Simultaneous polymerization and adhesion under hypoxia in sickle cell disease

Area of Science:

• Hematology
• Biophysics
• Molecular Medicine

Background:

• Sickle cell disease (SCD) involves red blood cell (RBC) polymerization and adhesion, crucial processes in vaso-occlusive crises.
• These dynamic processes have been studied independently, limiting understanding of their combined impact.

Purpose of the Study:

• To investigate the simultaneous and synergistic effects of deoxygenated sickle hemoglobin (HbS) polymerization and RBC adhesion.
• To elucidate the mechanisms underlying vaso-occlusive pain crisis in SCD.

Main Methods:

• Utilized a microfluidic platform to induce and study RBC sickling and adhesion in vitro.
• Employed molecular-level computational simulations (dissipative particle dynamics) for cytoadherence and biorheology analysis.
• Analyzed sickle RBC maturation stages (reticulocytes, mature erythrocytes, irreversibly sickled cells) for adhesion susceptibility.

Main Results:

• Hypoxia significantly increases sickle RBC adherence.
• HbS polymerization enhances adhesion in sickle reticulocytes and mature erythrocytes, but not irreversibly sickled cells.
• Sickle reticulocytes show unique adhesion dynamics due to HbS fiber projections.
• Demonstrated a bidirectional coupling between polymerization and adhesion.

Conclusions:

• Findings provide insights into the mechanistic pathways of vaso-occlusive crisis in SCD.
• Circulating reticulocytes may play a significant role in the onset of vaso-occlusion.
• Understanding these coupled processes is vital for developing targeted therapies for SCD.