Thrombocytopenia: the good, the bad and the ugly.

New thrombocytopenia may be associated with a variety of conditions and diagnosis can be challenging. Presentation can vary from life-threatening bleeding or thrombosis to an incidental finding in an asymptomatic patient. New thrombocytopenia requires urgent investigation. Investigations are mainly guided by findings from the clinical history, physical examination, full blood count and blood film analysis. Aside from the actively bleeding patient, rare but life-threatening causes of thrombocytopenia must be identified early as they require urgent treatment. These include thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, suspicion of new acute promyelocytic leukaemia, and vaccine-induced prothrombotic immune thrombocytopenia. Here, we discuss how to approach a patient with new thrombocytopenia, along with key differentials not to be missed.

Acute leukaemia: no reason to panic.

Acute leukaemia is characterised by uncontrolled expansion of immature leukocytes, either myeloid or lymphoid progenitors, leading to acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL), respectively. If left untreated, it is life-threatening and can lead to death within weeks. When acute leukaemia is suspected, urgent haematology input should be sought. Appropriate investigations are needed promptly to confirm diagnosis and start treatment. A multidisciplinary approach is vital to ensure appropriate management.

Targeting the Non-Canonical NF-κB Pathway in Chronic Lymphocytic Leukemia and Multiple Myeloma.

In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-κB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-κB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-κB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-κB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation.

Do more mature preterm babies with surgical necrotizing enterocolitis predominantly develop the colonic disease?

Background: The primary aim was to scrutinize our hypothesis: "Do more mature preterm (MMP) babies with surgical necrotizing enterocolitis (NEC) predominantly develop the colonic disease and are different in their response and behaviour in comparison to exceedingly preterm (EP) babies?" Secondary outcomes were to define time taken in developing NEC, time from diagnosis to laparotomy, requirement of parenteral nutrition (PN), and ventilatory support. Methods: We defined MMP babies as ≥30 weeks of gestation and EP babies as ≤29 weeks+6 days of gestation. Inclusion criteria were all babies <37 weeks with NEC requiring surgery (called surgical NEC group). Data were collected retrospectively and analyzed using QuickCalcs. Results: Of the total, 41% (97/234) of babies underwent laparotomy between 2010 and 2019. Totally, 81% were EP and 19% were MMP babies. Pure colonic involvement was seen in 9% of EP babies in comparison to 56% in the MMP babies (p=0.0001). Involvement of only the small bowel was seen in two-thirds of EP babies in comparison to only one-third in MMP babies (p=0.01). EP cohort required PN for 82 days (median) in comparison to 17 days (median) in the MMP cohort (p=0.001). Ventilation requirement in the EP group versus the MMP group was 24 vs 9 days (median), respectively (p=0.0006). Conclusions: MMP babies predominantly developed colonic disease, whereas EP babies predominantly developed small bowel disease. EP babies required a longer duration of PN and ventilation support. This study opens a new area of research to differentiate pathogenesis and maturation patterns of the small and large bowels in babies with NEC.

Reversal of Intestinal Failure in Children With Tufting Enteropathy Supported With Parenteral Nutrition at Home.

OBJECTIVES: The aim of the study was to review long-term outcome of intestinal epithelial dysplasia (IED)/tufting enteropathy (TE) patients treated with parenteral nutrition (PN) at home managed by an intestinal failure (IF) rehabilitation service. METHODS: Infants presenting from 1986 to 2010 with IF, and TE histology were retrospectively reviewed for up to 30 years. Data collected included outcome, presentation, nutrition (parenteral/enteral), country of residence, race, EpCAM gene, growth, bone age, and occupation. RESULTS: Thirteen patients (6 boys) in Malta and the UK with TE histology were established on home PN. Survival was 100% for UK children and 92% overall (1 death aged 13 months). Six patients (50% of the surviving 12) weaned off PN. Overall PN requirements reduced with increasing age and <7 infusions/week were needed by 10/12, 83% by 10 years, 6/8, 75% who had reached 15 years, 5/7, 71% who had reached 20, and all 4, 100% >25 years. Two of 12 cases weaned from PN by 10 years, 1 of 8 by 15 years, 3 of 7 by 20 years, and 3 of 4 or 75% >25 years. Seven Maltese patients homozygous for the same EPCAM gene abnormality had a similar outcome to the other cases. Weight, height, bone mineralization, bone age, and insulin-like growth factor-1 (IGF-1) levels were low, but improved with age. Patients achieved educational levels of parents and were employed. CONCLUSIONS: IED cases should have >92% chance of long-term survival and >50% chance of enteral autonomy by/in early adult life and 75% by 25 years. Even if PN dependent s/he can gain employment. Patients with IED managed on PN at home by an IF rehabilitation service should avoid intestinal transplant.