{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T02:52:50Z","timestamp":1779159170316,"version":"3.51.4"},"reference-count":54,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"publisher","award":["W81XWH1910606"],"award-info":[{"award-number":["W81XWH1910606"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS110008"],"award-info":[{"award-number":["R21NS110008"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R56NS116076"],"award-info":[{"award-number":["R56NS116076"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NR018848-S1"],"award-info":[{"award-number":["NR018848-S1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions.<\/jats:p>","DOI":"10.3390\/genes13010144","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T12:34:04Z","timestamp":1642163644000},"page":"144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3801-2974","authenticated-orcid":false,"given":"Olivia","family":"Edwards","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"Burris","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0749-3314","authenticated-orcid":false,"given":"Josh","family":"Lua","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-8933","authenticated-orcid":false,"given":"Diana J.","family":"Wilkie","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Nursing Science, University of Florida College of Nursing, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam O.","family":"Ezenwa","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Nursing Science, University of Florida College of Nursing, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3771-5109","authenticated-orcid":false,"given":"Sylvain","family":"Dor\u00e9","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL 32610, USA"},{"name":"Departments of Neurology, Psychiatry, Pharmaceutics, and Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/S0140-6736(12)61229-X","article-title":"Global epidemiology of sickle haemoglobin in neonates: A contemporary geostatistical model-based map and population estimates","volume":"381","author":"Piel","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"117510","DOI":"10.1016\/j.jns.2021.117510","article-title":"Stroke and stroke prevention in sickle cell anemia in developed and selected developing countries","volume":"427","author":"Bhattacharya","year":"2021","journal-title":"J. Neurol. Sci."},{"key":"ref_3","unstructured":"Sedrak, A., and Kondamudi, N.P. (2021). Sickle Cell Disease. StatPearls, StatPearls Publishing."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ashouri, R., Fangman, M., Burris, A., Ezenwa, M.O., Wilkie, D.J., and Dor\u00e9, S. (2021). Critical role of hemopexin mediated cytoprotection in the pathophysiology of sickle cell disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126408"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/S1474-4422(06)70469-0","article-title":"Pathophysiology and treatment of stroke in sickle-cell disease: Present and future","volume":"5","author":"Switzer","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/j.1751-553X.2007.00898.x","article-title":"Haptoglobin: A review of the major allele frequencies worldwide and their association with diseases","volume":"29","author":"Carter","year":"2007","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1590\/S1415-47572008000400002","article-title":"Polymorphism of human haptoglobin and its clinical importance","volume":"31","author":"Wobeto","year":"2008","journal-title":"Genet. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.bcmd.2013.10.001","article-title":"Haptoglobin and myeloperoxidase (-G463A) gene polymorphisms in Brazilian sickle cell patients with and without secondary iron overload","volume":"52","author":"Barbosa","year":"2014","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Atkinson, S.H., Rockett, K., Sirugo, G., Bejon, P.A., Fulford, A., O\u2019Connell, M.A., Bailey, R., Kwiatkowski, D.P., and Prentice, A.M. (2006). Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030172"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.ejim.2012.04.009","article-title":"Haptoglobin genotype and cardiovascular outcomes in diabetes mellitus-natural history of the disease and the effect of vitamin E treatment. Meta-analysis of the medical literature","volume":"23","author":"Vardi","year":"2012","journal-title":"Eur. J. Intern. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"592","DOI":"10.3389\/fphys.2018.00592","article-title":"Unique contribution of haptoglobin and haptoglobin genotype in aneurysmal subarachnoid hemorrhage","volume":"9","author":"Blackburn","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.bcmd.2018.07.002","article-title":"Serum haptoglobin and hemopexin levels are depleted in pediatric sickle cell disease patients","volume":"72","author":"Santiago","year":"2018","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"L765","DOI":"10.1152\/ajplung.00269.2018","article-title":"Depletion of haptoglobin and hemopexin promote hemoglobin-mediated lipoprotein oxidation in sickle cell disease","volume":"315","author":"Yalamanoglu","year":"2018","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_14","first-page":"4","article-title":"Differences in the clinical and genotypic presentation of sickle cell disease around the world","volume":"15","author":"Saraf","year":"2014","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"340","DOI":"10.3324\/haematol.13812","article-title":"Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: Association with hemolysis and hemoglobin oxygen desaturation","volume":"94","author":"Minniti","year":"2009","journal-title":"Haematologica"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1161\/CIRCULATIONAHA.111.032920","article-title":"Walk-PHASST Investigators Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom","volume":"124","author":"Sachdev","year":"2011","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fimmu.2019.00085","article-title":"Cell Type-Specific Roles of NF-\u03baB Linking Inflammation and Thrombosis","volume":"10","author":"Mussbacher","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1749-6632.2010.05735.x","article-title":"NF-\u03baB and innate immunity in ischemic stroke","volume":"1207","author":"Harari","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"a013433","DOI":"10.1101\/cshperspect.a013433","article-title":"Cell-free hemoglobin and its scavenger proteins: New disease models leading the way to targeted therapies","volume":"3","author":"Schaer","year":"2013","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/jcp.22195","article-title":"Sickle cell anemia and vascular dysfunction: The nitric oxide connection","volume":"224","author":"Akinsheye","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.mehy.2015.06.023","article-title":"Intravenous infusion of haptoglobin for the prevention of adverse clinical outcome in Sickle Cell Disease","volume":"85","author":"Quimby","year":"2015","journal-title":"Med. Hypotheses"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/jca.21447","article-title":"Safety, tolerability, and outcomes of regular automated red cell exchange transfusion in the management of sickle cell disease","volume":"31","author":"Tsitsikas","year":"2016","journal-title":"J. Clin. Apher."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1182\/asheducation-2016.1.625","article-title":"Sickle cell disease: When and how to transfuse","volume":"2016","author":"Howard","year":"2016","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"727569","DOI":"10.3389\/fneur.2021.727569","article-title":"Contribution of various types of transfusion to acute and delayed intracerebral hemorrhage injury","volume":"12","author":"Kumar","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.bjhh.2015.07.006","article-title":"Haptoglobin gene polymorphisms and interleukin-6 and -8 levels in patients with sickle cell anemia","volume":"37","author":"Vicari","year":"2015","journal-title":"Rev. Bras. Hematol. Hemoter."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2147\/TACG.S246607","article-title":"Haptoglobin Gene Polymorphism in Patients with Sickle Cell Anemia: Findings from a Nigerian Cohort Study","volume":"13","author":"Olatunya","year":"2020","journal-title":"Appl. Clin. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E92","DOI":"10.1002\/ajh.25728","article-title":"Haptoglobin genotype predicts severe acute vaso-occlusive pain episodes in children with sickle cell anemia","volume":"95","author":"Willen","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1159\/000320302","article-title":"Haptoglobin gene polymorphisms in sickle cell disease patients with different \u03b2S-globin gene haplotypes","volume":"19","author":"Adekile","year":"2010","journal-title":"Med. Princ. Pract."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/bjh.12791","article-title":"Haptoglobin, \u03b1-thalassaemia and glucose-6-phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania","volume":"165","author":"Cox","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1089\/gtmb.2010.0235","article-title":"Haptoglobin genotypes in sickle-cell disease","volume":"15","author":"Santos","year":"2011","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1177\/153537020523000109","article-title":"Proinflammatory cytokines and the hypermetabolism of children with sickle cell disease","volume":"230","author":"Hibbert","year":"2005","journal-title":"Exp. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1203\/pdr.0b013e31802d7754","article-title":"Energy expenditure, inflammation, and oxidative stress in steady-state adolescents with sickle cell anemia","volume":"61","author":"Akohoue","year":"2007","journal-title":"Pediatr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1182\/blood-2007-12-130567","article-title":"Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1 \u03b1","volume":"112","author":"Patel","year":"2008","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1189\/jlb.0708445","article-title":"Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy","volume":"85","author":"Lanaro","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.atherosclerosis.2006.04.032","article-title":"Haptoglobin genotype modulates the balance of Th1\/Th2 cytokines produced by macrophages exposed to free hemoglobin","volume":"191","author":"Guetta","year":"2007","journal-title":"Atherosclerosis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1104\/pp.15.00293","article-title":"Interplay of reactive oxygen species and nitric oxide: Nitric oxide coordinates reactive oxygen species homeostasis","volume":"167","author":"Lindermayr","year":"2015","journal-title":"Plant Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1177\/1479164116645247","article-title":"The haptoglobin 2-2 genotype is associated with inflammation and carotid artery intima-media thickness","volume":"13","author":"Dalan","year":"2016","journal-title":"Diab. Vasc. Dis. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"613860","DOI":"10.1155\/2015\/613860","article-title":"Interaction between the Haptoglobin 2 Phenotype and Diabetes Mellitus on Systolic Pulmonary Arterial Pressure and Nitric Oxide Bioavailability in Hemodialysis Patients","volume":"2015","author":"Dahan","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/jhh.2012.57","article-title":"Haptoglobin polymorphism affects nitric oxide bioavailability in preeclampsia","volume":"27","author":"Lacchini","year":"2013","journal-title":"J. Hum. Hypertens."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e18225","DOI":"10.1097\/MD.0000000000018225","article-title":"The role of hydroxyurea to prevent silent stroke in sickle cell disease: Systematic review and meta-analysis","volume":"98","author":"Hasson","year":"2019","journal-title":"Medicine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1182\/blood-2016-01-694562","article-title":"Silent cerebral infarcts and cerebral aneurysms are prevalent in adults with sickle cell anemia","volume":"127","author":"Kassim","year":"2016","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1182\/blood-2011-05-349621","article-title":"Associated risk factors for silent cerebral infarcts in sickle cell anemia: Low baseline hemoglobin, sex, and relative high systolic blood pressure","volume":"119","author":"DeBaun","year":"2012","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1081\/HEM-120005448","article-title":"Modification in the frequency of Hb C and Hb S in Burkina Faso: An influence of migratory fluxes and improvement of patient health care","volume":"26","author":"Simpore","year":"2002","journal-title":"Hemoglobin"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1007\/s00277-012-1465-7","article-title":"Greek Haemoglobinopathies Study Group A national registry of haemoglobinopathies in Greece: Deducted demographics, trends in mortality and affected births","volume":"91","author":"Voskaridou","year":"2012","journal-title":"Ann. Hematol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"748939","DOI":"10.5402\/2011\/748939","article-title":"Hemoglobin disorders in South India","volume":"2011","author":"Chandrashekar","year":"2011","journal-title":"ISRN Hematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1182\/blood-2010-01-261123","article-title":"Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease","volume":"117","author":"Hulbert","year":"2011","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1002\/pbc.24557","article-title":"Sickle cell disease related mortality in the United States (1999\u20132009)","volume":"60","author":"Hamideh","year":"2013","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"561917","DOI":"10.3389\/fimmu.2020.561917","article-title":"The worst things in life are free: The role of free heme in sickle cell disease","volume":"11","author":"Gbotosho","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1056\/NEJMoa1611770","article-title":"Crizanlizumab for the prevention of pain crises in sickle cell disease","volume":"376","author":"Ataga","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1182\/blood-2018-08-868893","article-title":"A phase 1\/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease","volume":"133","author":"Howard","year":"2019","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.jchromb.2006.08.012","article-title":"An improved method for haptoglobin 1-1, 2-1, and 2-2 purification using monoclonal antibody affinity chromatography in the presence of sodium dodecyl sulfate","volume":"845","author":"Yueh","year":"2007","journal-title":"J. Chromatogr. B Analyt. Technol. Biomed. Life Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3109\/10731199.2010.509705","article-title":"A simple and rapid procedure for purification of haptoglobin from human plasma fraction IV","volume":"39","author":"Sun","year":"2011","journal-title":"Artif. Cells Blood Substit. Immobil. Biotechnol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e3010","DOI":"10.1002\/btpr.3010","article-title":"Tangential flow filtration of haptoglobin","volume":"36","author":"Pires","year":"2020","journal-title":"Biotechnol. Prog."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Schaer, C.A., Owczarek, C., Deuel, J.W., Schauer, S., Baek, J.H., Yalamanoglu, A., Hardy, M.P., Scotney, P.D., Schmidt, P.M., and Pelzing, M. (2018). Phenotype-specific recombinant haptoglobin polymers co-expressed with C1r-like protein as optimized hemoglobin-binding therapeutics. BMC Biotechnol., 18.","DOI":"10.1186\/s12896-018-0424-3"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:15:02Z","timestamp":1760364902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,14]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["genes13010144"],"URL":"https:\/\/doi.org\/10.3390\/genes13010144","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,14]]}}}