{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T17:38:00Z","timestamp":1774114680909,"version":"3.50.1"},"reference-count":39,"publisher":"ASME International","issue":"2","content-domain":{"domain":["asmedigitalcollection.asme.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,2,1]]},"abstract":"<jats:p>Patients with sickle cell anemia (SCD) and pulmonary hypertension (PH) have a significantly increased risk of sudden death compared to patients with SCD alone. Sickled red blood cells (RBCs) are stiffer, more dense, more frequently undergo hemolysis, and have a sixfold shorter lifespan compared to normal RBCs. Here, we sought to investigate the impact of increased RBC stiffness, independent of other SCD-related biological and mechanical RBC abnormalities, on the hemodynamic changes that ultimately cause PH and increase mortality in SCD. To do so, pulmonary vascular impedance (PVZ) measures were recorded in control C57BL6 mice before and after \u223c50\u2009\u03bcl of blood (Hct\u2009=\u200945%) was extracted and replaced with an equal volume of blood containing either untreated RBCs or RBCs chemically stiffened with glutaraldehyde (Hct\u2009=\u200945%). Chemically stiffened RBCs increased mean pulmonary artery pressure (mPAP) (13.5\u2009\u00b1\u20090.6\u2009mmHg at baseline to 23.2\u2009\u00b1\u20090.7\u2009mmHg after the third injection), pulmonary vascular resistance (PVR) (1.23\u2009\u00b1\u20090.11\u2009mmHg*min\/ml at baseline to 2.24\u2009\u00b1\u20090.14\u2009mmHg*min\/ml after the third injection), and wave reflections (0.31\u2009\u00b1\u20090.02 at baseline to 0.43\u2009\u00b1\u20090.03 after the third injection). Chemically stiffened RBCs also decreased cardiac output, but did not change hematocrit, blood viscosity, pulmonary arterial compliance, or heart rate. The main finding of this study is that increased RBC stiffness alone affects pulmonary pulsatile hemodynamics, which suggests that RBC stiffness plays an important role in the development of PH in patients with SCD.<\/jats:p>","DOI":"10.1115\/1.4032187","type":"journal-article","created":{"date-parts":[[2015,12,8]],"date-time":"2015-12-08T17:35:50Z","timestamp":1449596150000},"update-policy":"https:\/\/doi.org\/10.1115\/crossmarkpolicy-asme","source":"Crossref","is-referenced-by-count":15,"title":["Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure"],"prefix":"10.1115","volume":"138","author":[{"given":"David A.","family":"Schreier","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Wisconsin, 2146 ECB, 1550 Engineering Drive, Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omid","family":"Forouzan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Wisconsin, 2146 ECB, 1550 Engineering Drive, Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy A.","family":"Hacker","sequence":"additional","affiliation":[{"name":"Department of Medicine, 1685 Highland Avenue, 5158 Medical Foundation Centennial Building, Madison, WI 53705-2281"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Sheehan","sequence":"additional","affiliation":[{"name":"Department of Medicine, 1685 Highland Avenue, 5158 Medical Foundation Centennial Building, Madison, WI 53705-2281"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Chesler","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Wisconsin, 2146 ECB, 1550 Engineering Drive, Madison, WI 53706;"},{"name":"Department of Medicine, 1685 Highland Avenue, 5158 Medical Foundation Centennial Building, Madison, WI 53705-2281 e-mail:"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"33","published-online":{"date-parts":[[2016,1,27]]},"reference":[{"key":"2019100604055162000_bib1","article-title":"Sickle-Cell Anaemia: Report by the Secretariat","year":"2006"},{"issue":"11","key":"2019100604055162000_bib2","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1056\/NEJM199709113371107","article-title":"Pathogenesis and Treatment of Sickle Cell Disease","volume":"337","year":"1997","journal-title":"N. Engl. J. Med."},{"issue":"9442","key":"2019100604055162000_bib3","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1016\/S0140-6736(04)17192-4","article-title":"Sickle-Cell Disease","volume":"364","year":"2004","journal-title":"Lancet"},{"issue":"4","key":"2019100604055162000_bib4","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.ccm.2013.08.006","article-title":"Pulmonary Hypertension Associated With Chronic Hemolytic Anemia and Other Blood Disorders","volume":"34","year":"2013","journal-title":"Clin. Chest Med."},{"issue":"5","key":"2019100604055162000_bib5","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1182\/blood-2010-02-268193","article-title":"Pulmonary Hypertension and Nitric Oxide Depletion in Sickle Cell Disease","volume":"116","year":"2010","journal-title":"Blood"},{"issue":"5","key":"2019100604055162000_bib6","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1177\/0309324711398809","article-title":"Microelasticity of Red Blood Cells in Sickle Cell Disease","volume":"46","year":"2011","journal-title":"J. Strain Anal. Eng."},{"issue":"2","key":"2019100604055162000_bib7","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.atherosclerosis.2006.04.015","article-title":"Endothelial Function and Arterial Stiffness in Sickle-Thalassemia Patients","volume":"191","year":"2007","journal-title":"Atherosclerosis"},{"issue":"4","key":"2019100604055162000_bib8","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1182\/blood-2002-03-0948","article-title":"Pulmonary Hypertension in Sickle Cell Disease: Cardiac Catheterization Results and Survival","volume":"101","year":"2003","journal-title":"Blood"},{"issue":"4","key":"2019100604055162000_bib9","first-page":"473","article-title":"Sickle Cells and Sudden Death","volume":"124","year":"1994","journal-title":"J. Lab. Clin. Med."},{"issue":"9","key":"2019100604055162000_bib10","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.amjmed.2004.03.034","article-title":"Pulmonary Hypertension in Sickle Cell Disease","volume":"117","year":"2004","journal-title":"Am. J. Med."},{"issue":"1","key":"2019100604055162000_bib11","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1002\/ajh.21058","article-title":"Pulmonary Hypertension Associated With Sickle Cell Disease: Clinical and Laboratory Endpoints and Disease Outcomes","volume":"83","year":"2008","journal-title":"Am. J. Hematol."},{"issue":"10","key":"2019100604055162000_bib12","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1053\/hupa.2002.128059","article-title":"Pulmonary Hypertension in Sickle Cell Hemoglobinopathy: A Clinicopathologic Study of 20 Cases","volume":"33","year":"2002","journal-title":"Hum. Pathol."},{"issue":"1","key":"2019100604055162000_bib13","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1183\/09031936.00134410","article-title":"Pulmonary Hypertension Diagnosed by Right Heart Catheterisation in Sickle Cell Disease","volume":"39","year":"2012","journal-title":"Eur. Respir. J."},{"issue":"3","key":"2019100604055162000_bib14","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1111\/j.1365-2141.2010.08097.x","article-title":"Exercise Capacity and Haemodynamics in Patients With Sickle Cell Disease With Pulmonary Hypertension Treated With Bosentan: Results of the ASSET Studies","volume":"149","year":"2010","journal-title":"Br. J. Haematol."},{"issue":"4","key":"2019100604055162000_bib15","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1182\/blood-2010-09-306167","article-title":"Hospitalization for Pain in Patients With Sickle Cell Disease Treated With Sildenafil for Elevated TRV and Low Exercise Capacity","volume":"118","year":"2011","journal-title":"Blood"},{"issue":"25 Suppl","key":"2019100604055162000_bib16","doi-asserted-by":"publisher","first-page":"D34","DOI":"10.1016\/j.jacc.2013.10.029","article-title":"Updated Clinical Classification of Pulmonary Hypertension","volume":"62","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"issue":"1","key":"2019100604055162000_bib17","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.mvr.2010.03.008","article-title":"The Dynamic Behavior of Chemically \u2018Stiffened\u2019 Red Blood Cells in Microchannel Flows","volume":"80","year":"2010","journal-title":"Microvasc. Res."},{"issue":"3","key":"2019100604055162000_bib18","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/BF01697397","article-title":"The Clinical Importance of Erythrocyte Deformability, a Hemorrheological Parameter","volume":"64","year":"1992","journal-title":"Ann. Hematol."},{"issue":"1","key":"2019100604055162000_bib19","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1083\/jcb.48.1.91","article-title":"Quantitation of Human Red Blood Cell Fixation by Glutaraldehyde","volume":"48","year":"1971","journal-title":"J. Cell Biol."},{"key":"2019100604055162000_bib20","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00059","article-title":"The Impact of Increased Hematocrit on Right Ventricular Afterload in Response to Chronic Hypoxia","volume":"117","year":"2014","journal-title":"J. Appl. Physiol."},{"issue":"5","key":"2019100604055162000_bib21","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.jbiomech.2011.11.020","article-title":"Persistent Vascular Collagen Accumulation Alters Hemodynamic Recovery From Chronic Hypoxia","volume":"45","year":"2012","journal-title":"J. Biomech."},{"issue":"4","key":"2019100604055162000_bib22","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1034\/j.1600-0609.2003.00027.x","article-title":"Optical Tweezers for Measuring Red Blood Cell Elasticity: Application to the Study of Drug Response in Sickle Cell Disease","volume":"70","year":"2003","journal-title":"Eur. J. Haematol."},{"issue":"51","key":"2019100604055162000_bib23","doi-asserted-by":"publisher","first-page":"20496","DOI":"10.1073\/pnas.0707122105","article-title":"Sickle Cell Vasoocclusion and Rescue in a Microfluidic Device","volume":"104","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"2","key":"2019100604055162000_bib24","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1080\/10739680490279410","article-title":"Sickle Red Cell Microrheology and Sickle Blood Rheology","volume":"11","year":"2004","journal-title":"Microcirculation"},{"key":"2019100604055162000_bib25","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0065-3233(08)60287-9","article-title":"Sickle Cell Hemoglobin Polymerization","volume":"40","year":"1990","journal-title":"Adv. Protein Chem."},{"issue":"5","key":"2019100604055162000_bib26","first-page":"H2003","article-title":"Contributions of Sickle Hemoglobin Polymer and Sickle Cell Membranes to Impaired Filterability","volume":"268","year":"1995","journal-title":"Am. J. Physiol."},{"issue":"9","key":"2019100604055162000_bib27","doi-asserted-by":"publisher","first-page":"5487","DOI":"10.1073\/pnas.77.9.5487","article-title":"Determination of Deoxyhemoglobin S Polymer in Sickle Erythrocytes Upon Deoxygenation","volume":"77","year":"1980","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"123","key":"2019100604055162000_bib28","doi-asserted-by":"publisher","first-page":"123ra126","DOI":"10.1126\/scitranslmed.3002738","article-title":"A Biophysical Indicator of Vaso-Occlusive Risk in Sickle Cell Disease","volume":"4","year":"2012","journal-title":"Sci. Transl. Med."},{"issue":"1","key":"2019100604055162000_bib29","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1146\/annurev-bioeng-070909-105339","article-title":"Sickle Cell Biomechanics","volume":"12","year":"2010","journal-title":"Annu. Rev. Biomed. Eng."},{"issue":"3","key":"2019100604055162000_bib30","doi-asserted-by":"publisher","first-page":"030506","DOI":"10.1117\/1.3556717","article-title":"Quantitative Microscopy and Nanoscopy of Sickle Red Blood Cells Performed by Wide Field Digital Interferometry","volume":"16","year":"2011","journal-title":"J. Biomed. Opt."},{"issue":"1","key":"2019100604055162000_bib31","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s10439-012-0635-z","article-title":"Impact of Acute Pulmonary Embolization on Arterial Stiffening and Right Ventricular Function in Dogs","volume":"41","year":"2013","journal-title":"Ann. Biomed. Eng."},{"key":"2019100604055162000_bib32","volume-title":"Hemodynamics","year":"1982"},{"key":"2019100604055162000_bib33","article-title":"The Mathematical Analysis of the Arterial Circulation in a State of Oscillatory Motion","year":"1957"},{"issue":"1","key":"2019100604055162000_bib34","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/jat.727","article-title":"A Good Practice Guide to the Administration of Substances and Removal of Blood, Including Routes and Volumes","volume":"21","year":"2001","journal-title":"J. Appl. Toxicol."},{"issue":"2","key":"2019100604055162000_bib35","first-page":"83","article-title":"Effects of Erythrocytapheresis Transfusion on the Viscoelasticity of Sickle Cell Blood","volume":"30","year":"2004","journal-title":"Clin. Hemorheol. Microcirc."},{"issue":"1\u20132","key":"2019100604055162000_bib36","first-page":"291","article-title":"Effect of Hydroxyurea on the Deformability of the Red Blood Cell Membrane in Patients With Sickle Cell Anemia","volume":"35","year":"2006","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"2019100604055162000_bib37","first-page":"178","volume-title":"Red Cell Rheology","year":"1978"},{"issue":"4","key":"2019100604055162000_bib38","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1021\/bp049974b","article-title":"Effect of Glutaraldehyde Concentration on the Physical Properties of Polymerized Hemoglobin-Based Oxygen Carriers","volume":"20","year":"2004","journal-title":"Biotechnol. Prog."},{"key":"2019100604055162000_bib39","volume-title":"Electron Microscopy: Principles and Techniques for Biologists","year":"1999"}],"container-title":["Journal of Biomechanical Engineering"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/asmedigitalcollection.asme.org\/biomechanical\/article-pdf\/doi\/10.1115\/1.4032187\/6093019\/bio_138_02_021012.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/asmedigitalcollection.asme.org\/biomechanical\/article-pdf\/doi\/10.1115\/1.4032187\/6093019\/bio_138_02_021012.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,6]],"date-time":"2019-10-06T08:05:57Z","timestamp":1570349157000},"score":1,"resource":{"primary":{"URL":"https:\/\/asmedigitalcollection.asme.org\/biomechanical\/article\/doi\/10.1115\/1.4032187\/371395\/Increased-Red-Blood-Cell-Stiffness-Increases"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,27]]},"references-count":39,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,2,1]]}},"URL":"https:\/\/doi.org\/10.1115\/1.4032187","relation":{},"ISSN":["0148-0731","1528-8951"],"issn-type":[{"value":"0148-0731","type":"print"},{"value":"1528-8951","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,27]]},"article-number":"021012"}}