Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.

BACKGROUND: A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes. METHODS: For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 µg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3-6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis. FINDINGS: Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32-55) was lower than in the non-VITT group (57 years; 41-62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2-4) than non-VITT patients (two, 2-3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022). INTERPRETATION: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate. FUNDING: None.

Symptomatic Erythrocytosis Due to Homozygosity for Hb Luton [HBA2: c.269A>T (or HBA1)] and α-Thalassemia: A Clinical Update.

A female proband homozygous for both Hb Luton [α89(FG1)His→Leu (CAC>CTC), HBA2: c.269A>T (or HBA1)], a high oxygen affinity hemoglobin (Hb), and for α(+)-thalassemia (α-thal), (-α(4.2), leftward deletion) was first described in 2012. This is a follow-up report of the same case. At the age of 18, the described patient presented with progressively worsening lethargy, headaches, dizziness, syncope and Raynaud's phenomenon. Following extensive cardiological and neurological investigation, it was felt that significant erythrocytosis was the most likely cause. Venesection followed by regular exchange transfusions were arranged with marked amelioration in symptomatology. In the vast majority of cases of high oxygen affinity Hbs, venesection is not recommended due to the asymptomatic phenotype and reduced oxygen delivery resulting from venesection. This update describes the evolving phenotype of this unique proband and, to the best of our knowledge, the first use of regular, long-term therapeutic red cell exchange transfusions in a case of high affinity Hb.

Antibody-drug conjugates for multiple myeloma.

Introduction: Antibody-drug conjugates (ADC) are a new class of treatment for multiple myeloma (MM) patients, delivering a potent cytotoxic agent directly to the myeloma cell. The target is defined by the specificity of the monoclonal antibody which is linked to the cytotoxic agent. This mechanism of action minimizes bystander cell injury and allows a favorable therapeutic window.Areas covered: This review describes the rationale, pre- and clinical data for ADCs that have been and are currently in development for MM. As the treatment landscape for MM rapidly evolves, the treatment paradigm and a description of novel agents in development including immunotherapies are provided to understand how ADCs may fit in the pathway.Expert opinion: ADCs have a significant potential for the treatment for MM. As they are 'off the shelf' treatments, they can be used across nearly all MM treatment centers and to a wide range of patients. Some ADCs have specific adverse events that may require specialist input to optimally manage. The most clinically advanced ADC is belantamab mafodotin which has demonstrated clinically meaningful responses in patients with heavily pre-treated MM. Additionally, it is being combined with standard of care agents and at earlier lines of treatment.

Blinatumomab, a bispecific B-cell and T-cell engaging antibody, in the treatment of B-cell malignancies.

Blinatumomab (Blincyto, Amgen), a bi-specific antibody, is a first-in-class, targeted immunotherapy agent for treatment of B-cell malignancies with a novel mechanism of action which involves in-vivo engagement of the patient's T cells with CD19-expressing tumour cells. Clinical trials have demonstrated its efficacy in relapsed B-cell Acute Lymphoblastic Leukaemia (B-ALL) and B-cell Non-Hodgkin's Lymphoma including in patients who are refractory to chemotherapy. This review summarises the development and design of Blinatumomab, the outcome of clinical studies demonstrating its efficacy and how to manage the administration, practically, including relevant toxicities. We compare and contrast it to other emerging agents for treatment of B-cell malignancies.

Service improvement system to enhance the safety of patients admitted on long-term warfarin.

It is common for hospital inpatients on warfarin to suffer from fluctuations in their INR (international normalised ratio). Raised INRs are potentially very dangerous and may result in acute life-threatening haemorrhages. Conversely, low INRs may increase the risk for the development of venous thromboembolism. Having observed many deranged INRs among hospital inpatients, we decided to focus our project on identifying the contributing factors to deranged INRs and ways to address this problem. We analysed the warfarin prescriptions on all drug charts and surveyed the junior doctor staff. Our results revealed poor knowledge and confidence levels on warfarin prescribing among junior doctor staff. This is likely to be reflected in the poor completion rate of warfarin prescriptions. We instituted practical changes to resolve the issue: most importantly, a change to the warfarin administration time from 6 pm to 2 pm, supported by a poster campaign to increase awareness of the problem. The objective of these changes was to reduce prescribing errors by reducing warfarin prescriptions out-of-hours, by the on-call doctors. We repeated the audit cycle twice. Although our interventions were successfully introduced as shown in our second audit cycle, the changes that were implemented were not sustained as shown in the third audit cycle. We identified a need for annual intervention to educate new junior doctor staff to ensure that the positive outcomes achieved are maintained in the long term.