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Introduction: Membranopathies encompass haemolytic disorders arising from genetic variants in erythrocyte membrane proteins, including hereditary spherocytosis and stomatocytosis. Congenital dyserythropoietic anaemia type II (CDA II) is associated with the SEC23B gene and can exhibit phenotypic similarities to membranopathies. Current treatment options for these conditions, apart from splenectomy, are primarily supportive. Mitapivat, a novel pyruvate kinase (PK) activator, has demonstrated efficacy in increasing haemoglobin levels and reducing haemolysis in patients with PK deficiency, thalassemia, sickle cell disease and a mouse model of hereditary spherocytosis., Methods and Analyses: Sa fe t y and eff i cacy of mitapivat s ul f ate in adult patients with er y throcyte membranopathies (SATISFY) is a prospective, multicentre, single-arm phase two trial involving approximately 25 adult patients (≥18 years) diagnosed with a membranopathy or CDA II. During the 8-week dose escalation period, subjects will receive an initial dose of 50 mg mitapivat two times per day and may increase to 100 mg two times per day at week 4 based on the safety and changes in haemoglobin levels. Patients tolerating mitapivat well may be eligible to continue in two consecutive 24-week fixed dose periods.The primary objective of this study is to evaluate the safety of mitapivat, assessed through the occurrence of treatment-emergent adverse events. Secondary objectives include assessing the effects of mitapivat on haemoglobin levels, haemolysis, erythropoiesis, patient-reported outcome measures and spleen size.SATISFY aims to assess the safety and efficacy of mitapivat in adult patients with red blood cell membranopathies and CDA II, with the aim of establishing proof-of-concept in patients living with these rare conditions., Ethics and Dissemination: NCT05935202/CTIS:2023-503271-24-01. Findings will be published in peer-reviewed journals., Trial Registration Number: Clinicaltrials.gov, NCT05935202. CTIS:2023-503271-24-01. Registered 07-July-2023. Protocol number: 2.1. https://clinicaltrials.gov/study/NCT05935202., Competing Interests: Competing interests: AG: consultant for Agios Pharmaceuticals, Bristol Myers Squibb, Novartis Pharmaceuticals, Novo Nordisk A/S, Pharmacosmos UK Ltd and Vertex Pharmaceuticals; received research support from Agios Pharmaceuticals, Novo Nordisk A/S, Saniona and Sanofi. EJvB: advisory committee member for Agios Pharmaceuticals.; received research funding from Agios Pharmaceuticals, Novartis Pharmaceuticals, Pfizer and RR Mechatronics International B.V. KHMK: consultant for Agios Pharmaceuticals, Alexion Pharmaceuticals, Inc., Bristol Myers Squibb, Forma Therapeutics, Pfizer, Novo Nordisk A/S and Vertex Pharmaceuticals; received honoraria from Bristol Myers Squibb and Novo Nordisk A/S; member of the data safety monitoring board of Bioverativ; received research funding from Agios Pharmaceuticals and Pfizer. RvW: consultant for Agios Pharmaceuticals; research funding from Agios Pharmaceuticals and Pfizer. MAER: research funding from Agios Pharmaceuticals and Axcella Health., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Clinically meaningful benefits in the signs, symptoms, and impacts of #PKDeficiency as assessed by disease-specific patient-reported outcome measures were observed in mitapivat-treated adult patients in two phase 3 clinical trials., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Abstract: Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE)., (© 2024 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Abstract: Advancements in orally bioavailable iron chelators and MRI methods have improved life expectancy and reproductive potential in thalassemia major (TM) and thalassemia intermedia (TI). Pregnancy is associated with adverse maternal and neonatal outcomes, frequency of which has not been well delineated. This systematic review aims to provide risk estimates of maternal and fetal outcomes in TM and TI and explore pregnancy's impact on iron homeostasis. Fifteen studies (429 participants, 684 pregnancies) were included. Meta-analysis revealed a higher thrombosis risk in TI (3.7%) compared to TM (0.92%), unchanged from prepregnancy. Heart failure risks in the earlier years appeared similar (TM 1.6% vs TI 1.1%), and maternal mortality in TM was 3.7%, but with current management, these risks are rare. Gestational diabetes and pre-eclampsia occurred in 3.9% and 11.3% of TM pregnancies, respectively. Caesarean section rates were 83.9% in TM and 67% in TI. No significant difference in stillbirth, small for gestational age neonates, or preterm birth incidence between TM and TI was observed. In TM pregnancies, red cell requirements significantly increased (from 102 to 139 ml/kg/year, P = 0.001), and 70% of TI pregnancies required blood transfusions. As expected, increased transfusion alongside chelation cessation led to a significant increase in serum ferritin during pregnancy (TM by 1005 ng/mL; TI by 332 ng/mL, P < 0.0001). Deterioration in iron status was further reflected by an increase in liver iron concentration (from 4.6 to 11.9 mg/g dry weight, P < 0.0001), and myocardial T2-star (T2∗) magnetic resonance imaging decreased (from 36.2 ± 2.5 ms to 31.1 ms) during pregnancy. These findings emphasize the elevated maternal risk of iron-related cardiomyopathy during pregnancy and labor, stressing the importance of cardiac monitoring and postpartum chelation therapy resumption., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Individuals with sickle cell disease (SCD) and central venous catheters (CVC) are at high risk for venous thromboembolism (VTE). Minimal data exist regarding the use of anticoagulation as thromboprophylaxis of VTE in this demographic, and as a result, clinical equipoise exists. Prophylactic dose rivaroxaban, a direct oral anticoagulant, is efficacious and safe as thromboprophylaxis in other demographics, and may be an optimal agent in SCD with CVC. Prior to conducting a full clinical trial to assess rivaroxaban as thromboprophylaxis in SCD with CVC, a pilot study is needed to gauge its feasibility., Methods and Analysis: THromboprophylaxis In Sickle Cell Disease pilot trial is an investigator-initiated, multicentre, double-blinded, randomised controlled trial (RCT) assessing if it is feasible and safe to conduct an adequately powered RCT comparing rivaroxaban to matching placebo as thromboprophylaxis in those with SCD and CVC. Fifty adult patients with SCD and CVC will be randomised to receive either rivaroxaban 10 mg daily or matching placebo for the duration of the CVC in situ for up to 1 year. After randomisation, follow-up visits will occur every 3 months. The primary outcomes pertain to the feasibility of a full trial and include numbers of eligible and recruited participants. Exploratory outcomes include overall incidence of VTE and bleeding complications, as well as quality of life. If the full trial is feasible, blinding will be maintained and patients in the pilot study will be included in the full trial., Ethics and Dissemination: The trial was initially approved by the University Health Network Research Ethics Board (REB) in Toronto, Canada. All sites will obtain approval from their respective REB prior to commencement of study activities. Study results will be disseminated through presentations at medical conferences and peer-reviewed publications., Trial Registration Number: NCT05033314., Competing Interests: Competing interests: SF has received research funding from the Canadian Hematology Society, and PFIZER; Honoraria from Novartis; and Consultancy fees from Novo Nordisk and Vertex. PB has received research funding from Bluebird, NOVARTIS, ROCHE Fabre Foundation and ADDMEDICA; Consultancy fees from AGIOS, EMMAUS, GBT, ROCHE, HEMANEXT, Bluebird, NOVARTIS, and ADDMEDICA; lecture fees from Jazz Pharma, NOVARTIS, and ADDMEDICA; is the cofounder of INNOVHEM, is on steering committees for NOVARTIS, ROCHE, ADDMEDICA, and PFIZER. KHMK has received research funding from AGIOS and PFIZER; Consulting fees from Alexion Pharmaceuticals, AGIOS, Bristol Myers Squibb, Forma Therapeutics, Pfizer, Novo Nordisk, and Vertex; Honoraria for speaking from AGIOS, and Bristol Myers Squibb; and is a member of a Data Safety Monitoring Board or Advisory Board for Bioverativ/Sanofi/Sangamo. The other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Allogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never been compared in clinical trials., Objective: To compare the safety and efficacy of HSCT and GT to assist clinicians and patients in making informed treatment decisions., Methods: Phase I-III clinical trials and case reports/series were included. Regimens included HSCT from all stem cell sources, lentiviral gene therapy, and gene editing, with any conditioning regimen. We searched Medline and EMBASE databases as of 1st June 2020 for studies reporting HSCT and GT outcomes in SCD. The Newcastle-Ottawa scale was used to assess the risk of bias. Descriptive statistics and post-hoc imputation for standard deviations of mean change in FEV1 and FVC were performed., Results: In total, 56 studies (HSCT, n  = 53; GT, n  = 3) representing 1,198 patients met inclusion criteria (HSCT, n  = 1,158; GT, n  = 40). Length of follow-up was 3,881.5 and 58.7 patient-years for HSCT and GT, respectively. Overall quality of evidence was low, with no randomized controlled trials identified. Two-year overall survival for HSCT was 91%; mortality was 2.5% for GT. Acute chest syndrome and vaso-occlusive episodes were reduced post-HSCT and GT. Meta-analysis was not possible due to lack of comparator and heterogeneity in outcome measures reporting. Very few studies reported post-transplant end-organ function. Six secondary malignancies (5 post-HSCT, 1 post-GT) were reported., Discussion: Reporting of SCD-related complications and patient-important outcomes is lacking for both strategies. We advocate for standardized reporting to better compare outcomes within and between treatment groups.

Over the past decade, evidence has been mounting on the detrimental clinical sequelae of untreated anemia in patients with non-transfusion-dependent β-thalassemia (NTDT). There are no pharmacologic agents that are specifically approved for the management of anemia in NTDT, and available options such as splenectomy, transfusion therapy, and hydroxyurea each come with their own shortcomings, especially for long-term use. Luspatercept is an erythroid maturation agent that has been evaluated in a Phase 2, randomized trial and showed a significant benefit in raising hemoglobin level by at least 1 g/dL in adults with NTDT and a baseline hemoglobin level ≤10 g/dL. These data led to luspatercept's approval by the European Commission for the treatment of anemia in adults with NTDT and presents the first evidence-based approach for a novel agent that is able to ameliorate anemia in this patient population., Competing Interests: K.M.M. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. A.T.T. reports consultancy fees Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma, Silence Therapeutics and Ionis Pharmaceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and Agios Pharmaceuticals. A.K. reports receiving advisory board fees and consulting fees from Agios Pharmaceuticals, Amgen, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor Pharma; and research support, paid to his institution, from Celgene/Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb, Chiesi Farmaceutici, CRISPR Therapeutics/Vertex, and Novartis; and personal fees from Bristol Myers Squibb. K.H.M.K. reports consultancy fees from Agios Pharmaceuticals, Alexion, Apellis, bluebird bio, Celgene/Bristol Myers Squibb, Forma, Pfizer, Novo Nordisk, Vertex, and Novartis; honoraria from Alexion and Novartis; membership on an advisory committee for Agios Pharmaceuticals and Bioverativ/Sanofi/Sangamo; and research funding from Pfizer. S.S. reports consultancy fees from Agios Pharmaceuticals, Bluebird bio, Bristol Myers Squibb, Forma, and Chiesi; and serving on a clinical trial steering committee for CRISPR/Vertex CTX001 for thalassemia. M.D.C. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma and Ionis Pharmaceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. The authors report no other conflicts of interest in this work., (© 2023 Musallam et al.)

Introduction: Pyruvate kinase (PK) deficiency is a rare, under-recognised, hereditary condition that leads to chronic haemolytic anaemia and potentially serious secondary complications, such as iron overload, cholecystitis, pulmonary hypertension and extramedullary haematopoiesis. It is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the PKLR gene. Due to its rarity and clinical heterogeneity, information on the natural history and long-term clinical course of PK deficiency is limited, presenting major challenges to patient management, the development of new therapies and establishing disease-specific treatment recommendations. The Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry is an initiative to address the gaps in the knowledge of PK deficiency. This manuscript describes the objectives, study design and methodology for the Peak Registry., Methods and Analysis: The Peak Registry is an observational, longitudinal, global registry of adult and paediatric patients with a genetically confirmed diagnosis of PK deficiency. The Peak Steering Committee is composed of 11 clinicians and researchers with experience in the diagnosis and management of PK deficiency from 10 countries, a patient representative and representatives from the sponsor (Agios Pharmaceuticals). The registry objective is to foster an understanding of the longitudinal clinical implications of PK deficiency, including its natural history, treatments and outcomes, and variability in clinical care. The aim is to enrol up to 500 participants from approximately 60 study centres across 20 countries over 7 years, with between 2 and 9 years of follow-up. Data will include demographics, diagnosis history, genotyping, transfusion history, relevant clinical events, medications, emergency room visits and hospitalisations., Ethics and Dissemination: Registry protocol and informed consent forms are approved by institutional review boards/independent ethics committees at each study site. The study is being conducted in accordance with the Declaration of Helsinki. Registry data will be published in peer-reviewed journal articles and conference publications., Trial Registration Number: NCT03481738., Competing Interests: Competing interests: RFG receives research funding from Agios Pharmaceuticals, Novartis Pharmaceuticals and Sobi, and is a consultant for Agios Pharmaceuticals and Sanofi. EJvB is an advisory committee member for Agios Pharmaceuticals and receives research funding from Agios Pharmaceuticals, Novartis Pharmaceuticals, Pfizer and RR Mechatronics International B.V. BG is a consultant for Agios Pharmaceuticals. AG is a consultant for Agios Pharmaceuticals, bluebird bio, Bristol Myers Squibb, Novartis Pharmaceuticals, Novo Nordisk A/S and Pharmacosmos UK and receives research support from Agios Pharmaceuticals, Saniona, and Sanofi. KHMK is a consultant for Agios Pharmaceuticals, Alexion Pharmaceuticals, Apellis Pharmaceuticals, bluebird bio, Celgene Corporation, Novartis Pharmaceuticals and Pfizer, receives honoraria from Alexion Pharmaceuticals and Novartis Pharmaceuticals, is a member of the data safety monitoring board of Bioverativ and receives research funding from Agios Pharmaceuticals and Pfizer. CL receives payment as a patient representative on the Agios Pharmaceuticals PK Deficiency Patient Advocacy Advisory Council. DML is a consultant and advisory committee member for Agios Pharmaceuticals and Novartis Pharmaceuticals and is a member of the data safety monitoring board of Cerus Corporation. HK, J-LVC, DP and VV have no conflicts of interest to disclose. JL, ANB and YY are employees of Agios Pharmaceuticals and are shareholders in the company. CB is a former employee of Agios Pharmaceuticals. PB is a scientific advisor for Agios Pharmaceuticals., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Insulin resistance (IR) with associated compensatory hyperinsulinemia (HI) are early abnormalities in the etiology of prediabetes (preT2D) and type 2 diabetes (T2D). IR and HI also associate with increased erythrocytosis. Hemoglobin A1c (HbA1c) is commonly used to diagnose and monitor preT2D and T2D, but can be influenced by erythrocytosis independent of glycemia., Methods: We undertook bidirectional Mendelian randomization (MR) in individuals of European ancestry to investigate potential causal associations between increased fasting insulin adjusted for BMI (FI), erythrocytosis and its non-glycemic impact on HbA1c. We investigated the association between the triglyceride-glucose index (TGI), a surrogate measure of IR and HI, and glycation gap (difference between measured HbA1c and predicted HbA1c derived from linear regression of fasting glucose) in people with normoglycemia and preT2D., Results: Inverse variance weighted MR (IVWMR) suggested that increased FI increases hemoglobin (Hb, b=0.54 ± 0.09, p=2.7 x 10 -10 ), red cell count (RCC, b=0.54 ± 0.12, p=5.38x10 -6 ) and reticulocyte (RETIC, b=0.70 ± 0.15, p=2.18x10 -6 ). Multivariable MR indicated that increased FI did not impact HbA1c (b=0.23 ± 0.16, p=0.162) but reduced HbA1c after adjustment for T2D (b=0.31 ± 0.13, p=0.016). Increased Hb (b=0.03 ± 0.01, p=0.02), RCC (b=0.02 ± 0.01, p=0.04) and RETIC (b=0.03 ± 0.01, p=0.002) might modestly increase FI. In the observational cohort, increased TGI associated with decreased glycation gap, (i.e., measured HbA1c was lower than expected based on fasting glucose, (b=-0.09 ± 0.009, p<0.0001)) in people with preT2D but not in those with normoglycemia (b=0.02 ± 0.007, p<0.0001)., Conclusions: MR suggests increased FI increases erythrocytosis and might potentially decrease HbA1c by non-glycemic effects. Increased TGI, a surrogate measure of increased FI, associates with lower-than-expected HbA1c in people with preT2D. These findings merit confirmatory studies to evaluate their clinical significance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nguyen, Khafagy, Hashemy, Kuo, Roshandel, Paterson and Dash.)

This study sought to link neurocognitive profiles in sickle cell disease (SCD) patients with clinical characteristics. We conducted a prospective cohort study of adults with SCD who underwent comprehensive neuropsychological assessment at the UMGGR clinic at Henri Mondor Hospital, Créteil (France). A cluster analysis was performed based on neuropsychological testing scores. The association between clusters and clinical profiles was assessed. Between 2017 and 2021, 79 patients with a mean age of 36 [range 19-65] years were included. On principal component analysis, a 5-factor model presented the best fit (Bartlett's sphericity test [χ 2 (171) = 1345; p < 0.001]), explaining 72% of the variance. The factors represent distinct cognitive domains and anatomical regions. On hierarchical classification, three clusters emerged. Cluster 1 ( n = 24) presented deficits in all five factors compared to Cluster 3 ( n = 33). Cluster 2 ( n = 22) had deficits in all factors, but to a lesser extent than Cluster 1. MoCA scores mirrored the severity of these cognitive deficits. Age, genotype and stroke prevalence did not differ significantly between clusters. However, the time of first stroke occurrence differed significantly between Cluster 1 and 2-3: 78% of strokes occurred during childhood, whereas 80% and 83% occurred during adulthood in Clusters 2 and 3, respectively. Educational attainment was also reduced in Cluster 1. SCD patients with childhood stroke seem to be at increased risk of a global cognitive deficit profile. In addition to existing methods of primary and secondary stroke prevention, early neurorehabilitation should be prioritized in order to reduce the long-term cognitive morbidity of SCD.

Objectives: Obstructive sleep apnea (OSA) is reported to be a cause of secondary polycythemia. The present study (i) reviewed the literature reporting the prevalence of secondary polycythemia in patients with OSA and (ii) determined the effect of continuous positive airway pressure (CPAP) therapy on hemoglobin and hematocrit levels in patients with OSA., Methods: We searched MEDLINE, Embase and Cochrane for studies of adult patients with OSA that reported hemoglobin and/or hematocrit levels. We performed summary estimates of (i) polycythemia prevalence and a subgroup analysis according to OSA severity, and (ii) change in hemoglobin and hematocrit levels following treatment with CPAP., Results: Synthesis of seven studies including 3,654 patients revealed an overall polycythemia prevalence of 2% (95% CI 1-4%); 2% (95% CI 1-3%) in mild-to moderate and 6 % (95% CI 3-12%) in severe OSA. In the pooled analysis of ten single-arm trials including 434 patients, CPAP treatment reduced hemoglobin by 3.76 g/L (95% CI -4.73 to -2.80 g/L). Similarly, pooled analysis of ten single-arm trials including 356 patients without baseline polycythemia showed that CPAP treatment reduced hematocrit by 1.1% (95% CI -1.4 to -0.9%)., Conclusion: Our pooled analysis supports an increased prevalence of secondary polycythemia in OSA. This estimated prevalence is likely underestimated due to the change in the polycythemia diagnostic criteria in 2016. Future randomized controlled trials are needed to evaluate the effect of CPAP in patients with baseline polycythemia., Highlights: Pooled analysis shows OSA is associated with an increased prevalence of secondary polycythemiaPrevalence of polycythemia is greater in severe OSACPAP treatment for OSA reduces both the hemoglobin and hematocrit.

In patients with sickle cell disease (SCD), the delivery of oxygen to the brain is compromised by anemia, abnormal rheology, and steno-occlusive vascular disease. Successful compensation depends on an increase in oxygen supply such as that provided by an increase in cerebral blood flow (CBF). We used magnetic resonance imaging to provide a high-resolution assessment of the ability of SCD patients to respond to a vasoactive stimulus in middle, anterior, and posterior cerebral artery territories for both white and gray matter. Cerebrovascular reactivity (CVR) was measured as the blood oxygen level dependent signal (a surrogate for CBF) response to an increase in the end tidal partial pressure of CO 2 (P ET CO 2 ). The dynamic aspect of the response was measured as the time constant of the first order response kinetics (tau). To confirm and support these findings we used an alternative examination of the response, transfer function analysis (TFA), to measure the responsiveness (gain), the speed of response (phase), and the consistency of the response over time (coherence). We tested 34 patients with SCD and compared the results to those of 24 healthy controls participants. The results from a three-way ANOVA showed that patients with SCD have reduced CVR (p < 0.001) and lower coherence (p < 0.001) in gray matter and white matter and reduced gain in gray matter only (p < 0.001). In terms of the speed of the response to CO 2 , tau (p < 0.001) and TFA phase (p < 0.001) were increased in SCD patients compared to healthy control subjects. These findings show that the cerebrovascular responsiveness to CO 2 in patients with SCD is both decreased and slowed compared to healthy controls., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Despite increased cerebral blood flow (CBF), cerebral infarcts occur in patients with sickle cell disease (SCD). This suggests increased CBF does not meet metabolic demand possibly due to compromised cerebral vasodilatory response. Hypothesis: In adult SCD patients, cerebrovascular reactivity (CVR) and speed of vasodilatory response (tau) to a standardized vasodilatory stimulus, are reduced compared to normal subjects. Methods: Functional brain imaging performed as part of routine care in adult SCD patients without known large vessel cerebral vasculopathy was reviewed retrospectively. CVR was calculated as the change in CBF measured as the blood-oxygenation-level-dependent (BOLD)-magnetic resonance imaging signal, in response to a standard vasoactive stimulus of carbon dioxide (CO 2 ). The tau corresponding to the best fit between the convolved end-tidal partial pressures of CO 2 and BOLD signal was defined as the speed of vascular response. CVR and tau were normalized using a previously generated atlas of 42 healthy controls. Results: Fifteen patients were included. CVR was reduced in grey and white matter (mean Z-score for CVR -0.5 [-1.8 to 0.3] and -0.6 [-2.3 to 0.7], respectively). Tau Z-scores were lengthened in grey and white matter (+0.9 [-0.5 to 3.3] and +0.8 [-0.7 to 2.7], respectively). Hematocrit was the only significant independent predictor of CVR on multivariable regression. Conclusion: Both measures of cerebrovascular health (CVR and tau) in SCD patients were attenuated compared to normal controls. These findings show that CVR represents a promising tool to assess disease state, stroke risk, and therapeutic efficacy of treatments in SCD and merits further investigation., Competing Interests: JF and DM contributed to the development of the automated end-tidal targeting device, RespirAct™ (Thornhill Research Inc., TRI) used in this study and have equity in the company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Forté, Sobczyk, Poublanc, Duffin, Hare, Fisher, Mikulis and Kuo.)

In patients with sickle cell disease (SCD) the delivery of oxygen to the brain is compromised by anemia, abnormal rheology, and steno-occlusive vascular disease. Meeting demands for oxygen delivery requires compensatory features of brain perfusion. The cerebral vasculature's regulatory function and reserves can be assessed by observing the flow response to a vasoactive stimulus. In a traditional approach we measured voxel-wise change in Blood Oxygen-Level Dependent (BOLD) MRI signal as a surrogate of cerebral blood flow (CBF) in response to a linear progressive ramping of end-tidal partial pressure of carbon dioxide (PETCO 2 ). Cerebrovascular reactivity (CVR) was defined as ΔBOLD/ΔPETCO 2 . We used a computer model to fit a virtual sigmoid resistance curve to the progressive CBF response to the stimulus, enabling the calculation of resistance parameters: amplitude, midpoint, range response, resistance sensitivity and vasodilatory reserve. The quality of the resistance sigmoid fit was expressed as the r 2 of the fit. We tested 35 patients with SCD, as well as 24 healthy subjects to provide an indication of the normal ranges of the resistance parameters. We found that gray matter CVR and resistance amplitude, range, reserve, and sensitivity are reduced in patients with SCD compared to healthy controls, while resistance midpoint was increased. This study is the first to document resistance measures in adult patients with SCD. It is also the first to score these vascular resistance measures in comparison to the normal range. We anticipate these data will complement the current understanding of the cerebral vascular pathophysiology of SCD, identify paths for therapeutic interventions, and provide biomarkers for monitoring the progress of the disease., Competing Interests: JF and DM contributed to the development of the automated end-tidal targeting device, RespirAct™ (Thornhill Research Inc., TRI) used in this study and have equity in the company. OS and JD receive salary support from TRI. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sayin, Sobczyk, Poublanc, Mikulis, Fisher, Kuo and Duffin.)

Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic hemolytic anemia. Although recognition of the disease spectrum has recently expanded, data describing its impact on health-related quality of life (HRQoL) are limited. In this prospective international cohort of 254 patients (131 adults and 123 children) with PKD, we used validated measures to assess the impact of disease on HRQoL (EuroQol 5-Dimension Questionnaire, Pediatric Quality of Life Inventory Generic Core Scale version 4.0, and Functional Assessment of Cancer Therapy-Anemia) and fatigue (Patient Reported Outcomes Measurement Information System Fatigue and Pediatric Functional Assessment of Chronic Illness Therapy-Fatigue). Significant variability in HRQoL and fatigue was reported for adults and children, although individual scores were stable over a 2-year interval. Although adults who were regularly transfused reported worse HRQoL and fatigue compared with those who were not (EuroQol-visual analog scale, 58 vs 80; P = .01), this difference was not seen in children. Regularly transfused adults reported lower physical, emotional, and functional well-being and more anemia symptoms. HRQoL and fatigue significantly differed in children by genotype, with the worst scores in those with 2 severe PKLR mutations; this difference was not seen in adults. However, iron chelation was associated with significantly worse HRQoL scores in children and adults. Pulmonary hypertension was also associated with significantly worse HRQoL. Additionally, 59% of adults and 35% of children reported that their jaundice upset them, identifying this as an important symptom for consideration. Although current treatments for PKD are limited to supportive care, new therapies are in clinical trials. Understanding the impact of PKD on HRQoL is important to assess the utility of these treatments. This trial was registered at www.clinicaltrials.gov as #NCT02053480., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Sickle cell disease (SCD) induces a chronic prothrombotic state. Central venous access devices (CVADs) are commonly used for chronic transfusions and iron chelation in this population. CVADs are an additional venous thromboembolism (VTE) risk factor. The role of thromboprophylaxis in this setting is uncertain. The objectives are: (1) to determine whether thromboprophylaxis reduces VTE risk in SCD patients with CVAD and (2) to explore characteristics associated with VTE risk. We identified adults with SCD and CVAD intended for chronic use (≥3 months) at two comprehensive SCD centers. Thromboprophylaxis presence; type; intensity; and patient-, catheter-, and treatment-related VTE risk factors were recorded. Among 949 patients, 49 had a CVAD (25 without and 24 with VTE prophylaxis). Thromboprophylaxis type and intensity varied widely. Patients without thromboprophylaxis had higher VTE rates (rate ratio (RR) = 4.0 (95% confidence interval: 1.2−12.6), p = 0.02). Hydroxyurea was associated with lower VTE rates (RR = 20.5 (6.4−65.3), p < 0.001). PICC lines and Vortex and Xcela Power implantable devices were associated with higher rates compared with Port-a-Cath (RR = 5.8 (1.3−25.9), p = 0.02, and RR = 58.2 (15.0−225.0), p < 0.001, respectively). Thromboprophylaxis, hydroxyurea, and CVAD subtype were independently associated with VTE. The potentially protective role of thromboprophylaxis and hydroxyurea for VTE prevention in patients with SCD and CVAD merits further exploration.

Importance: Adults with sickle cell disease (SCD) disproportionally experience early cognitive decline; however, guidance on the optimal screening strategy for cognitive dysfunction is lacking, and several available tools are biased by language, educational level, socioeconomic status, and race/ethnicity. The Rowland Universal Dementia Assessment Scale (RUDAS) was specifically designed for cognitive screening in multicultural populations., Objective: To ascertain the prevalence of suspected dementia in adults with SCD using the RUDAS, and to identify whether age, sex, educational level, several biological variables, and SCD complications were associated with RUDAS scores., Design, Setting, and Participants: This multicenter, bilingual, cross-sectional study was conducted in 2 SCD comprehensive care centers in Canada (Centre Hospitalier de l'Université Montréal in Montréal and University Health Network in Toronto). Participants were adults aged 18 years or older and were enrolled in the study between July 1, 2018, and July 30, 2019. All outpatients were eligible and offered study participation, unless they had an acute medical condition that required inpatient care or they were unable to follow study instructions., Interventions: The RUDAS was administered by trained personnel in either French or English, according to the patient's language preference. A questionnaire on social determinants of health was also administered, and participants underwent screening for anxiety and depression., Main Outcomes and Measures: Proportion of participants with RUDAS scores that were suggestive of dementia and the RUDAS score. Any score lower than 23 points was suggestive of dementia, a score between 23 and 27 points indicated a possible association with mild neurocognitive disorder, and a score higher than 27 points was normal., Results: A total of 252 adult patients with SCD were included (136 women [54.0%]; mean [range] age, 34.8 [18-75] years). Overall, 29 patients (11.5%) had RUDAS scores that were suggestive of dementia, and this proportion increased with age (15 [8.7%] in the 18-39 years age group, 10 [14.5%] in the 40-59 years age group, and 4 [36.4%] in the ≥60 years age group). The RUDAS scores were not associated with sex, language, SCD genotype, and SCD complications. The highest level of education was significantly associated with the RUDAS score; however, the association was small (η2 = 0.02; 95% CI, 0.00-0.07; P = .02). In a multivariable analysis, lower glomerular filtration rate (r = 0.40; 95% CI, 0.29-0.50; P < .001) and increasing age (r = -0.37; 95% CI, -0.47 to -0.26; P < .001), but not SCD genotype or disease severity, were associated with lower RUDAS scores., Conclusions and Relevance: This study found that using the RUDAS revealed a high prevalence of suspected dementia in adult patients with SCD that was associated with worsening kidney function and age. Cognition should be screened in all adult patients with SCD, regardless of age, disease severity, and SCD genotype; further validation of the RUDAS is ongoing.

Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including pyruvate kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell pyruvate and ATP deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency., (© 2020 Wiley Periodicals, Inc.)

The issue of multiple testing, also termed multiplicity, is ubiquitous in studies where multiple hypotheses are tested simultaneously. Genome-wide association study (GWAS), a type of genetic association study that has gained popularity in the past decade, is most susceptible to the issue of multiple testing. Different methodologies have been employed to address the issue of multiple testing in GWAS. The purpose of the review is to examine the methodologies employed in dealing with multiple testing in the context of gene discovery using GWAS in sickle cell disease complications., Competing Interests: Declaration of conflicting interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.H.M.K. disclosed the following conflicts of interests: consultancy services were provided by Agios, Alexion, and Novartis; grants/grants pending from Apo-Pharma and Phoenicia Biosciences; honoraria were given by Alexion and Novartis; and travel/accommodations expenses were covered/reimbursed by Novartis.