Abstract
Abnormal sickle red blood cell (sRBC) biomechanics, including pathological deformability and adhesion, correlate with clinical severity in sickle cell disease (SCD). Clinical intravenous fluids (IVFs) of various tonicities are often used during treatment of vaso-occlusive pain episodes (VOE), the major cause of morbidity in SCD. However, evidence-based guidelines are lacking, and there is no consensus regarding which IVFs to use during VOE. Further, it is unknown how altering extracellular fluid tonicity with IVFs affects sRBC biomechanics in the microcirculation, where vaso-occlusion takes place. Here, we report how altering extracellular fluid tonicity with admixtures of clinical IVFs affects sRBC biomechanical properties by leveraging novel in vitro microfluidic models of the microcirculation, including 1 capable of deoxygenating the sRBC environment to monitor changes in microchannel occlusion risk and an “endothelialized” microvascular model that measures alterations in sRBC/endothelium adhesion under postcapillary venular conditions. Admixtures with higher tonicities (sodium 5 141 mEq/L) affected sRBC biomechanics by decreasing sRBC deformability, increasing sRBC occlusion under normoxic and hypoxic conditions, and increasing sRBC adhesion in our microfluidic human microvasculature models. Admixtures with excessive hypotonicity (sodium 5 103 mEq/L), in contrast, decreased sRBC adhesion, but overswelling prolonged sRBC transit times in capillary-sized microchannels. Admixtures with intermediate tonicities (sodium 5 111-122 mEq/L) resulted in optimal changes in sRBC biomechanics, thereby reducing the risk for vaso-occlusion in our models. These results have significant translational implications for patients with SCD and warrant a large-scale prospective clinical study addressing optimal IVF management during VOE in SCD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2654-2663 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 130 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 14 2017 |
Bibliographical note
Funding Information:This work was supported by the National Science Foundation CAREER Award 1150235 (W.A.L.); National Institutes of Health, National Heart, Lung, and Blood Institute grants 5U01-HL117721 (W.A.L.), R01HL121264 (W.A.L.), U54HL112309 (W.A.L.), R21HL130818 (D.K.W.), and R56HL132906 (D.K.W.); and American Heart Association grant 13SDG6450000 (D.K.W.) and predoctoral fellowship grant 16PRE31020025 (X.L.).
Funding Information:
The authors thank all the patients who donated blood for the advancement of science and the improvement of treatments for sickle cell disease. The authors also thank all members of the W.A.L. laboratory who contributed to thoughtful discussion during the experimental process and during preparation of the manuscript. The authors also thank the clinical research coordinators at the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta for assistance in obtaining and transporting samples. The authors also thank Yvonne Data at the University of Minnesota Medical Center for assistance with blood sample collection, identification, and transport. In addition, the authors thank the Minnesota Nano-fabrication Center for support with device fabrication and assembly, John M. Higgins at the Center for Systems Biology at Harvard Medical School, and the Department of Pathology at Massachusetts General Hospital for assistance with tracking blood velocities in deoxygenation experiments. Last, this work was performed in part at the Georgia Tech Institute for Electronics and Nanotechnology, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (Grant ECCS-1542174). This work was supported by the National Science Foundation CAREER Award 1150235 (W.A.L.); National Institutes of Health, National Heart, Lung, and Blood Institute grants 5U01-HL117721 (W.A.L.), R01HL121264 (W.A.L.), U54HL112309 (W.A.L.), R21HL130818 (D.K.W.), and R56HL132906 (D.K.W.); and American Heart Association grant 13SDG6450000 (D.K.W.) and predoctoral fellowship grant 16PRE31020025 (X.L.).
Funding Information:
The authors thank all the patients who donated blood for the advancement of science and the improvement of treatments for sickle cell disease. The authors also thank all members of the W.A.L. laboratory who contributed to thoughtful discussion during the experimental process and during preparation of the manuscript. The authors also thank the clinical research coordinators at the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta for assistance in obtaining and transporting samples. The authors also thank Yvonne Data at the University of Minnesota Medical Center for assistance with blood sample collection, identification, and transport. In addition, the authors thank the Minnesota Nano-fabrication Center for support with device fabrication and assembly, John M. Higgins at the Center for Systems Biology at Harvard Medical School, and the Department of Pathology at Massachusetts General Hospital for assistance with tracking blood velocities in deoxygenation experiments. Last, this work was performed in part at the Georgia Tech Institute for Electronics and Nanotechnology, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (Grant ECCS-1542174).
Publisher Copyright:
© 2017 by The American Society of Hematology.