Elucidating Mechanisms Involved in Hydroxyurea-Mediated Reduction in Red-Cell Endothelial Interactions in Sickle Cell Disease

Kimera Harris, Urvashi Thongam, Eric VanBuren, Jennell White Department of Pharmacology, Wayne State University School of Medicine 540 E Canfield St., Detroit, MI 48202

Vaso-occlusion is the hallmark of sickle cell disease (SCD) resulting in frequent pain, organ damage, and early death. Red blood cells (RBCs) contribute to vaso-occlusive episodes (VOEs) by abnormally adhering to the vascular endothelium.  Hydroxyurea (HU), the standard of care for SCD management, reduces the frequency of VOEs, in part, by reducing adhesion receptor expression and red cell adhesion, however, regulatory mechanisms are unknown. Very late antigen-4(VLA-4), the most characterized adhesion receptor in SCD, is highly expressed on immature RBCs (reticulocytes) present in SCD patients in increased numbers. Reticulocytes and VLA-4 cell surface expression are increased during VOEs and decreased in HU-treated patients. We previously demonstrated that VLA-4-mediated adhesion is reduced in HU-treated patients. Others have shown that VLA-4 activity, and subsequent adhesion, is regulated with cell signaling pathways although these mechanisms have not been defined in RBCs or SCD. Our more recent data demonstrates that HU modulates VLA-4-mediated adhesion in whole blood samples collected from SCD patients within minutes suggesting rapid erythroid signaling pathways may be involved. Ongoing studies are aimed at understanding the effect of HU on VLA-4 activity and this relationship with sickle reticulocyte adhesion. Flow cytometric and functional adhesion approaches will be utilized to assess VLA-4 activity and VLA-4 binding affinity, respectively.  This study aims to reveal novel pathways that target VLA-4 to reduce VOEs in SCD.

Additional Abstract Information

Presenter: Kimera Harris

Institution: Wayne State University

Type: Poster

Subject: Biochemistry

Status: Approved

Time and Location

Session: Poster 1
Date/Time: Mon 1:30pm-2:30pm
Session Number: 2173