One Haemolytic Anaemia May Hide Another: Paroxysmal Nocturnal Haemoglobinuria Masquerading As Plasmodium Falciparum Infection.

Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, genetic and acquired haematologic disease that causes complement-mediated intravascular haemolytic anaemia, thrombosis and bone marrow failure. Case description: A 27-year-old migrant patient attended the emergency department in a context of fever and chills over the previous few days as well as chronic fatigue, dyspnoea and chest pain. His medical history included chronic anaemia and erectile dysfunction. Initial biology showed a haemoglobin of 6.3 g/dl, platelets of 25,000/µl, total leucocytes of 3,500/µl with 1,500 neutrophils. B12 vitamin, folic acid, ferritin and thyroid stimulating hormone were normal. Lactate dehydrogenase levels were high and haptoglobin was non-measurable. C-reactive protein was 46.1 mg/l. A thick blood smear revealed Plasmodium falciparum infection with 0.1% parasitaemia. The patient was treated with an oral combination of artemether and lumefantrine. Three weeks later, the patient consulted the infectious disease department given the lack of clinical improvement. The cytopenias worsened, and lactate dehydrogenase (LDH) and reticulocytes increased. Tests for schistocytes, a thick blood smear for malaria and a direct Coombs test were negative; a myelogram was reassuring. An abdominal, pelvic and thoracic CT scan showed a mild hepatomegaly with no focal lesion and no splenomegaly or adenomegaly. A 12-colour flow cytometry unveiled a PNH clone on 90.9545% of neutrophils and 80.7371% of monocytes. Discussion: PNH patients can be vulnerable to parasites infection (such as P. falciparum) as it may trigger breakthrough haemolysis through uncontrolled resurgence of activity of the complement system. In our patient, P. falciparum infection was a confounding factor, as it commonly causes haemolytic anaemia and thrombocytopenia, and patients living in malaria-endemic regions can carry low parasitaemia while being slightly symptomatic or asymptomatic. LEARNING POINTS: Plasmodium falciparum infection can cause breakthrough haemolysis in patients with paroxysmal nocturnal haemoglobinuria.Low P. falciparum parasitemia in patients living in malaria-endemic regions is not always significant as these patients often carry acquired immunity.Patients from malaria-endemic regions presenting with severe sickness and low P. falciparum parasitemia must be assessed for other diseases, as it cannot explain heavy illness.Patients presenting with haemolytic anaemia, no schistocytes, a negative direct Coombs test and other unexplained cytopenia such as thrombocytopenia/neutropenia and other unexplained clinical manifestations such as dyspnoea, chest pain or erectile dysfunction should be assessed for paroxysmal nocturnal haemoglobinuria.

The effects of drone transportation on blood component quality: A prospective randomised controlled laboratory study.

The use of uncrewed aerial vehicles (drones) has increased over the last decade. However, their application in healthcare has not been fully examined, in part, due to regulations preventing flight beyond the visual line of sight. This prospective randomised controlled laboratory study aimed to determine whether the in vitro quality of packed red blood cell components is maintained when transported by drone, beyond visual line of sight. Ten identical pairs of packed red blood cell units were randomly allocated to transport by drone or by ground vehicle (1:1, allocation concealment) 68 km between two hospitals in Northumbria, UK. Markers of blood component quality were compared at 8, 14, 28 and 35 days following blood unit manufacture. There was no statistical difference in haemolysis, potassium concentration, total haemoglobin, glucose and lactate, haematocrit and mean cell volume, between the two groups, up to the date of unit expiry. The temperature of the packed red blood cell units did not deviate outside the recommended 2-10°C for transportation, regardless of the allocated group. Blood component transport was faster by drone, but did not reach statistical significance. This study demonstrates the feasibility and safety of flying blood components by drone between hospitals in the United Kingdom.

Adjustment of lactate dehydrogenase concentration results according to the haemolysis index following in vitro haemolysis.

In the presence of haemolysis, the interpretation of the Lactate dehydrogenase (LDH) activity result is a major operational challenge for medical laboratories: if the origin is intravascular, then the measurement will reflect the clinical reality, but in extravascular haemolysis, the laboratory will be confronted with an artefactual increase leading to false-positive high results. The aim of our study was to evaluate the adjustment of LDH concentration results according to the haemolysis index (HI). After designed a mathematical model to correct the LDH measured as a function of the haemolysis index using a Cobas 8000 analyser (Roche diagnostics, Mannheim, Germany), LDH measurement of seventy-four duplicate samples were tested before and after exposure to extravascular haemolysis process. After in vitro haemolysis process, a significant increase haemolysis index (Man-Whitney U-Test p < 0.0001) were observed. Before process the HI median was 4 [2.0 - 6.75] and after HI median was 18 [10 - 35.75]. Without correction, LDH results showed a significant increase (p < 0.001) after haemolysis process and substantial analytical discrepancies (31/74) were observed according to TEa of CLIA. After correction, data showed no significant difference (p = 0.497) and the mathematical algorithm allowed to reduce the analytical discrepancies (2/74). If haemolysis was present in vitro, the mathematical algorithm increased the accuracy of the LDH results. However, the lack of discrimination between in vivo and in vitro haemolysis requires caution and the results should be reported only as a commentary to inform the clinician.

Long-term efficacy and safety of continued complement C1s inhibition with sutimlimab in cold agglutinin disease: CADENZA study Part B.

Background: Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated. Methods: The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. Findings: In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment vs 9.3 g/dL at baseline), bilirubin (≤20.0 µmol/L on-treatment vs 35.0 µmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD. Interpretation: The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs. Funding: Sanofi.

Changes in Red Cell Morphology and Haematological Laboratory Parameters Associated With Alectinib.

BACKGROUND: Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-mutated non-small-cell lung cancer. Recently, the association between alectinib and red cell morphological abnormalities has been reported in a few case series. This retrospective observational study aims to determine the frequency of occurrence of acanthocytosis in patients taking alectinib and to evaluate the red cell indices, biochemical markers of haemolysis and eosin-5-maleimide (EMA) binding assay results in patients receiving alectinib. METHODS: Patients who were on alectinib and had a complete blood count test performed in Queen Elizabeth Hospital Haematology Laboratory between 1 May 2021 and 31 August 2021 were included in the study. Haematological investigations that had been performed before and after the commencement of alectinib were reviewed. RESULTS: Fifty patients receiving alectinib were evaluated in this analysis. One hundred per cent of patients showed 3+ acanthocytes on the peripheral blood smears. Compared with the test results before starting alectinib, the post-alectinib blood tests showed a significantly lower haemoglobin concentration, red blood cell count and haematocrit; and a significantly higher mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and red cell distribution width. All the tested patients showed a marked reduction in EMA mean channel fluorescence compared with normal control. CONCLUSION: Our cohort revealed that alectinib caused significant acanthocytosis in all patients. Alectinib was also associated with changes in red cell indices and biochemical markers of haemolysis, compatible with a spherocytic and anisopoikilocytic morphology with haemolysis. Patients on alectinib had reduced EMA binding.

Study of Haemolysis in Patients of Leprosy Being Administered Multi-Drug Therapy at a Tertiary Care Hospital in Western Maharashtra: A Prospective Study.

Introduction: Dapsone forms the backbone of multi-drug therapy (MDT) in leprosy and many other dermatological disorders. Haemolysis is its common side effect which often necessitates drug stoppage. Currently, wide variation in data of haemolysis with dapsone exists in literature ranging from 24.7% to 83% and none of the studies point towards the timing of onset of haemolysis/timing of maximal haemolysis which is important in therapeutic decision making regarding continuing or stopping the drug. This study aimed to answer such unanswered questions. Objectives: Primary: To estimate the fall in haemoglobin (Hb) levels after administering MDT for 3 months in patients with leprosy. Secondary: To determine factors associated with Hb change - age, glucose-6-phosphate dehydrogenase (G6PD) status, pole of leprosy and duration of MDT taken (if any). Materials and Methods: All freshly diagnosed cases of Hansen's disease were studied for 3 months. At baseline, demographic data (age, sex), skin biopsy, slit skin smear and G6PD were taken. Haemoglobin (Hb), serum glutamate oxaloacetate transferase (SGOT), serum glutamate pyruvate transferase (SGPT), serum bilirubin, lactate dehydrogenase (LDH), reticulocyte count, peripheral blood smear (PBS) along with clinical photography was done at baseline, 1, 2 and 3 months. Results: Out of the 48 patients who completed the study: Mean Hb (g/dL) decreased from 13.37 at baseline to a minimum of 12.08 at 2 months, and then increased to 12.34 at 3 months. Of 42 patients (87.5%) with a fall in Hb, 13 (27.1%) had severe (fall >20%), 17 (35.4%) had moderate (fall 10-20%), 12 (25%) had mild fall (fall <10%) and in 6 (12.5%), there was no haemolysis. Reticulocyte count, LDH, SGOT and SGPT were significantly associated with haemolysis. Severe haemolysis occurred more frequently in the lepromatous spectrum. Conclusion: Dapsone causes maximal fall of hemoglobin by 1.29 g/dl at two months following which it increases. The fall of hemoglobin is reversible and hemoglobin starts to increase by 3 months of therapy making cessation of the drug unnecessary in most of the patients.

Consensus recommendations for optimising the diagnosis and treatment of paroxysmal nocturnal haemoglobinuria in Singapore.

Introduction: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematologic disease characterised by intravascular haemolysis, thrombophilia and bone marrow failure. There is a lack of established clinical guidance on the screening, diagnosis and manage-ment of PNH in Singapore. A relatively low level of awareness among healthcare professionals regarding PNH manifestations further contributes to diagnostic delays. Additionally, limited access to complement inhibitors, like eculizumab, may delay treatment and impact patient outcomes. Method: Nine haematologists from different institu-tions in Singapore convened to formulate evidence-based consensus recommendations for optimising the diagnosis and management of patients with PNH and improving access to novel treatments. The experts reviewed the existing literature and international guidelines published from January 2010 to July 2023, focusing on 7 clinical questions spanning PNH screening, diagnostic criteria, investigations, treatment and monitoring of subclinical and classic disease, PNH with underlying bone marrow disorders, and PNH in pregnancy. A total of 181 papers were reviewed to formulate the statements. All experts voted on the statements via 2 rounds of Delphi and convened for an expert panel discussion to finetune the recommendations. Results: Sixteen statements have been formulated for optimising the screening, diagnosis and management of PNH. Upon confirmation of PNH diagnosis, individuals with active haemolysis and/or thrombosis should be considered for anti-complement therapy, with eculizumab being the only approved drug in Singapore. Conclusion: The current recommendations aim to guide the clinicians in optimising the screening, diagnosis and management of PNH in Singapore.

Mild Systemic Inflammation Increases Erythrocyte Fragility.

There is growing evidence that inflammation impairs erythrocyte structure and function. We assessed the impact of mild systemic inflammation on erythrocyte fragility in three different settings. In order to investigate causation, erythrocyte osmotic fragility was measured in mice challenged with a live attenuated bacterial strain to induce low-grade systemic inflammation; a significant increase in erythrocyte osmotic fragility was observed. To gather evidence that systemic inflammation is associated with erythrocyte fragility in humans, two observational studies were conducted. First, using a retrospective study design, the relationship between reticulocyte-based surrogate markers of haemolysis and high-sensitivity C-reactive protein was investigated in 9292 healthy participants of the UK Biobank project. Secondly, we prospectively assessed the relationship between systemic inflammation (measured by the urinary neopterin/creatinine ratio) and erythrocyte osmotic fragility in a mixed population (n = 54) of healthy volunteers and individuals with long-term medical conditions. Both human studies were in keeping with a relationship between inflammation and erythrocyte fragility. Taken together, we conclude that mild systemic inflammation increases erythrocyte fragility and may contribute to haemolysis. Further research is needed to assess the molecular underpinnings of this pathway and the clinical implications in inflammatory conditions.

Screening, genotyping and haematological analysis of glucose-6-phosphate dehydrogenase deficiency in the blood donors of Wuxi City, China.

BACKGROUND AND OBJECTIVES: To investigate the prevalence, genotype and haematological characteristics of glucose-6-phosphate dehydrogenase (G6PD) deficiency in the blood donor population of Wuxi area (Jiangsu Province, China) and to assess the impact of their red blood cell (RBC) units on clinical transfusion. MATERIALS AND METHODS: We conducted genotyping and large-scale screening for G6PD enzyme activity in the blood donors of Wuxi City. In addition, we assessed the haematological parameters of G6PD-deficient and non-deficient blood donors, and investigated the adverse transfusion reactions in patients transfused with G6PD-deficient blood. RESULTS: We investigated 17,113 blood donors, among whom 44 (0.26%) were tested positive for G6PD deficiency. We identified 40 G6PD gene variants, among which c.1388G>A, c.1376G>T, c.1024C>T and c.95A>G were common. In addition, we identified two novel G6PD gene variants, c.1312G>A and c.1316G>A. The G6PD-deficient and non-deficient blood samples showed a significant difference in the RBC, mean corpuscular volume (MCV), mean corpuscular Hb (MCH), RBC distribution width, total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) values. However, the two samples showed no significant difference in the haemolysis rate at the end of the storage period. Finally, transfusion with G6PD-deficient RBC units did not lead to any adverse transfusion reactions. CONCLUSION: The positive rate of G6PD deficiency in the blood donor population of Wuxi City is 0.26%, and the genetic variants identified in this population are consistent with the common genetic variants observed in the Chinese population. Blood centres can establish a database on G6PD-deficient blood donors and mark their RBC units to avoid their use for special clinical patients.

Determinants of the haemoglobin level in patients with sickle cell disease living in sub-Saharan Africa: Major impact of the country of residence and independent effects of leucocyte and platelet counts and haemolysis.

The degree of anaemia in sickle cell disease (SCD) is a well-known contributor to morbidity and mortality. We aimed to explore the factors affecting haemoglobin (Hb) level in African SCD patients, considering haemolysis biomarkers (LDH and bilirubin level, and reticulocyte count), leucocyte and platelet counts and socio-demographic characteristics (gender, age group, country of residence and BMI). The research was part of the CADRE multinational cohort and involved 3699 SCD patients living in Mali, Senegal, Ivory Coast, Democratic Republic of Congo, Gabon and Cameroon: 2936 SS/Sß0, 587 SC and 176 Sß + patients with median Hb level of 8, 11.3 and 11.2 g/dL respectively (p < 0.001). In multivariate analysis conducted in 1394 SS/Sß0 patients, living in Cameroon, female gender, lower BMI, higher haemolysis markers (especially LDH) and higher leucocyte and platelet counts were independently associated with lower Hb level (all p < 0.05). In 497 SC and 156 Sß + patients, female gender (p < 0.001), lower BMI (p < 0.05) and higher platelet counts (p < 0.001) were independently associated with lower Hb level. Anaemia in African SCD patients is not only associated with haemolysis but also with the country of residence, lower BMI and leucocyte or platelet counts which might reflect inflammation related to infectious burden in the region.

Preparation and Characterization of Ferulic Acid Hydrogel and Its Application as a Local Drug Delivery Agent in Periodontitis.

Introduction Periodontitis, a persistent inflammatory condition, impacts the tissues supporting teeth. Beyond mechanically eradicating the biofilm, additional host-modulating agents can aid in the treatment of periodontitis. Among these, gels are a very popular choice for use in the field of dentistry as these systems boast high biocompatibility and bioadhesiveness. These qualities make them easily administered and fabricated. They are typically placed into the periodontal site via wide-port needle syringes. Many investigations have demonstrated that hydrogels possess the ability for controlled drug release and aid in periodontal wound healing. Hence, this study aimed to develop a ferulic acid hydrogel and assess its effectiveness for managing periodontitis. Materials and methods Ferulic acid hydrogel was prepared followed by haemolysis assay and biocompatibility assay. After the in vitro analysis, a clinical trial was conducted: 20 patients were divided into Group A (comprising patients in whom scaling and root planing (SRP) was done) and Group B (comprising patients in whom SRP along with hydrogel application was done). Each patient's pocket depth (PD), clinical attachment loss (CAL), gingival index (GI), and plaque index (PI) were recorded at baseline and at three months. Intergroup and intragroup comparisons of the parameters were made. Results Ferulic acid hydrogels exhibit a minimal ratio of red blood cell destruction, indicating their low haemolytic activity. Beyond 94 hours, ferulic acid hydrogel demonstrates minimal toxicity towards human fibroblasts, suggesting it has good biocompatibility. When clinical parameters were compared after three months of treatment with SRP alone, significant reductions were observed in all parameters. However, when hydrogel application was done along with SRP, greater reduction was seen in terms of all clinical parameters indicating the efficacy of the ferulic acid hydrogel as an adjunct.  Conclusion Ferulic acid has distinct haemolytic activity as well as good biocompatibility. Its use also led to a considerable reduction in all clinical parameters, necessitating its role as a local drug delivery agent in the treatment of periodontitis.

Newly synthesized surfactants as antimicrobial and anti-adhesion agents.

Quaternary ammonium salts (QAS) are widely used in medicine, industry and agriculture as disinfectants, biocides, and fungicides. QAS have the ability to coat various surfaces, prevent adhesion of microorganisms to them and inhibit the formation of biofilm. A group of surfactants derived from benzoic acid with different chemical structures was tested: monomeric QAS with different alkyl chain lengths (C12, C14, C16), gemini QAS containing 12-carbon alkyl chains and linkers of various lengths (3,4,6 methylene groups), as well as multifunctional QAS. Among the tested surfactants, monomeric QAS showed the highest bactericidal and fungicidal activity. All three groups of tested compounds inhibited the filamentation of C. albicans. The best antimicrobial activity was demonstrated by the monomeric surfactant C12AA, while the multifunctional equivalent (2xC12AA) was characterized by good anti-adhesive activity. All tested compounds are non-mutagenic and cause low hemolysis of sheep erythrocytes. Multifunctional and gemini surfactants are also non-toxic.

A case of haemoglobinuria in a cat after near-drowning.

The aim of this study is to describe a case of haemoglobinuria in a cat after near-drowning. A 6-year-old male neutered domestic short hair cat weighing 6.5 kg with a pre-existing seizure disorder presented to an emergency hospital after near-drowning in a swimming pool during a seizure episode. On presentation, the patient was obtunded, dyspnoeic, bradycardic and hypothermic. Imaging revealed evidence of severe bilateral pulmonary infiltrates. Treatment with intravenous diazepam, amoxicillin, fluid therapy, active warming and oxygen therapy was administered. The cat developed haemoglobinuria approximately 6 h after nearly drowning. Despite improvements in mentation, pulse quality and heart rate, respiratory compromise and poor oxygen saturation persisted, prompting euthanasia approximately 10 h after admission. To the author's knowledge, this is the first reported clinical case of haemoglobinuria following near-drowning in veterinary medicine.

Recommendations for blood sampling in emergency departments from the European Society for Emergency Medicine (EUSEM), European Society for Emergency Nursing (EuSEN), and European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase. Executive summary.

AIM: Blood Sampling Guidelines have been developed to target European emergency medicine-related professionals involved in the blood sampling process (e.g. physicians, nurses, phlebotomists working in the ED), as well as laboratory physicians and other related professionals. The guidelines population focus on adult patients. The development of these blood sampling guidelines for the ED setting is based on the collaboration of three European scientific societies that have a role to play in the preanalytical phase process: EuSEN, EFLM, and EUSEM. The elaboration of the questions was done using the PICO procedure, literature search and appraisal was based on the GRADE methodology. The final recommendations were reviewed by an international multidisciplinary external review group. RESULTS: The document includes the elaborated recommendations for the selected sixteen questions. Three in pre-sampling, eight regarding sampling, three post-sampling, and two focus on quality assurance. In general, the quality of the evidence is very low, and the strength of the recommendation in all the questions has been rated as weak. The working group in four questions elaborate the recommendations, based mainly on group experience, rating as good practice. CONCLUSIONS: The multidisciplinary working group was considered one of the major contributors to this guideline. The lack of quality information highlights the need for research in this area of the patient care process. The peculiarities of the emergency medical areas need specific considerations to minimise the possibility of errors in the preanalytical phase.

Clinical profile and serological correlation with haemolysis in DAT-positive autoimmune haemolytic anaemia patients in Bangladesh.

Discerning the type of autoimmune haemolytic anaemia (AIHA) is crucial for transfusion support and initiation of treatment. This study aimed to establish the clinical profile and serological character of red cell autoantibodies and to investigate the relationship with haemolysis in AIHA patients who were direct antiglobulin test (DAT)-positive. A total of 59 DAT-positive AIHA patients were included in this study. Clinical, laboratory and serological findings were evaluated to find the gradation of haemolysis and to investigate its correlation with age, sex, type of autoantibody and level of autoantibody. Study findings revealed that most patients (89.8%) had haemolysis, wherein moderate haemolysis (67.8%) was predominant. Weakness, palpitations, fever, pallor, tachycardia and splenomegaly were common among patients with severe and moderate haemolysis. The majority (66.1%) had an associated disorder. Warm autoantibody was the most common, followed by cold and mixed cases. The severity of haemolysis correlated strongly with the strength of the DAT reaction (Cramer V 0.636, p<0.001). These findings may be useful to clinicians while determining a treatment plan. The direct relationship between severity of haemolysis and strength of DAT needs further exploration in a large population to establish whether it can be used as a tool to formulate a treatment plan when assessing AIHA patients in low resourced countries.

Acalypha indica induced acute oxidative haemolysis and methaemoglobinaemia: two case reports.

BACKGROUND: Herbal products and traditional remedies are commonly used by individuals worldwide for the management of common ailments, even though most are not without risks. Acalypha indica is a popular medicinal plant consumed in some Asian countries. CASE PRESENTATION: This case report presents a 40-year-old previously unevaluated Sri Lankan female and her 8-year-old son who presented with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency related acute intravascular oxidative haemolysis and methaemoglobinaemia precipitated by Acalypha indica consumption, successfully managed with supportive care and blood transfusion. CONCLUSIONS: This case highlights the potential hemolytic and methaemoglobinaemic effects of ingesting oxidant herbal products and the importance of considering such exposures in patients presenting with hemolysis and multiorgan involvement, particularly in communities where herbal product intake is popular. Healthcare providers should be aware of the risks associated with traditional remedies and maintain a high index of suspicion to ensure prompt recognition and appropriate management.

Understanding the complexities of space anaemia in extended space missions: revelations from microgravitational odyssey.

Space travel exposes astronauts to several environmental challenges, including microgravity and radiation exposure. To overcome these stressors, the body undergoes various adaptations such as cardiovascular deconditioning, fluid shifts, metabolic changes, and alterations in the state of the bone marrow. Another area of concern is the potential impact of these adaptations on erythrocyte and haemoglobin concentrations, which can lead to what is commonly referred to as space anaemia or microgravity-induced anaemia. It is known that anaemia may result in impaired physical and cognitive performance, making early detection and management crucial for the health and wellbeing of astronauts during extended space missions. However, the effects and mechanisms of space anaemia are not fully understood, and research is underway to determine the extent to which it poses a challenge to astronauts. Further research is needed to clarify the long-term effects of microgravity on the circulatory system and to investigate possible solutions to address spaceflight-induced anaemia. This article reviews the potential link between spaceflight and anaemia, based on existing evidence from simulated studies (e.g., microgravity and radiation studies) and findings from spaceflight studies (e.g., International Space Station and space shuttle missions).

Biallelic hexokinase 1 (HK1) variants causative of non-spherocytic haemolytic anaemia: A case series with emphasis on the HK1 promoter variant and literature review.

The hexokinase (HK) enzyme plays a key role in red blood cell energy production. Hereditary non-spherocytic haemolytic anaemia (HNSHA) caused by HK deficiency is a rare disorder with only 12 different disease-associated variants identified. Here, we describe the clinical features and genotypes of four previously unreported patients with hexokinase 1 (HK1)-related HNSHA, yielding two novel truncating HK1 variants. The patients' phenotypes varied from mild chronic haemolytic anaemia to severe infantile-onset transfusion-dependent anaemia. Three of the patients had mild haemolytic disease caused by the common HK1 promoter c.-193A>G variant combined with an intragenic HK1 variant, emphasizing the importance of including this promoter variant in the haemolytic disease gene panels. HK activity was normal in a severely affected patient with a homozygous HK1 c.2599C>T, p.(His867Tyr) variant, but the affinity for ATP was reduced, hampering the HK function. In cases of HNSHA, kinetic studies should be considered in the functional studies of HK. We reviewed the literature of previously published patients to provide better insight into this rare disease and add to the understanding of genotype-phenotype correlation.

Response to comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'.

In our recent paper on the clinical pharmacology of tafenoquine (Watson et al., 2022), we used all available individual patient pharmacometric data from the tafenoquine pre-registration clinical efficacy trials to characterise the determinants of anti-relapse efficacy in tropical vivax malaria. We concluded that the currently recommended dose of tafenoquine (300 mg in adults, average dose of 5 mg/kg) is insufficient for cure in all adults, and a 50% increase to 450 mg (7.5 mg/kg) would halve the risk of vivax recurrence by four months. We recommended that clinical trials of higher doses should be carried out to assess their safety and tolerability. Sharma and colleagues at the pharmaceutical company GSK defend the currently recommended adult dose of 300 mg as the optimum balance between radical curative efficacy and haemolytic toxicity (Sharma et al., 2024). We contend that the relative haemolytic risks of the 300 mg and 450 mg doses have not been sufficiently well characterised to justify this opinion. In contrast, we provided evidence that the currently recommended 300 mg dose results in sub-maximal efficacy, and that prospective clinical trials of higher doses are warranted to assess their risks and benefits.