Intracellular Hemoglobin S Polymerization and the Clinical
Severity of Sickle Cell Anemia
William N. Poillon,
Bak C. Kim, and
Oswaldo Castro
From the Center for Sickle Cell Disease and Department of Pediatrics
and Child Health, Howard University College of Medicine, Washington,
DC.
Recent work has enabled us to quantitate the four
variables (2,3-DPG concentration, pHi, non-S
hemoglobin composition, and O2 saturation) that modulate
the equilibrium solubility (csat) of Hb S inside sickle
erythrocytes (SS RBCs). Using measured values of mean corpuscular
hemoglobin concentration (MCHC), 2,3-DPG concentration, and %Hb (F+A2), along with estimates of pHi
and the 
csat due to partial oxygenation of SS RBCs in
the microcirculation, we calculated the mean polymer fraction
(fp) in erythrocytes from 46 SS homozygotes. Values of
fp derived from the conservation of mass equation ranged
from 0.30 to 0.59. MCHC and %Hb F were major determinants of the
magnitude of fp; 2,3-DPG concentration and pHi
also contributed, but to a lesser extent. A clinical severity score
(CSS) was assigned to each patient based on mean hospitalization rate.
There was a weak, but statistically significant, negative correlation
between fp and steady state hematocrit (P = .017), but none between fp and whole blood hemoglobin
concentration (P = .218). Although there was no correlation
between fp and mean number of hospitalization days per
year, patients with the greatest number of admissions and
hospitalization days were found only among those who had an
fp > 0.45. All five patients who died during the
follow-up period (median, 7 years; range, 3 to 10 years) had fp values 
0.48. However, patients with few admissions,
low hospitalization days, and long survivals occurred at all
fp levels. These results suggest that the clinical course
of homozygous SS disease cannot be predicted by mean fp
calculations, which assume a homogeneous distribution of the five
variables that modulate intraerythrocytic polymerization. A
heterogeneous distribution is more likely; so the amount of polymerized
Hb S could vary considerably among cell populations. Factors such as
membrane abnormalities and endothelial cell interactions may also
contribute to clinical severity.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1777-1783
© 1998 by The American Society of Hematology.
