enhanced performance associated with aging. We propose that, akin to the well-established field of positive psychology and the emerging field of positive clinical psychology, the nascent fields of positive neurology and positive neuropsychology offer new avenues to understand brain-behavior relationships, with both theoretical and therapeutic implications

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Inherited thrombocytopenias are a heterogeneous group of disorders characterised by abnormally low platelet counts which can be associated with abnormal bleeding. Next generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease causing genes. However its full potential has not previously been utilised. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown aetiology with platelet counts varying from 11-186x109 /L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified “pathogenic” or “likely pathogenic” variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases which include novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia

Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding

Background: A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity. Objective: To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found. Methods: Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry. Results: We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining. Conclusions: Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count

Medicinal cannabis users downplaying and shifting stigma: Articulations of the ‘natural’, of what is/is not a ‘drug’ and oppositions with ‘chemical’ substances

Whilst sympathy exists among the general public for chronically ill and/or disabled people who use cannabis medicinally, cannabis remains a prohibited substance in the UK. How do medicinal cannabis users negotiate this potential stigma when talking about their use of this substance? I reflect on the spoken discourses of 10 medicinal cannabis users (from a sample of 32), obtained by way of qualitative interviews, adopting a critical discourse analysis approach to the data. Specifically, I focus on their articulations around three related themes: cannabis as a ‘natural’ substance, discursive oppositions between cannabis and other substances and articulations about what is/is not a ‘drug’. I examine how participants articulated these themes in ways that attempted to negotiate the potential for stigma that talking about their substance use involved. I found they used rhetorical strategies that downplay their own deviance, attempt to shift the application of stigma to users of other substances or both. I argue that the more powerful the discursive resources that are articulated, the less rhetorical work an individual has to do to negotiate positive moral standing in an encounter. I also consider to what degree these articulations involved constructions emphasising individual self-control. I argue that in asserting that cannabis is a ‘natural’ substance (and therefore is less inherently risky to use than manufactured substances) the participants do emphasise their individual self-control

Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects

Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants and analysed for CYP2C9*2, *3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first 6 months’ treatment time spent within the target International Normalised Ratio (INR) range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C9*2 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (odds ratio (OR; per additional copy) 4.18, 95% confidence interval (CI) 1.42, 12.34). CYP2C9*2 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR (heterozygotes vs homozygotes) 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population