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Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality.To compare current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better understand the issues affecting prompt initiation of PEX.The trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP.Data on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on-site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two-thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation.This is the first multi-center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life-saving intervention.

Resistance to immunomodulatory drugs (IMiDs®) is a major cause of treatment failure, disease relapse and ultimately poorer outcomes in multiple myeloma (MM). In order to optimally deploy IMiDs and their newer derivates CRBN E3 ligase modulators (CELMoDs®) into future myeloma therapeutic regimens, it is imperative to understand the mechanisms behind the inevitable emergence of IMiD resistance. IMiDs bind and modulate Cereblon (CRBN), the substrate receptor of the CUL4CRBNE3 ubiquitin ligase, to target novel substrate proteins for ubiquitination and degradation. Most important of these are IKZF1 and IKZF3, key MM survival transcription factors which sustain the expression of myeloma oncogenes IRF4 and MYC. IMiDs directly target MM cell proliferation, but also stimulate T/NK cell activation by their CRBN-mediated effects, and therefore enhance anti-MM immunity. Thus, their benefits in myeloma are directed against tumor and immune microenvironment – and in considering the mechanisms by which IMiD resistance emerges, both these effects must be appraised. CRBN-dependent mechanisms of IMiD resistance, includingCRBNgenetic aberrations, CRBN protein loss and CRBN-substrate binding defects, are beginning to be understood. However, only a proportion of IMiD-resistant cases are related to CRBN and therefore additional mechanisms, which are currently less well described, need to be sought. These include resistance within the immune microenvironment. Here we review the existing evidence on both tumor and immune microenvironment mechanisms of resistance to IMiDs, pose important questions for future study, and consider how knowledge regarding resistance mechanism may be utilized to guide treatment decision making in the clinic.

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.

IgM paraprotein-associated peripheral neuropathy (PN) in patients without overt evidence of lymphoma is a recognised clinical entity of unknown aetiology. Interrogating the bone marrow B-cell or plasma cell clones underlying paraproteinemic neuropathies may improve our understanding of both pathogenesis and treatment options. This retrospective observational analysis of IgM paraprotein-associated PN identified five patients with small pathological MYD88 L265P and CD20-positive B-cell clones in their bone marrow using multi-parametric flow cytometry, who have shown durable neurological response to rituximab. We posit that multi-parametric flow cytometry may be instrumental in identifying the cellular source of the paraprotein in IgM paraprotein-associated PN, and thus directing appropriate immunomodulatory therapy. Further understanding of these small pathological B-cell clones may also provide additional insight into mechanisms of monoclonal gammopathy of clinical significance overall.

The bottom line A previously well 25 year old man presents to his general practitioner with a six month history of crampy abdominal pain, bloating, and diarrhoea, with passage of loose stools up to six times a day. There is urgency but no incontinence. On clinical examination he has mild lower abdominal tenderness, but digital rectal examination is normal. Chronic diarrhoea can be defined pragmatically as the passage of loose stools more than three times a day for at least four weeks.1 A patient’s own perception of diarrhoea may be markedly different, and it is essential to clarify—for example, faecal incontinence is commonly misconstrued as diarrhoea.1 Irritable bowel syndrome (IBS), a functional disorder, is the most prevalent cause of chronic diarrhoea.2 Other important causes include inflammation (inflammatory bowel disease (IBD), microscopic colitis, and more rarely infection), bile acid diarrhoea, malabsorption (coeliac disease, lactose intolerance, and pancreatic insufficiency), drugs, food additives, and endocrine conditions (thyrotoxicosis and diabetes). Clinicians should always be mindful of an underlying cancer, particularly in patients over 45 years, and …