VITT, COVID-19 and the Expert Haematology Panel: the story of how the UK responded to emerging cases of vaccine-induced immune thrombocytopenia and thrombosis during the vaccination programme

The COVID-19 pandemic has resulted in the development of highly effective vaccines that provide hope to the global community for reducing the spread of SARS-CoV-2 and limiting the mortality and morbidity caused by the disease. These vaccines have been produced using differing technologies, taken through clinical trials, and rolled out across the UK at unprecedented speed. However, the recent emergence of rare cases of life-threatening thrombosis in association with thrombocytopenia has threatened to derail one particular vaccine, the Oxford AstraZeneca ChAdOx1 vaccine, upon which many countries are dependent for their vaccination programmes. The story of how this situation has been managed in the UK at the height of the vaccine roll-out represents a remarkable collective endeavour on the part of the haematology community, working closely with other acute medical and surgical professionals within the NHS and the UK health regulatory bodies, to provide rapid expert guidance that has saved lives and helped keep the national vaccination programme on track

Management of sickle cell disease in pregnancy. A British Society for Haematology Guideline

This guideline was compiled according to the British Societyof Haematology (BSH) process at https://b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. The Grad-ing of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluatelevels of evidence and to assess the strength of recommenda-tions. The GRADE criteria can be found at http://www.gradeworkinggroup.or

Fractional exhaled nitric oxide for the management of asthma in adults: Systematic review

The aim of this review was to evaluate the clinical effectiveness of fractional exhaled nitric oxide (FeNO) measured in a clinical setting for the management of asthma in adults. 13 electronic databases were searched and studies were selected against predefined inclusion criteria. Quality assessment was conducted using QUADAS-2. Class effect meta-analyses were performed. Six studies were included. Despite high levels of heterogeneity in multiple study characteristics, exploratory class effect meta-analyses were conducted. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63–1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43–1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of −0.24 (95% CI −0.56–0.07). No statistically significant differences for health-related quality of life or asthma control were found. FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or ICS use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most

Understanding thrombosis with thrombocytopenia syndrome after COVID-19 vaccination

Safety and efficacy of vaccines against the SARS-CoV-2 coronavirus has been demonstrated in clinical trials and next by their real world use through the course of the ongoing COVID-19 pandemic. However, very rare adverse events have been detected post-authorization in certain parts of the world. This meeting report summarizes an EMA workshop’s discussion on the epidemiology, clinical presentation and biology of thrombosis with thrombocytopenia syndrome after adenovirus vector COVID-19 vaccination. General agreement was reached by international regulators, scientists and developers on the steps needed to fill the gaps in the characterization of this new syndrome. In particular, actions should be taken to improve the post-vaccination surveillance activities in low and middle income countries and investigate potential genetic predisposition factors

The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran

Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation and likely to be soon approved in Europe for treatment of venous thrombosis. Predictable pharmacokinetics and a reduced risk of intracranial haemorrhage do not negate the potential risk of haemorrhage. Unlike warfarin, there is no reversal agent and measurement of the anticoagulant effect is not ‘routine’. The prothrombin time/international normalised ratio response to dabigatran is inconsistent and should not be measured when assessing a patient who is bleeding or needs emergency surgery. The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT. Commercially available DTI assays provide a quantitative measurement of active dabigatran concentration in the plasma. If a patient receiving dabigatran presents with bleeding: omit/delay next dose of dabigatran; measure APTT and thrombin time (consider DTI assay if available); administer activated charcoal, with sorbitol, if within 2 h of dabigatran ingestion; give tranexamic acid (1 g intravenously if significant bleeding); maintain renal perfusion and urine output to aid dabigatran excretion. Dabigatran exhibits low protein binding and may be removed by dialysis. Supportive care should form the mainstay of treatment. If bleeding is life/limb threatening, consider an additional haemostatic agent. There is currently no evidence to support the choice of one haemostatic agent (FEIBA, recombinant factor VIIa, prothrombin complex concentrates) over another. Choice will depend on access to and experience with available haemostatic agent(s)

Mepolizumab for Treating Severe Eosinophilic Asthma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company (GlaxoSmithKline) that manufactures mepolizumab (Nucala(®)) to submit evidence on the clinical and cost effectiveness of mepolizumab for the treatment of severe eosinophilic asthma. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). The ERG produced a review of the evidence for the clinical and cost effectiveness of mepolizumab as add-on to standard of care (SoC) compared with SoC and omalizumab, based upon the company's submission to NICE. The clinical-effectiveness evidence in the company's submission was based predominantly on three randomised controlled trials (DREAM, MENSA and SIRIUS) comparing add-on mepolizumab with placebo plus SoC. The relevant population was defined in terms of degree of asthma severity (four or more exacerbations in the previous year and/or dependency on maintenance oral corticosteroids [mOCS]) and degree of eosinophilia (a blood eosinophil count of ≥ 300 cells/µl in the previous year) based on post hoc subgroup analyses of the pivotal trials. Other subpopulations were considered throughout the appraisal, defined by different eosinophil measurements, number of exacerbations and dependency (or lack thereof) on mOCS. Statistically significant reductions in clinically significant exacerbations were observed in patients receiving mepolizumab compared with SoC meta-analysed across MENSA and DREAM in the modified intention-to-treat (ITT) population (rate ratio [RR] 0.51; 95% confidence interval [CI] 0.42-0.62) as well as in the relevant population (RR 0.47; 95% CI 0.36-0.62). In terms of quality of life, differences on the St. George's Respiratory Questionnaire in MENSA for add-on subcutaneous mepolizumab 100 mg vs. placebo were 7 and 7.5 units in the modified ITT and relevant populations, respectively. A number of issues in the clinical evidence base warrant caution in its interpretation. The ERG noted that the definition of SoC used in the trials differed from that in clinical practice, where patients with severe uncontrolled asthma start treatment with a mOCS. The company's economic post-consultation analysis incorporating a confidential patient access scheme (PAS) estimated that the incremental cost-effectiveness ratio (ICER) for add-on mepolizumab compared with SoC was £27,418 per quality-adjusted life-year (QALY) gained in the relevant population if patients stopped mepolizumab after 1 year unless (1) the number of exacerbations decreased at least 50% or (2) a reduction in corticosteroids dose was achieved whilst maintaining asthma control. The ERG applied an age adjustment to all utilities and corrected the post-continuation assessment utilities, which resulted in an ICER for add-on mepolizumab compared with SoC of £29,163 per QALY gained. The ERG noted that this ICER was not robust for patients who continued treatment due to a corticosteroid dose reduction where exacerbations had decreased by less than 50%, because corticosteroid dose reduction was not allowed in the main trial in which the evidence was gathered (MENSA). The NICE appraisal committee (AC) concluded that add-on mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults for the relevant population when the stopping rule suggested by the company was applied. The AC also concluded that the comparison between mepolizumab and omalizumab was not clinically relevant or methodologically robust

THE OBSTETRIC HEMATOLOGI MANUAL

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A case series review of patients with Thrombocytopenia and Absent-Radii syndrome (TARS) and their management during pregnancy

Bleeding diatheses due to platelet-related disorders can present challenges to treating clinicians especially in the context of peri- and post-partum patients in the obstetric setting. TARS is an inherited disorder characterised by reduced bone marrow platelet production, skeletal deformities affecting radii and other limbs; cardiac, renal, and other heterogeneous anomalies may occur. It is caused by co-inheritance of a microdeletion and a nucleotide polymorphism in the RBM8A gene on chromosome 1. Bleeding phenotype is more severe than platelet numbers might predict especially in infants but improves with age. There is minimal literature regarding impact in pregnancy and puerperium. We describe management of three pregnancies in the haematology-obstetrics clinic. As platelet counts normally decrease through pregnancy, close monitoring is required in TAR syndrome. No major bleeding was seen antenatally but two required platelet transfusion during labour. No other treatment definitely improves bleeding, although case reports of steroids claim variable success. Tranexamic acid may be helpful, and thrombopoietin agonists represent a potential future option.&nbsp