Publications by authors named "Eduard J van Beers"

59 Publications

Health-Related Quality of Life and Fatigue in Children and Adults with Pyruvate Kinase Deficiency.

Blood Adv 2021 Sep 1. Epub 2021 Sep 1.

Harvard Medical School, United States.

Pyruvate kinase deficiency (PKD) is the most common cause of congenital non-spherocytic 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 assessed the disease impact on HRQoL (EuroQL-5D, PedsQL, FACT-An) and fatigue (PROMIS Fatigue, PedsFACIT-F) using validated measures. Significant variability in HRQoL and fatigue was reported for both adults and children although individual scores were stable over a 2-year interval. While adults who were regularly transfused reported worse HRQoL and fatigue compared to those who were not regularly transfused (EQ-VAS 58 vs. 80, p=0.01), this difference was not seen in children. Regularly transfused adults reported lower physical, emotional, and functional well-being and more anemia symptoms. Both HRQoL and fatigue significantly differed in children by genotype with the worst scores in those with two severe PKLR mutations; this difference was not seen in adults. However, iron chelation was associated with significantly worse HRQoL scores in both children and adults. Pulmonary hypertension was also associated with significantly worse HRQoL. In PKD-specific symptom assessment, 59% of adults and 35% of children reported that their jaundice upset them, identifying this as an important symptom for consideration. While current treatments for PK deficiency are limited to supportive care, new therapies are currently in clinical trials. Understanding the impact of PKD on HRQoL is important to assess the utility of these treatments. (Clinicaltrials.gov number NCT02053480).
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http://dx.doi.org/10.1182/bloodadvances.2021004675DOI Listing
September 2021

Lactate dehydrogenase to carboxyhemoglobin ratio as a biomarker of heme release to heme processing is associated with higher tricuspid regurgitant jet velocity and early death in sickle cell disease.

Am J Hematol 2021 09 10;96(9):E315-E318. Epub 2021 Jun 10.

Van Creveldkliniek, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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http://dx.doi.org/10.1002/ajh.26243DOI Listing
September 2021

Dried blood spot metabolomics reveals a metabolic fingerprint with diagnostic potential for Diamond Blackfan Anaemia.

Br J Haematol 2021 Jun 17;193(6):1185-1193. Epub 2021 May 17.

Department of Paediatric Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

The diagnostic evaluation of Diamond Blackfan Anaemia (DBA), an inherited bone marrow failure syndrome characterised by erythroid hypoplasia, is challenging because of a broad phenotypic variability and the lack of functional screening tests. In this study, we explored the potential of untargeted metabolomics to diagnose DBA. In dried blood spot samples from 18 DBA patients and 40 healthy controls, a total of 1752 unique metabolite features were identified. This metabolic fingerprint was incorporated into a machine-learning algorithm, and a binary classification model was constructed using a training set. The model showed high performance characteristics (average accuracy 91·9%), and correct prediction of class was observed for all controls (n = 12) and all but one patient (n = 4/5) from the validation or 'test' set (accuracy 94%). Importantly, in patients with congenital dyserythropoietic anaemia (CDA) - an erythroid disorder with overlapping features - we observed a distinct metabolic profile, indicating the disease specificity of the DBA fingerprint and underlining its diagnostic potential. Furthermore, when exploring phenotypic heterogeneity, DBA treatment subgroups yielded discrete differences in metabolic profiles, which could hold future potential in understanding therapy responses. Our data demonstrate that untargeted metabolomics in dried blood spots is a promising new diagnostic tool for DBA.
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http://dx.doi.org/10.1111/bjh.17524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251760PMC
June 2021

Effects of Genotypes and Treatment on Oxygenscan Parameters in Sickle Cell Disease.

Cells 2021 Apr 5;10(4). Epub 2021 Apr 5.

Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, 69008 Lyon, France.

(1) Background: The aim of the present study was to compare oxygen gradient ektacytometry parameters between sickle cell patients of different genotypes (SS, SC, and S/β) or under different treatments (hydroxyurea or chronic red blood cell exchange). (2) Methods: Oxygen gradient ektacytometry was performed in 167 adults and children at steady state. In addition, five SS patients had oxygenscan measurements at steady state and during an acute complication requiring hospitalization. (3) Results: Red blood cell (RBC) deformability upon deoxygenation (EImin) and in normoxia (EImax) was increased, and the susceptibility of RBC to sickle upon deoxygenation was decreased in SC patients when compared to untreated SS patients older than 5 years old. SS patients under chronic red blood cell exchange had higher EImin and EImax and lower susceptibility of RBC to sickle upon deoxygenation compared to untreated SS patients, SS patients younger than 5 years old, and hydroxyurea-treated SS and SC patients. The susceptibility of RBC to sickle upon deoxygenation was increased in the five SS patients during acute complication compared to steady state, although the difference between steady state and acute complication was variable from one patient to another. (4) Conclusions: The present study demonstrates that oxygen gradient ektacytometry parameters are affected by sickle cell disease (SCD) genotype and treatment.
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http://dx.doi.org/10.3390/cells10040811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067408PMC
April 2021

Comorbidities and complications in adults with pyruvate kinase deficiency.

Eur J Haematol 2021 Apr 24;106(4):484-492. Epub 2021 Jan 24.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Objectives: Pyruvate kinase (PK) deficiency is caused by PKLR gene mutations, leading to defective red blood cell glycolysis and hemolytic anemia. Rates of comorbidities and complications by transfusion history and relative to the general population remain poorly quantified.

Methods: Data for patients aged ≥ 18 years with two confirmed PKLR mutations were obtained from the PK deficiency Natural History Study (NCT02053480). Frequencies of select conditions were compared with an age- and sex-matched cohort from a general insured US population without PK deficiency.

Results: Compared with the matched population (n = 1220), patients with PK deficiency (n = 122) had significantly higher lifetime rates of osteoporosis, liver cirrhosis, and pulmonary hypertension; splenectomy and cholecystectomy rates were also significantly higher in the 8 years before the index date. Sixty-five (53.3%) patients with PK deficiency were classified as regularly transfused, 30 (24.6%) as occasionally transfused, and 27 (22.1%) as never transfused. Regularly transfused patients were significantly more likely than never transfused patients to have had splenectomy, cholecystectomy, and/or thrombosis. Liver iron overload was reported in 62% of patients and occurred regardless of transfusion cohort.

Conclusions: Even never transfused patients with PK deficiency had higher rates of select comorbidities and complications than individuals without PK deficiency.
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http://dx.doi.org/10.1111/ejh.13572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985869PMC
April 2021

Methodological aspects of oxygen gradient ektacytometry in sickle cell disease: Effects of sample storage on outcome parameters in distinct patient subgroups.

Clin Hemorheol Microcirc 2021 ;77(4):391-394

"Vascular Biology and Red Blood Cell" Team, Laboratory LIBM EA7424, University of Lyon 1, Lyon, France.

Sickle cell disease (SCD) is a genetic disorder characterized by the production of an abnormal hemoglobin (Hb), which, under deoxygenation, may polymerize and cause a mechanical distortion of red blood cell (RBC) into a crescent-like shape. Recently a method, using ektacytometry principle, has been developed to assess RBC deformability as a function of oxygen tension (pO2) and is called oxygen gradient ektacytometry (oxygenscan). However, standardization of this test is needed to properly assess the tendency of sickling of RBCs under deoxygenation and to allow comparisons between different laboratories. The study compared the oxygenscan responses during blood storage between distinct populations of SCD patients. Blood from 40 non-transfused homozygous SCD patients (HbSS), 16 chronically transfused HbSS patients, and 14 individuals with compound heterozygous hemoglobin SC disease (HbSC) at steady-state was collected in EDTA tubes. Measurements were performed within 4 hours after collection and after 24 hours of storage at 4°C. We showed that storage affected the minimum RBC deformability reached during deoxygenation (EImin) in both non-transfused HbSS and HbSC patients and the maximum RBC deformability (EImax) measured before deoxygenation (i.e., in normoxia) in the three groups. In contrast, the tendency of RBCs to sickle under deoxygenation (i.e., the point of sickling; PoS) remained rather stable between the two time of measurements. Collectively, since the time between blood sampling and analysis affects some key oxygen gradient ektacytometry-derived parameters we recommend that each laboratory performs oxygenscan measurements at a standardized time point.
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http://dx.doi.org/10.3233/CH-201037DOI Listing
May 2021

Untargeted metabolic profiling in dried blood spots identifies disease fingerprint for pyruvate kinase deficiency.

Haematologica 2020 09 10;Online ahead of print. Epub 2020 Sep 10.

Central Diagnostic Laboratory-Research, University Medical Center Utrecht, Utrecht.

The diagnostic evaluation and clinical characterization of rare hereditary anemia (RHA) is to date still challenging. In particular, there is little knowledge on the broad metabolic impact of many of the molecular defects underlying RHA. In this study we explored the potential of untargeted metabolomics to diagnose a relatively common type of RHA: Pyruvate Kinase Deficiency (PKD). In total, 1903 unique metabolite features were identified in dried blood spot samples from 16 PKD patients and 32 healthy controls. A metabolic fingerprint was identified using a machine learning algorithm, and subsequently a binary classification model was designed. The model showed high performance characteristics (AUC 0.990, 95%CI 0.981-0.999) and an accurate class assignment was achieved for all newly added control (13) and patient samples (6), with the exception of one patient (accuracy 94%). Important metabolites in the metabolic fingerprint included glycolytic intermediates, polyamines and several acyl carnitines. In general, the application of untargeted metabolomics in dried blood spots is a novel functional tool that holds promise for diagnostic stratification and studies on disease pathophysiology in RHA.
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http://dx.doi.org/10.3324/haematol.2020.266957DOI Listing
September 2020

The variable manifestations of disease in pyruvate kinase deficiency and their management.

Haematologica 2020 09 1;105(9):2229-2239. Epub 2020 Sep 1.

Dana/Farber Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.3324/haematol.2019.240846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556504PMC
September 2020

Interplay of erythropoietin, fibroblast growth factor 23, and erythroferrone in patients with hereditary hemolytic anemia.

Blood Adv 2020 04;4(8):1678-1682

Van Creveldkliniek, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Recently, erythropoietin (EPO) was identified as regulator of fibroblast growth factor 23 (FGF23). Proteolytic cleavage of biologically active intact FGF23 (iFGF23) results in the formation of C-terminal fragments (cFGF23). An increase in cFGF23 relative to iFGF23 suppresses FGF receptor signaling by competitive inhibition. EPO lowers the i:cFGF23 ratio, thereby overcoming iFGF23-mediated suppression of erythropoiesis. We investigated EPO-FGF23 signaling and levels of erythroferrone (ERFE) in 90 patients with hereditary hemolytic anemia (www.trialregister.nl [NL5189]). We show, for the first time, the importance of EPO-FGF23 signaling in hereditary hemolytic anemia: there was a clear correlation between total FGF23 and EPO levels (r = +0.64; 95% confidence interval [CI], 0.09-0.89), which persisted after adjustment for iron load, inflammation, and kidney function. There was no correlation between iFGF23 and EPO. Data are consistent with a low i:cFGF23 ratio. Therefore, as expected, we report a correlation between EPO and ERFE in a diverse set of hereditary hemolytic anemias (r = +0.47; 95% CI, 0.14-0.69). There was no association between ERFE and total FGF23 or iFGF23, which suggests that ERFE does not contribute to the connection between FGF23 and EPO. These findings open a new area of research and might provide potentially new druggable targets with the opportunity to ameliorate ineffective erythropoiesis and the development of disease complications in hereditary hemolytic anemias.
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http://dx.doi.org/10.1182/bloodadvances.2020001595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189297PMC
April 2020

Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency.

Am J Hematol 2020 05 6;95(5):472-482. Epub 2020 Mar 6.

Department of Pediatrics, University of Würzburg, Würzburg, Germany.

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.
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http://dx.doi.org/10.1002/ajh.25753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127999PMC
May 2020

Liver Iron Retention Estimated from Utilization of Oral and Intravenous Radioiron in Various Anemias and Hemochromatosis in Humans.

Int J Mol Sci 2020 Feb 6;21(3). Epub 2020 Feb 6.

Departments of Haematology and Internal Medicine, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.

Patients with hereditary hemochromatosis and non-transfusion-dependent hereditary anemia develop predominantly liver iron-overload. We present a unique method allowing quantification of liver iron retention in humans during first-pass of Fe-labeled iron through the portal system, using standard ferrokinetic techniques measuring red cell iron uptake after oral and intravenous Fe administration. We present data from patients with iron deficiency (ID; N = 47), hereditary hemochromatosis (HH; N = 121) and non-transfusion-dependent hereditary anemia (HA; N = 40). Mean mucosal iron uptake and mucosal iron transfer (±SD) were elevated in patients with HH (59 ± 18%, 80 ± 15% respectively), HA (65 ± 17%, 74 ± 18%) and ID (84 ± 14%, 94 ± 6%) compared to healthy controls (43 ± 19%, 64 ± 18%) ( < 0.05) resulting in increased iron retention after 14 days compared to healthy controls in all groups ( < 0.01). The fraction of retained iron utilized for red cell production was 0.37 ± 0.17 in untreated HA, 0.55 ± 0.20 in untreated HH and 0.99 ± 0.22 in ID ( < 0.01). Interestingly, compared to red blood cell iron utilization after oral iron administration, red blood cell iron utilization was higher after injection of transferrin-bound iron in HA and HH. Liver iron retention was considerably higher in HH and HA compared to ID. We hypothesize that albumin serves as a scavenger of absorbed Fe(II) for delivering albumin-bound Fe(III) to hepatocytes.
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http://dx.doi.org/10.3390/ijms21031077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037197PMC
February 2020

AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes.

Haematologica 2021 01 1;106(1):238-249. Epub 2021 Jan 1.

Laboratory of Clinical Chemistry and Haematology, University Medical Center Utrecht.

Pyruvate kinase (PK) deficiency is a rare hereditary disorder affecting red cell (RBC) glycolysis, causing changes in metabolism including a deficiency in ATP. This affects red cell homeostasis, promoting premature removal of RBCs from the circulation. In this study we characterized and evaluated the effect of AG-348, an allosteric activator of PK that is currently in clinical trials for treatment of PK deficiency, on RBCs and erythroid precursors from PK-deficient patients. In 15 patients ex vivo treatment with AG-348 resulted in increased enzymatic activity in all patient cells after 24 hours (mean increase 1.8-fold, range 1.2-3.4). ATP levels increased (mean increase 1.5-fold, range 1.0-2.2) similar to control cells (mean increase 1.6-fold, range, 1.4-1.8). Generally, PK thermostability was strongly reduced in PK-deficient RBCs. Ex vivo treatment with AG-348 increased residual activity 1.4 to >10-fold than residual activity of vehicle-treated samples. Protein analyses suggests that a sufficient level of PK protein is required for cells to respond to AG-348 treatment ex-vivo, as treatment effects were minimal in patient cells with very low or undetectable levels of PK-R. In half of the patients, ex vivo treatment with AG-348 was associated with an increase in RBC deformability. These data support the hypothesis that drug intervention with AG-348 effectively upregulates PK enzymatic activity and increases stability in PK-deficient RBCs over a broad range of PKLR genotypes. The concomitant increase in ATP levels suggests that glycolytic pathway activity may be restored. AG-348 treatment may represent an attractive way to correct the underlying pathologies of PK deficiency. (AG-348 is currently in clinical trials for the treatment of PK deficiency. ClinicalTrials.gov: NCT02476916, NCT03853798, NCT03548220, NCT03559699).
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http://dx.doi.org/10.3324/haematol.2019.238865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776327PMC
January 2021

Characterization of Sickling During Controlled Automated Deoxygenation with Oxygen Gradient Ektacytometry.

J Vis Exp 2019 11 5(153). Epub 2019 Nov 5.

Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht University.

In sickle cell disease (SCD), a single point mutation in the gene coding for beta-globin causes the production of abnormal hemoglobin S (HbS). When deoxygenated, HbS can polymerize, forming rigid rods of hemoglobin, resulting in the sickling of red blood cells (RBCs). These sickled RBCs have significantly reduced deformability, causing vaso-occlusion, which leads to numerous SCD-related clinical complications, including pain, stroke, and organ damage. RBC deformability is also reduced by RBC dehydration, resulting in dense red blood cells that are more likely to sickle. To date, there is not a single widely available, rapid, and reproducible laboratory assay capable of predicting the disease severity or directly monitoring the treatment effects for novel, non-fetal hemoglobin inducing therapies. In this study, we describe a protocol to measure RBC deformability as a function of pO2 that allows for the quantitation of sickling behavior in SCD patients. Oxygen gradient ektacytometry measures RBC deformability, expressed as the elongation index (EI), as a function of pO2. RBCs are exposed to a fixed shear stress of 30 Pa during one round of deoxygenation and reoxygenation. Six readout parameters are produced. Of these, the point of sickling (PoS), defined as the pO2 at which maximum EI (EImax) shows a 5% decrease, and minimum EI during deoxygenation (EImin) are the most informative, reflecting an individual patient's pO2 at which sickling starts and the minimal deformability of a patient's red blood cells, respectively. PoS is associated with an individual patient's hemoglobin affinity for oxygen, whereas EImin shows a strong correlation with fetal hemoglobin levels. We conclude that oxygen gradient ektacytometry is a promising technique to monitor the treatment of patients with SCD, as a biomarker for anti-sickling agents in clinical and preclinical trials, and an important tool to study sickling behavior of RBCs from individuals with SCD and sickle cell traits.
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http://dx.doi.org/10.3791/60213DOI Listing
November 2019

Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency.

N Engl J Med 2019 09;381(10):933-944

From the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston (R.F.G.), and Agios Pharmaceuticals, Cambridge (A.J.B., S.B., L.H., C.K., P.H., M.-H.J., C.B.) - all in Massachusetts; Hôpital Saint Vincent de Paul, Lille (C.R.), and Unité des Maladies Génétiques du Globule Rouge, Centre Hospitalier Universitaire Henri Mondor, Créteil (F.G.) - both in France; Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (D.M.L.); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (W.B.); Central Pennsylvania Clinic, Belleville (D.H.M.), and Children's Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania, Philadelphia (J.L.K.); Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (E.J.B.); University of Utah, Salt Lake City (H.Y.); Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit (Y.R.); University of Toronto, Toronto (K.H.M.K.); Weill Cornell Medical College, New York (S.S.); Bruce A. Silver Clinical Science and Development, Dunkirk, MD (B.S.); and Stanford University School of Medicine, Palo Alto, CA (B.G.).

Background: Pyruvate kinase deficiency is caused by mutations in and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells.

Methods: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase.

Results: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense mutation and were associated with the red-cell pyruvate kinase protein level at baseline.

Conclusions: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).
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http://dx.doi.org/10.1056/NEJMoa1902678DOI Listing
September 2019

The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research.

Front Physiol 2019 26;10:304. Epub 2019 Mar 26.

Van Creveldkliniek, Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias. FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production. Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade.
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http://dx.doi.org/10.3389/fphys.2019.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443968PMC
March 2019

Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients.

Am J Hematol 2019 05 8;94(5):575-584. Epub 2019 Mar 8.

Laboratory of Clinical Chemistry & Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

In sickle cell disease (SCD), sickle hemoglobin (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These sickled RBCs have strongly reduced deformability, leading to vaso-occlusive crises and chronic hemolytic anemia. To date, there are no reliable laboratory parameters or assays capable of predicting disease severity or monitoring treatment effects. We here report on the oxygenscan, a newly developed method to measure RBC deformability (expressed as Elongation Index - EI) as a function of pO . Upon a standardized, 22 minute, automated cycle of deoxygenation (pO median 16 mmHg ± 0.17) and reoxygenation, a number of clinically relevant parameters are produced in a highly reproducible manner (coefficients of variation <5%). In particular, physiological modulators of oxygen affinity, such as, pH and 2,3-diphosphoglycerate showed a significant correlation (respectively R = -0.993 and R = 0.980) with Point of Sickling (PoS ), which is defined as the pO where a 5% decrease in EI is observed during deoxygenation. Furthermore, in vitro treatment with antisickling agents, including GBT440, which alter the oxygen affinity of hemoglobin, caused a reproducible left-shift of the PoS, indicating improved deformability at lower oxygen tensions. When RBCs from 21 SCD patients were analyzed, we observed a significantly higher PoS in untreated homozygous SCD patients compared to treated patients and other genotypes. We conclude that the oxygenscan is a state-of-the-art technique that allows for rapid analysis of sickling behavior in SCD patients. The method is promising for personalized treatment, development of new treatment strategies and could have potential in prediction of complications.
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http://dx.doi.org/10.1002/ajh.25443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518936PMC
May 2019

Clinical Remission of Delta-Aminolevulinic Acid Dehydratase Deficiency Through Suppression of Erythroid Heme Synthesis.

Hepatology 2019 07 6;70(1):434-436. Epub 2019 Jun 6.

Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1002/hep.30543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618255PMC
July 2019

Organ involvement occurs in all forms of hereditary haemolytic anaemia.

Br J Haematol 2019 05 5;185(3):602-605. Epub 2018 Sep 5.

Van Creveldkliniek, University Medical Centre Utrecht, Utrecht, Netherlands.

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http://dx.doi.org/10.1111/bjh.15575DOI Listing
May 2019

Iron overload in patients with rare hereditary hemolytic anemia: Evidence-based suggestion on whom and how to screen.

Am J Hematol 2018 11 21;93(11):E374-E376. Epub 2018 Sep 21.

Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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http://dx.doi.org/10.1002/ajh.25251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220762PMC
November 2018

Oxidative stress in sickle cell disease; more than a DAMP squib.

Clin Hemorheol Microcirc 2018 ;68(2-3):239-250

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Sickle cell disease (SCD) is a monogenetic disorder marked by hemolytic anemia and vaso-occlusive complications. The hallmark of SCD is the intracellular polymerization of sickle hemoglobin (HbS) after deoxygenation, and the subsequent characteristic shape change (sickling) of red cells. Vaso-occlusion occurs after endothelial activation, expression of adhesion molecules and subsequent adhesion of leucocytes and sickle erythrocytes to the vascular wall. Here we review how oxidative stress from various sources influences this process. Emerging evidence points towards a dominant mechanism in which innate immune receptors, such as Toll like receptor 4, activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidases to produce reactive oxygen species (ROS) which in turn enables downstream pro-inflammatory signaling and subsequent endothelial activation. By serving as an iron donor for the Fenton reaction, heme radically increases the amount of ROS further, thereby increasing the signal originating from the innate immune receptor and downstream effects of innate immune receptor activation. In SCD this results in the production of pro-inflammatory cytokines, endothelial activation and leucocyte adhesion, and eventually vaso-occlusion. Any intervention to stop this cascade, including Toll like receptor blockade, NADPH oxidase inhibition, ROS reduction, heme scavenging, iron chelation, or anti-adhesion molecule antibodies has been successfully used in pre-clinical studies and holds promise for patients with SCD.
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http://dx.doi.org/10.3233/CH-189010DOI Listing
May 2018

Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study.

Blood 2018 05 16;131(20):2183-2192. Epub 2018 Mar 16.

Zentrum für Kunder-und Jugendmedizin, Heidelberg, Germany.

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin ( = .007), lower indirect bilirubin ( = .005), and missense mutations ( = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.
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http://dx.doi.org/10.1182/blood-2017-10-810796DOI Listing
May 2018
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