most common pathological conditions causing morbidity for patients with sickle
cell disease are chronic hemolytic anemia and
acute vaso-occlusive events[26,27].
patients primarily suffer from chronic hemolytic
anemia. Chronic hemolysis of SCD is due to Hb S auto-oxidation and
destruction of unstable Hb S-containing RBC as well as more general
destruction of sickle RBCs. The general destruction of sickled RBCs results
from sequestration and phagocytosis[79-81]. Because of this mass red cell
destruction, the mean lifespan of a sickle cell is reduced to
24 days instead of the
normal 120 days.
hematological investigation, a number of parameters characterize the anemia and
"stress" imparted on the hemopoietic system due to chronic hemolysis
of sickle RBCs. First and foremost, SCD results in a state of anemia:
low total Hb levels due to lysis of Hb from sickled, damaged, or
sequestered RBCs. Markers of
hemolysis in SCD include increased free Hb in plasma or urine and iron
deposition on the sickle RBC membrane. In addition, due to mass red cell
destruction, the hematocrit (volume of packed RBCs) is also typically reduced
45% in normal persons to
30% in SCD patients in steady
20% in SCD patients during
crisis periods. Furthermore, red cell indices of SCD patients reveal
peripheral reticulocytosis, including many stress reticulocytes, indicative
of high red cell turnover and decreased maturation time.
cells are sequestered in the reticuloendothelial system (a network of lymphatic tissue) or sinusoids of the
spleen. Engorgement of the spleen with sickled RBCs is a common occurrence and
usually underlies the splenomegaly seen in young SCD patients[27,79]. Since
sickled RBCs differ from the normal red cell, including the aberrant membrane
surface expression of complement 3b(C3b), immunoglobulins (IgG), and Band 3
clustered with denatured Hb S, they undergo recognition and engulfment by
macrophage in the bone marrow , spleen and/or liver (Kuffler cell) and
monocytes in the general circulation[27,80].
In addition to chronic hemolysis, the main clinical component of SCD is microvascular trapping of sickled RBCs[27,83]. There are several inter-related factors that impact on vaso-occlusion in SCD, these include the following: RBC density, RBC rigidity, membrane anomalies, blood viscosity and endothelial cell adhesion. These aspects of vaso-occlusion will be discussed in the section covering SCD pathophysiology.
is an "uncompensated" blood disorder, wherein the intrinsically
normal marrow undergoes hyperplasia, resulting in early release of immature
RBCs (reticulocytosis). However, this still does not compensate for the mass
peripheral red cell destruction. Increased red cell turnover (destruction)
causes hemopoietic stress, often resulting in the mobilization of early sickle
erythroid progenitors, and increased proliferation of
sickle erythroid progenitors[121,122].
Clinical reports from young and adolescent SCD patients have described a reduced growth curve (low weight) and delay in sexual maturation[123,124] in these individuals. Both males and females are affected, although males show a more pronounced growth failure. It is also noteworthy that the degree of developmental delay is correlated with disease severity and/or level of Hb S.