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The most common pathological conditions causing morbidity for patients with sickle cell disease are chronic hemolytic anemia  and acute vaso-occlusive events[26,27].


SCD patients primarily suffer from chronic hemolytic anemia. Chronic hemolysis of SCD is due to Hb S auto-oxidation[26] and destruction of unstable Hb S-containing RBC[26] as well as more general destruction of sickle RBCs[78]. 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[78] instead of the normal 120 days[82].

Diagnostic Blood Indices

From hematological investigation, a number of parameters characterize the anemia and "stress" imparted on the hemopoietic system due to chronic hemolysis of sickle RBCs[26]. 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[27].  Markers of hemolysis in SCD include increased free Hb in plasma or urine[27] and iron deposition on the sickle RBC membrane[75]. In addition, due to mass red cell destruction, the hematocrit (volume of packed RBCs) is also typically reduced from ~ 45% in normal persons to ~ 30% in SCD patients in steady state and ~ 20% in SCD patients during crisis periods[26]. Furthermore, red cell indices of SCD patients reveal peripheral reticulocytosis[27], including many stress reticulocytes, indicative of high red cell turnover and decreased maturation time.

Sequestration & Erythrophagocytosis

Sickled 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[75], they undergo recognition and engulfment by macrophage in the bone marrow [81], spleen and/or liver (Kuffler cell) and monocytes in the general circulation[27,80].

Microvascular trapping/ vaso-occlusion

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.

Hemopoiesis/Erythropoiesis in SCD

SCD is an "uncompensated" blood disorder[26], wherein the intrinsically normal marrow undergoes hyperplasia[27], resulting in early release of immature RBCs (reticulocytosis)[27]. 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].

Delayed Growth

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[123].