Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients ...with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A.
We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose one participant, intermediate dose one participant, and high dose seven participants) and were followed through 52 weeks.
Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected.
The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all seven participants. In this small study, no safety events were noted, but no safety conclusions can be drawn. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .).
Liver biopsy is required when clinically important information about the diagnosis, prognosis or management of a patient cannot be obtained by safer means, or for research purposes. There are several ...approaches to liver biopsy but predominantly percutaneous or transvenous approaches are used. A wide choice of needles is available and the approach and type of needle used will depend on the clinical state of the patient and local expertise but, for non-lesional biopsies, a 16-gauge needle is recommended. Many patients with liver disease will have abnormal laboratory coagulation tests or receive anticoagulation or antiplatelet medication. A greater understanding of the changes in haemostasis in liver disease allows for a more rational, evidence-based approach to peri-biopsy management. Overall, liver biopsy is safe but there is a small morbidity and a very small mortality so patients must be fully counselled. The specimen must be of sufficient size for histopathological interpretation. Communication with the histopathologist, with access to relevant clinical information and the results of other investigations, is essential for the generation of a clinically useful report.
This is a collaboration between the British Society of Gastroenterology (BSG) and the European Society of Gastrointestinal Endoscopy (ESGE), and is a scheduled update of their 2016 guideline on ...endoscopy in patients on antiplatelet or anticoagulant therapy. The guideline development committee included representatives from the British Society of Haematology, the British Cardiovascular Intervention Society, and two patient representatives from the charities Anticoagulation UK and Thrombosis UK, as well as gastroenterologists. The process conformed to AGREE II principles and the quality of evidence and strength of recommendations were derived using GRADE methodology. Prior to submission for publication, consultation was made with all member societies of ESGE, including BSG. Evidence-based revisions have been made to the risk categories for endoscopic procedures, and to the categories for risks of thrombosis. In particular a more detailed risk analysis for atrial fibrillation has been employed, and the recommendations for direct oral anticoagulants have been strengthened in light of trial data published since the previous version. A section has been added on the management of patients presenting with acute GI haemorrhage. Important patient considerations are highlighted. Recommendations are based on the risk balance between thrombosis and haemorrhage in given situations.
Real‐world registry studies of older patients with iTTP highlight diagnostic difficulties in comparison to patients less than 60 years of age with greater risk of renal injury, atypical neurological ...features and less profound cytopenia, which can result in diagnostic delays. However, there is no clear signal of significantly increased toxicity from full active treatment.
Commentary on: Gómez‐Seguí et al. Immune thrombotic thrombocytopenic purpura in older patients: results from the Spanish TTP Registry (REPTT). Br J Haematol 2023;203:860–871.
Real‐world registry studies of older patients with iTTP highlight diagnostic difficulties in comparison to patients less than 60 years of age with greater risk of renal injury, atypical neurological ...features and less profound cytopenia, which can result in diagnostic delays. However, there is no clear signal of significantly increased toxicity from full active treatment.Commentary on: Gómez‐Seguí et al. Immune thrombotic thrombocytopenic purpura in older patients: results from the Spanish TTP Registry (REPTT). Br J Haematol 2023;203:860–871.
Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia ...A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial ( NCT02576795 ), liver biopsy samples were collected 2.6-4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.
This is a collaboration between the British Society of Gastroenterology (BSG) and the European Society of Gastrointestinal Endoscopy (ESGE), and is a scheduled update of their 2016 guideline on ...endoscopy in patients on antiplatelet or anticoagulant therapy. The guideline development committee included representatives from the British Society of Haematology, the British Cardiovascular Intervention Society, and two patient representatives from the charities Anticoagulation UK and Thrombosis UK, as well as gastroenterologists. The process conformed to AGREE II principles, and the quality of evidence and strength of recommendations were derived using GRADE methodology. Prior to submission for publication, consultation was made with all member societies of ESGE, including BSG. Evidence-based revisions have been made to the risk categories for endoscopic procedures, and to the categories for risks of thrombosis. In particular a more detailed risk analysis for atrial fibrillation has been employed, and the recommendations for direct oral anticoagulants have been strengthened in light of trial data published since the previous version. A section has been added on the management of patients presenting with acute GI haemorrhage. Important patient considerations are highlighted. Recommendations are based on the risk balance between thrombosis and haemorrhage in given situations.
Antibiotics are one of the most widely used medications in today's neonatal intensive care units. Indiscriminate antibiotic usage persists in preterm newborns who are symptomatic due to factors ...linked to prematurity rather than being septic. Previous studies in older infants suggest that prior antibiotic administration is associated with possible dysmotility and microbial dysbiosis in the intestinal tract. We hypothesize that early antibiotic administration impacts high-risk preterm infants' tolerance to enteral feeding advancement.
As part of the Routine Early Antibiotic Use in SymptOmatic Preterm Neonates study, symptomatic preterm newborns without maternal infection risk factors were randomized to receive or not receive antibiotics, with C1 receiving antibiotics and C2 not. Of the 55 newborns that underwent pragmatic randomization, 28 preterm neonates in group C1 received antibiotics.
The premature neonates in the randomized groups who received antibiotics and those who did not showed no differences in sustained feeding tolerance.
Our investigation of the risk of feeding issues in babies who get antibiotics early in life revealed no differences between neonates who received antibiotics and those who did not when the randomized controlled trial data alone was reviewed. Given the sample sizes, it is uncertain if the preceding analysis is powerful enough to detect differences (a significant percentage of neonates who were randomly assigned to NOT get antibiotics subsequently received early treatment due to changing clinical conditions). This affirms the requirement for a meticulously designed prospective randomized study.
· Defining feeding tolerance for the first time in neonates.. · Patients from the REASON trial were evaluated.. · Preterm neonates were the focus of this study..
Electronic clinical decision support (CDS) within Electronic Health Records has been used to improve patient safety, including reducing unnecessary blood product transfusions. We assessed the ...effectiveness of CDS in controlling inappropriate red blood cell (RBC) and platelet transfusion in a large acute hospital and how speciality specific behaviours changed in response.
We used segmented linear regression of interrupted time series models to analyse the instantaneous and long term effect of introducing blood product electronic warnings to prescribers. We studied the impact on transfusions for patients in critical care (CC), haematology/oncology (HO) and elsewhere.
In non-CC or HO, there was significant and sustained decrease in the numbers of RBC transfusions after introduction of alerts. In CC the alerts reduced transfusions but this was not sustained, and in HO there was no impact on RBC transfusion. For platelet transfusions outside of CC and HO, the introduction of alerts stopped a rising trend of administration of platelets above recommended targets. In CC, alerts reduced platelet transfusions, but in HO alerts had little impact on clinician prescribing.
The findings suggest that CDS can result in immediate change in user behaviour which is more obvious outside specialist settings of CC and HO. It is important that this is then sustained. In CC and HO, blood transfusion practices differ. CDS thus needs to take specific circumstances into account. In this case there are acceptable reasons to transfuse outside of these crude targets and CDS should take these into account.
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