Oxygen-dependent flow of sickle trait blood as an in vitro therapeutic benchmark for sickle cell disease treatments

Xinran Lu, Anwesha Chaudhury, John M. Higgins, David K. Wood

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Although homozygous sickle cell disease is often clinically severe, the corresponding heterozygous state, sickle cell trait, is almost completely benign despite the fact that there is only a modest difference in sickle hemoglobin levels between the two conditions. In both conditions, hypoxia can lead to polymerization of sickle hemoglobin, changes in red cell mechanical properties, and impaired blood flow. Here, we test the hypothesis that differences in the oxygen-dependent rheological properties in the two conditions might help explain the difference in clinical phenotypes. We use a microfluidic platform that permits quantification of blood rheology under defined oxygen conditions in physiologically sized microchannels and under physiologic shear rates. We find that, even with its lower sickle hemoglobin concentration, sickle trait blood apparent viscosity increases with decreasing oxygen tension and may stop flowing under completely anoxic conditions, though far less readily than the homozygous condition. Sickle cell trait blood flow becomes impaired at significantly lower oxygen tension than sickle cell disease. We also demonstrate how sickle cell trait can serve as a benchmark for sickle cell disease therapies. We characterize the rheological effects of exchange transfusion therapy by mixing sickle blood with nonsickle blood and quantifying the transfusion targets for sickle hemoglobin composition below which the rheological response resembles sickle trait. These studies quantify the differences in blood flow phenotypes of sickle cell disease and sickle cell trait, and they provide a potentially powerful new benchmark for evaluating putative therapies in vitro.

Original languageEnglish (US)
Pages (from-to)1227-1235
Number of pages9
JournalAmerican Journal of Hematology
Volume93
Issue number10
DOIs
StatePublished - Oct 2018

Bibliographical note

Funding Information:
American Heart Association, Grant/Award Numbers: 13SDG645000016PRE31020025, 13SDG6450000,16PRE31020025;NationalHeart, Lung, and Blood Institute, Grant/Award Numbers: HL114476R01HL132906R21HL130818 R56HL132906, R01HL132906, R56HL132906, R21HL130818;NationalInstitutesofHealth,Grant/ Award Number: DP2DK098087; Life Sciences Research Foundation

Funding Information:
information American Heart Association, Grant/Award Numbers: 13SDG645000016PRE31020025, 13SDG6450000,16PRE31020025;NationalHeart, Lung, and Blood Institute, Grant/Award Numbers: HL114476R01HL132906R21HL130818 R56HL132906, R01HL132906, R56HL132906, R21HL130818;National Institutes ofHealth,Grant/Award Number: DP2DK098087; Life Sciences Research Foundation The authors would like to thank Jos? Valdez, Athena Geisness, Dr. Greg Vercelloti, and Dr. Bob Molokie for helpful discussions. For assistance with blood sample collection, identification, testing, and transport, the authors would like to thank members of the MGH Clinical Laboratories and the MGH Clinical Research Program, including John Yablonski, Chhaya Patel, and Hasmukh Patel, and Dr. Bronner Goncalves. The authors would also like Dr. Yvonne Data with the University of Minnesota Medical Center for assistance with blood sample collection as well as the University of Minnesota Advanced Research and Diagnostic Laboratory for assistance with blood sample identification and testing. Additionally, the authors would like to thank the Minnesota Nanofabrication Center for support with microfluidic device fabrication. Finally, the authors would like to thank all the patients and blood sample donors who helped make this work possible. This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) under Grants R21HL130818, R56HL132906, and R01HL132906. X.L. was supported under American Heart Association Pre-Doctoral Fellowship 16PRE31020025. A.C. was supported as a Good Ventures Fellow of the Life Sciences Research Foundation (LSRF). J.M.H was supported by a National Institutes of Health (NIH) Director's New Innovator Award (DP2DK098087) and NHLBI Grant HL114476. D.K.W. was supported under American Heart Association Grant 13SDG6450000.

Funding Information:
The authors would like to thank José Valdez, Athena Geisness, Dr. Greg Vercelloti, and Dr. Bob Molokie for helpful discussions. For assistance with blood sample collection, identification, testing, and transport, the authors would like to thank members of the MGH Clinical Laboratories and the MGH Clinical Research Program, including John Yablonski, Chhaya Patel, and Hasmukh Patel, and Dr. Bronner Goncalves. The authors would also like Dr. Yvonne Data with the University of Minnesota Medical Center for assistance with blood sample collection as well as the University of Minnesota Advanced Research and Diagnostic Laboratory for assistance with blood sample identification and testing. Additionally, the authors would like to thank the Minnesota Nanofabrication Center for support with microfluidic device fabrication. Finally, the authors would like to thank all the patients and blood sample donors who helped make this work possible. This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) under Grants R21HL130818, R56HL132906, and R01HL132906. X.L. was supported under American Heart Association Pre-Doctoral Fellowship 16PRE31020025. A.C. was supported as a Good Ventures Fellow of the Life Sciences Research Foundation (LSRF). J.M.H was supported by a National Institutes of Health (NIH) Director's New Innovator Award (DP2DK098087) and NHLBI Grant HL114476. D.K.W. was supported under American Heart Association Grant 13SDG6450000.

Publisher Copyright:
© 2018 Wiley Periodicals, Inc.

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