Validation of the newly proposed Brighton Collaboration case definition for vaccine-induced immune thrombocytopenia and thrombosis.

Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a newly recognized syndrome mediated by anti-platelet factor 4 antibodies induced by Covid-19 adenovirus-vectored vaccines including ChAdOx1 nCoV-19 and Ad26.COV2.S. This study validated a proposed Brighton Collaboration case definition for VITT. A data collection form was developed and used to capture the variations in VITT criteria and assess their level of diagnostic certainty from adjudicated positive VITT case datasheets in Germany (n = 71), UK (n = 220), Australia (n = 203), and Taiwan (n = 56). We observed high prevalence of each component of the proposed VITT definition in positive cases (84%-100%), except for the occurrence of thrombosis or thromboembolism criterion in only 34% of VITT cases in Taiwan. The sensitivity of this proposed definition was 100% for Germany and UK, 92% for Australia, and 89% for Taiwan cases. These findings support the validity of this case definition for VITT.

Anti-platelet factor 4 immunothrombotic syndromes.

Anti-platelet factor 4 immunothrombotic syndromes comprise a group of disorders that include heparin-induced thrombocytopenia and vaccine-induced immune thrombocytopenia and thrombosis. These are highly prothrombotic, immunological disorders characterised by specific clinical and pathological criteria which include thrombocytopenia and thrombosis. While they are predominantly triggered by heparin and the adenoviral vector vaccines, respectively, other provoking factors have been described, as well as spontaneous forms. The unexplained co-occurrence of thrombocytopenia with thrombosis should raise suspicion and prompt testing. This nutshell review discusses the pathophysiology, presenting features and diagnostic criteria for these conditions.

Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Venous thromboembolism in pregnant obese Individuals.

Venous thrombosis and thromboembolism (VTE) remain the leading cause of direct maternal deaths, occurring within 42 days of the end of pregnancy in the UK. Pregnancy is associated with an overall 10-fold higher incidence of VTE than in the non-pregnant state and has been reported to reach up to 30-fold higher in the puerperium. This increased risk is further exacerbated by maternal obesity in a relationship that appears to be proportional with increasing Body Mass Index (BMI). Maternal obesity is the most common health problem in women of reproductive age with clinically significant health risks to women during pregnancy and after delivery. It is associated with poor perinatal and maternal outcomes, The incidence of maternal obesity has increased significantly worldwide over the last few decades and increasingly, pregnancy is being complicated by extreme or morbid obesity. In this review we discuss the challenges associated with the diagnosis and management of VTE in obese pregnant women and provide a review of the available current evidence.

Thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced immune thrombocytopenia and thrombosis (VITT): Brighton Collaboration case definitions and guidelines for data collection, analysis, and presentation of immunisation safety data.

This is a revision of the online November 2021 Brighton thrombosis with thrombocytopenia syndrome (TTS) case definition and a new Brighton Collaboration case definition for vaccine-induced immune thrombocytopenia and thrombosis (VITT). These case definitions are intended for use in clinical trials and post-licensure pharmacovigilance activities to facilitate safety data comparability across multiple settings. They are not intended to guide clinical management. The case definitions were developed by a group of subject matter and Brighton Collaboration process experts as part of the Coalition for Epidemic Preparedness Innovations (CEPI)-funded Safety Platform for Evaluation of vACcines (SPEAC). The case definitions, each with defined levels of diagnostic certainty, are based on relevant published evidence and expert consensus and are accompanied by specific guidelines for TTS and VITT data collection and analysis. The document underwent peer review by a reference group of vaccine safety stakeholders and haematology experts to ensure case definition useability, applicability and scientific integrity.

Qualitative study of the consequences of vaccine-induced immune thrombocytopenia and thrombosis: the experiences of family members.

OBJECTIVES: To explore the experiences of family members of patients who died or survived following a diagnosis of vaccine-induced immune thrombocytopenia and thrombosis (VITT). DESIGN: A semistructured qualitative study, conducted via Zoom. SETTING: Participants discussed their experiences during hospitalisation and following discharge. PARTICIPANTS: Sixteen family members of patients with VITT (survivors=11; bereaved=5), recruited via a Facebook support group and advertising on Twitter. RESULTS: Analysis identified two themes common to both groups of participants: the stress of hospitalisation and the experience of multiple losses. A third theme, living with VITT, was unique to the survivor group and a fourth, battling against the system, was predominantly reported by bereaved participants. CONCLUSIONS: This is a significantly challenged group of people, with multiple emotional, financial, social and psychological losses. These losses have been compounded by experiences of limited governmental and societal recognition of the problems they face.

Living with vaccine-induced immune thrombocytopenia and thrombosis: a qualitative study.

OBJECTIVES: To explore the experiences of people up to 18 months after being diagnosed with vaccine-induced immune thrombocytopenia and thrombosis (VITT). DESIGN: A semistructured qualitative study, conducted via Zoom, of a cohort of people with VITT. SETTING: Participants discussed their experiences of hospitalisation and following discharge. PARTICIPANTS: 14 individuals diagnosed with VITT, recruited via a Facebook support group and advertising on Twitter. RESULTS: Thematic analysis identified challenges of obtaining medical care and diagnosis; fear of the severity of symptoms and unclear prognosis; and lack of family support due to isolation imposed by the COVID-19 pandemic. Once home, participants experienced continued significant symptoms; fear of recurrence; inadequate medical knowledge of their condition; and difficulties coping with residual physical disabilities and psychosocial losses. Also reported were feelings of isolation and abandonment due to lack of government support. CONCLUSIONS: This is a significantly challenged group of people, with multiple health, financial, social and psychological losses. These losses have been compounded by experiences of limited governmental and societal recognition of the problems they face.

Clear and present danger: Mechanical heart valves in pregnancy.

Specialists in Obstetric Haematology continue to be challenged by pregnant women with mechanical heart valves, who are at high risk of death or severe morbidity. Effective anticoagulation to reduce valve thrombosis inevitably increases risk of obstetric haemorrhage and fetal loss or harm, and difficult decisions need to be made. Lester and mulitdisciplinary colleagues on behalf of the British Society for Haematology review available evidence and provide comprehensive recommendations to guide management in this difficult area. Commentary on: Lester et al. British Society for Haematology guideline for anticoagulant management of pregnant individuals with mechanical heart valves. Br J Haematol 2023;202:465-478.

COVID-19-related adrenal haemorrhage: Multicentre UK experience and systematic review of the literature.

OBJECTIVE: Adrenal haemorrhage (AH) is an uncommon, usually incidental imaging finding in acutely unwell patients. AH has been reported during coronavirus disease 2019 (COVID-19) infection and following ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccination. The Society for Endocrinology (SfE) established a task force to describe the UK experience of COVID-19-related AH. DESIGN: A systematic literature review was undertaken. A survey was conducted through the SfE clinical membership to identify patients with COVID-19-related AH using a standardized data collection tool. RESULTS: The literature search yielded 25 cases of COVID-19-related AH (19 bilateral; 13 infection-related, and 12 vaccine-related). Eight UK centres responded to the survey with at least one case. A total of 18 cases were included in the descriptive study, including 11 from the survey and 7 UK-based patients from the systematic review. Seven patients (4 males; median age 53 (range 26-70) years), had infection-related AH (four bilateral). Median time from positive COVID-19 test to AH detection was 8 (range 1-30) days. Eleven cases of vaccine-related AH (eight bilateral) were captured (3 males; median age 47 (range 23-78) years). Median time between vaccination (nine Oxford-AstraZeneca and two Pfizer-BioNTech) and AH was 9 (range 2-27) days; 9/11 AH occurred after the first vaccine dose. Acute abdominal pain was the commonest presentation (72%) in AH of any cause. All 12 patients with bilateral AH and one patient with unilateral AH required glucocorticoid replacement. CONCLUSION: Adrenal haemorrhage with consequential adrenal insufficiency can be a complication of COVID-19 infection and vaccination. Adrenal function assessment is mandatory to avoid the potentially fatal consequences of unrecognized adrenal insufficiency.

Real world reduction in red cell transfusion with restrictive transfusion threshold in haematology inpatients.

OBJECTIVES: The aim of this study was to assess the reduction in red cell transfusions following a change in the red cell transfusion threshold for haematology inpatients from 80 to 70 g/L. BACKGROUND: Haematology patients are among the high users of red blood cells. We reduced the threshold for transfusion of haematology inpatients to 70 g/L. This was based on evidence provided by randomised controlled trial published in 2020 that showed restrictive transfusion is non-inferior to liberal transfusion. METHOD: We assessed red cell transfusions for haematology inpatients at Oxford University Hospitals NHS Foundation Trust for 9 months before and 9 months after a change in red cell transfusion threshold from 80 to 70 g/L. RESULTS: After the change in threshold to 70 g/L or less from 80 g/L, the median number of red cell transfusions per month reduced to 88 from 111. This was a 23% reduction in the total number of red cells administered per month. CONCLUSION: These results show the real-world reductions in transfusion that can be made by putting local transfusion guidelines in line with the international recommendations. This is of particular importance at a time of national blood shortage.

Drug-induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data.

Many medications have been reported to be associated with thrombotic thrombocytopenic purpura (TTP) through pharmacovigilance data and published case reports. Whilst there are existing data available regarding drug-induced thrombotic microangiopathy, there is no available synthesis of evidence to assess drug-induced TTP (DI-TTP). Despite this lack of evidence, patients with TTP are often advised against using many medications due to the theoretical risk of DI-TTP. This systematic review evaluated the evidence for an association of medications reported as potential triggers for TTP. Of 5098 records available 261 articles were assessed further for eligibility. Fifty-seven reports, totalling 90 patients, were included in the final analysis. There were no cases where the level of association was rated as definite or probable, demonstrating a lack of evidence of any drug causing DI-TTP. This paucity of evidence was also demonstrated in the pharmacovigilance data, where 613 drugs were reported as potential causes of TTP without assessment of the strength of association. This systematic review demonstrates the need for standardised reporting of potential drugs causing TTP. Many reports omit basic information and, therefore, hinder the chance of finding a causative link if one exists.

Maternal iron deficiency anaemia in pregnancy: Lessons from a national audit.

We describe the management and the prevalence of iron deficiency anaemia (IDA) during pregnancy by comparison to standards. A cross-sectional national cohort study of women who had given birth six weeks prior to data collection was conducted at maternity units in the UK and Ireland. Participating centres collected data from 10 consecutive pregnant women. Analysis was descriptive to define the prevalence of IDA in pregnancy and the puerperium, and to compare the outcomes in women who had IDA with women who did not have anaemia anytime during pregnancy. Eighty-six maternity units contributed data on 860 pregnancies and births. The overall prevalence of IDA during pregnancy was 30.4% and in the puerperium 20%. Anaemic women were more likely to be from ethnic minorities, odds ratio 2.23 (1.50, 3.32). Adherence to national guidance was suboptimal, and the prevalence of anaemia in pregnancy remains very high. There is pressing need to explore barriers to early identification and effective management of iron deficiency. IDA should be considered a major public health problem in the UK.

Kidney Transplantation From Deceased Donors With Vaccine-induced Immune Thrombocytopenia and Thrombosis: An Updated Analysis of the UK Experience.

BACKGROUND: The emergence and attendant mortality of vaccine-induced immune thrombocytopenia and thrombosis (VITT) as a consequence of vaccination against severe acute respiratory syndrome coronavirus 2 have resulted in some patients with VITT being considered as deceased organ donors. Outcomes after kidney transplantation in this context are poorly described. Because the disease seems to be mediated by antiplatelet factor 4 antibodies, there is a theoretical risk of transmission via passenger leukocytes within the allograft. METHODS: We analyzed the experience of kidney transplantation from donors with VITT in the United Kingdom between January and June 2021. We followed-up all recipients of kidney-only transplants from donors with VITT to detect major postoperative complications or features of disease transmission and assess graft survival and function. RESULTS: There were 16 kidney donors and 30 single kidney transplant recipients in our study period. Of 11 preimplantation biopsies, 4 showed widespread glomerular microthrombi. After a median of 5 mo, patient and graft survival were 97% and 90%, respectively. The median 3-mo estimated glomerular filtration rate was 51 mL/min/1.73 m 2 . Two recipients had detectable antiplatelet factor 4 antibodies but no evidence of clinical disease after transplantation. Major hemorrhagic complications occurred in 3 recipients, all of whom had independent risk factors for bleeding, resulting in the loss of 2 grafts. The involvement of VITT could not be completely excluded in one of these cases. CONCLUSIONS: The UK experience to date shows that favorable outcomes are possible after kidney transplantation from donors with VITT but highlights the need for ongoing vigilance for donor-related complications in these patients.

A case of ChAdOx1 vaccine-induced thrombocytopenia and thrombosis syndrome leading to bilateral adrenal haemorrhage and adrenal insufficiency.

Summary: Vaccine-induced thrombosis and thrombocytopenia (VITT) after vaccination against SARS-CoV-2 with the adenoviral vector-based vaccines ChAdOx1 and Ad26.COV2.S has been associated with adrenal pathology, such as bilateral adrenal vein thrombosis, adrenal cortex haemorrhage and adrenal insufficiency in 6% of patients. We report the case of a 23-year-old woman who presented at 8 days after ChAdOx1 vaccination with a low platelet count of 43 × 109/L, raised d dimers >100 000 ng/mL and multiple lobar and segmental pulmonary emboli. Anti-platelet factor 4 antibodies were detected confirming definite VITT in accordance with the UK diagneostic criteria. At 16 days post-vaccine, further imaging showed bilateral adrenal haemorrhage, non-occlusive splenic vein thrombosis and right ventricular thrombosis. Her cortisol level was <25 nmol/L. She was treated with anticoagulation, plasmapheresis, immunosuppression and steroid replacement. She had high anti-spike titre and positive anti-nucleocapsid titres for SARS-CoV-2. She developed seizures secondary to posterior reversible encephalopathy, requiring intensive care. After 4 weeks in hospital, she was discharged on warfarin, hydrocortisone and fludrocortisone replacement. Short synacthen tests 3 and 9 months later showed no recovery of adrenal function, although magnetic resonance imaging of the adrenal glands showed resolving adrenal haemorrhage. Adrenal insufficiency secondary to bilateral adrenal vein thrombosis and adrenal haemorrhage should be suspected in patients with VITT and treated promptly. Adrenal vein thrombosis can occur either as the initial presentation of VITT or days to weeks after the development of thrombosis in other sites. Further studies are required to provide insight on adrenal function recovery after VITT. Learning points: Adrenal insufficiency secondary to bilateral adrenal vein thrombosis and adrenal cortex haemorrhage should be suspected in patients with vaccine-induced thrombosis and thrombocytopenia (VITT) and treated promptly. Adrenal vein thrombosis can occur as the initial presentation of VITT or even days to weeks later after the development of thrombosis in other more classic sites (e.g. pulmonary or cerebral vasculature). Completion of vaccination schedule against SARS-CoV-2 post-VITT using an mRNA-based vaccine should be recommended to patients post-VITT as mRNA-based vaccines have not been associated with VITT but confer protection against SARS-CoV-2. There is paucity of data regarding the potential for recovery of adrenal function after bilateral adrenal haemorrhage in the context of VITT, and thus, more studies are needed to inform clinical practice. The need for disease registries for rare conditions, such as VITT, is crucial as direct cooperation and sharing of information by clinicians might enable quicker identification of disease patterns than would have been possible via established reporting tools of adverse events.

The psychiatric and psychological sequelae of vaccine-induced immune thrombotic thrombocytopenia (VITT).

This review paper explores the potential psychiatric and psychological sequelae of vaccine-induced immune thrombotic thrombocytopenia, also called vaccine-induced immune thrombocytopenia, and thrombosis (VITT). In the absence of any literature to date we have extrapolated data from similar conditions, particularly data pertaining to the critical care population. We discuss both the direct and indirect effects of thrombosis, likely psychiatric and psychological challenges during recovery, and ethical issues around vaccination. We have also suggested a comprehensive guide to the psychiatric assessment and management of patients presenting with VITT with the aim of early identification of problems and maximizing rehabilitation potential and quality of life.

Clinical picture of VITT.

This chapter explores the clinical features of vaccine-induced immune thrombotic thrombocytopenia, also called vaccine-induced immune thrombocytopenia and thrombosis (VITT). Whilst the etiology is distinct from other causes of thrombotic thrombocytopenia syndrome (TTS), presentation may be similar and hence the need for strict diagnostic criteria to ensure accurate and prompt diagnosis and early treatment. Studies have identified prognostic markers of the disease, directing therapy and management pathways, and mortality and morbidity from this rare but life-threatening and potentially disabling consequence of the ChAdOx1 nCov-19 vaccine has declined.