Image by Betty Pace
A sickled red blood cell beside a normal one
Researchers say they have gained new insight that may help explain how vaso-occlusive crises (VOCs) occur in patients with sickle cell disease (SCD).
The team assessed how red blood cell (RBC) adhesion and polymerization of deoxygenated sickle hemoglobin affect the mechanisms underlying VOCs.
Experiments showed that hypoxia enhances sickle RBC adherence, and hemoglobin S polymerization enhances adherence for sickle reticulocytes and mature erythrocytes.
However, sickle reticulocytes have “unique adhesion dynamics” and therefore appear more likely to cause VOCs.
The researchers described these discoveries in an article set to be published this week in the Proceedings of the National Academy of Sciences.
To investigate how RBCs interact with blood vessels to set off a VOC, the researchers built a microfluidic system that mimics post-capillary vessels. These vessels, which carry deoxygenated blood away from the capillaries, are where vaso-occlusions are most likely to occur.
The microfluidic system is designed to allow the researchers to control the oxygen level. The team used the system to test blood from eight SCD patients.
The researchers found that, under hypoxic conditions, sickle RBCs are two to four times more likely to adhere to the blood vessel walls than they are when oxygen levels are normal.
The team also found that hemoglobin S polymerization enhances the adherence of sickle reticulocytes and sickle mature erythrocytes. The hemoglobin S forms stiff fibers that grow and push the cell membrane outward, and these fibers help the cells adhere more firmly to the lining of the blood vessel.
“There has been little understanding of why, under hypoxia, there is much more adhesion,” said study author Subra Suresh, DSc, of Nanyang Technological University in Singapore.
“The experiments of this study provide some key insights into the processes and mechanisms responsible for increased adhesion.”
The researchers also found that, in SCD patients, reticulocytes are more likely than mature erythrocytes to adhere to blood vessels.
“We observed the growth of sickle hemoglobin fibers stretching reticulocytes within minutes,” said study author Dimitrios Papageorgiou, PhD, of the Massachusetts Institute of Technology in Cambridge.
“It looks like they’re trying to grab more of the surface and adhere more strongly.”
The researchers said these and other findings suggest polymerization and adhesion stimulate each other.
The team now hopes to devise a more complete model of vaso-occlusion that combines their new findings with previous work. The previous work involved measuring how long it takes SCD patients’ blood cells to stiffen, making them more likely to block blood flow in tiny blood vessels.
The researchers also hope their findings might help them devise a way to predict VOCs in individual SCD patients.