{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:26:31Z","timestamp":1786976791707,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016471","name":"Agios Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016471","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013297","name":"Eurostars","doi-asserted-by":"publisher","award":["E115561"],"award-info":[{"award-number":["E115561"]}],"id":[{"id":"10.13039\/100013297","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pyruvate kinase (PK) is a key enzyme involved in the final step of glycolysis, essential to produce adenosine triphosphate (ATP). Relatively decreased red blood cell (RBC) PK activity (reflected by a lower PK\/hexokinase [HK] ratio) and PK thermostability (PK activity after exposure to heat) were recently identified as pathophysiological features of sickle cell disease (SCD). In this study, we investigated whether impaired PK function is associated with sickle RBC properties and SCD\u2010related clinical manifestations. This study included 97 non\u2010transfused patients with SCD (88 HbSS, 9 HbS\/\u03b20 thalassemia). PK thermostability was correlated with RBC parameters such as reticulocyte count (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.402,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and hemoglobin F (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.394,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001), and indicators of impaired functional properties of sickle RBCs, such as the point of sickling (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.417,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001), oxygen affinity (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.408,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) and RBC adhesion to laminin (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.322,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.024). Additionally, a low PK\/HK ratio correlated with decreased PK thermostability (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.308,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002), decreased RBC deformability (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.268,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.009), and elevated 2,3\u2010diphosphoglycerate levels (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.244,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.016). Multivariate Poisson regression analysis demonstrated that reduced PK thermostability and PK\/HK ratio were associated with a higher incidence of SCD\u2010related clinical complications. For every 10\u2010unit decrease in PK thermostability and 1\u2010unit decrease in PK\/HK ratio, the incidence of SCD\u2010related clinical complications increased by 11% (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.012) and 10% (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.019), respectively. Altogether, these findings indicate that impaired PK function is related to compromised sickle RBC properties and SCD\u2010related clinical manifestations. This supports the relevance and underlines the potential of PK activation therapy.\n                  <\/jats:p>","DOI":"10.1002\/ajh.27644","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T05:03:34Z","timestamp":1740114214000},"page":"785-796","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pyruvate Kinase Function Correlates With Red Blood Cell Properties and Clinical Manifestations in Sickle Cell Disease"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0821-7995","authenticated-orcid":false,"given":"M. J. M.","family":"Traets","sequence":"first","affiliation":[{"name":"Department of Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. F.","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"van der Veen","sequence":"additional","affiliation":[{"name":"Center for Benign Hematology, Thrombosis and Hemostasis\u2014Van Creveldkliniek University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"van Pelt","sequence":"additional","affiliation":[{"name":"Department of Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9377-0367","authenticated-orcid":false,"given":"M. J.","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. A.","family":"van Oirschot","sequence":"additional","affiliation":[{"name":"Department of Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. R. A.","family":"de Wilde","sequence":"additional","affiliation":[{"name":"Department of Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. J.","family":"Jans","sequence":"additional","affiliation":[{"name":"Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. W.","family":"van Solinge","sequence":"additional","affiliation":[{"name":"Department of Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. E. M.","family":"Schols","sequence":"additional","affiliation":[{"name":"Department of Hematology Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. N.","family":"Lauw","sequence":"additional","affiliation":[{"name":"Department of Hematology, Erasmus MC University Medical Center  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. H.","family":"Cnossen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children's Hospital University Medical Center  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Nur","sequence":"additional","affiliation":[{"name":"Department of Hematology Amsterdam University Medical Center  Amsterdam the Netherlands"},{"name":"Department of Molecular Hematology Sanquin Research and Landsteiner Laboratory  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4426-5743","authenticated-orcid":false,"given":"B. 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