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Impact of extracellular fluid tonicity on sickle red blood cell deformability and adhesion

Marcus A. Carden, Meredith E. Fay, Xinran Lu, Robert G. Mannino, Yumiko Sakurai, Jordan C. Ciciliano, Caroline E. Hansen, Satheesh Chonat, Clinton H. Joiner, David K. Wood and Wilbur A. Lam

Key points

  • IV fluids are used when treating VOE but guidelines are lacking, and how IV fluid tonicity affects sickle red cell biomechanics is unknown.

  • Modifying extracellular fluid tonicity alters deformability, adhesivity, and occlusion-risk of sickle RBCs in microfluidic vascular models.

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 one 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 post-capillary venular conditions. Admixtures with higher tonicities (sodium = 141 mEq/L) impacted 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 = 103 mEq/L), on the other hand, decreased sRBC adhesion, but overswelling prolonged sRBC transit times in capillary-sized microchannels. Admixtures with intermediate tonicities (sodium = 111-122 mEq/L) resulted in optimal changes in sRBC biomechanics, thereby reducing the risk of 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.

  • Submitted April 24, 2017.
  • Accepted September 24, 2017.