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572 Part V Red Blood Cells

A A B C D

Fig. 41.1 SICKLE RED BLOOD CELL (RBC) MORPHOLOGIES. Blood smears prepared under differing
conditions, using antecubital blood from the same sickle cell anemia patient. (A) Venous blood at a PO 2
~40 mm Hg was fixed immediately to document RBC shapes occurring in vivo. Several RBC morphologies
are evident, including two granular (raisin-like) cells, five somewhat elongated cells, and two highly elongated
and curved cells. (B) Unfixed blood was fully oxygenated. Most cells resumed normal shape, but one elongated,
irreversibly sickled cell remains present. (C) The oxygenated cells from (B) were then partially deoxygenated,
upon which they assumed classic holly-leaf forms typical of rapid deoxygenation. (D) The partially deoxygen-
ated cells from (C) were then fully deoxygenated (PO 2 ~ 0 mm Hg) and display the more elongated shape
having fewer spikes that is assumed by sickle RBC that have deoxygenated more slowly. The physical–chemical
basis for these shapes is presented in Fig. 41.5. (Reproduced with permission from Obata K, Mattiello J, Asakura K,
et al: Exposure of blood from patients with sickle cell disease to air changes the morphological, oxygen-binding, and sickling
properties of sickled erythrocytes. Am J Hematol 81:26, 2006).

Senegal

Arab-India
Benin
Cameroon Bantu
Malaria
Sickle cell gene

Fig. 41.2 SICKLE GENE AND MALARIA. The five regions in which the sickle gene achieved high allelic
frequency are superimposed on shading that identifies the Old World distribution of the sickle gene and of
historic, endemic malaria. (Reproduced with permission from Friedman MJ, Trager W: The biochemistry of resistance
S
to malaria. Sci Am 244:154, 1981; and from Nagel RL, Steinberg MH: Genetics of the β gene: origins, epidemiology,
and epistasis in sickle cell anemia. In Steinberg MH: Forget BG, Higgs DR, Nagel RL, editors: Disorders of hemoglobin:
Genetics, pathophysiology, and clinical management, Cambridge, 2001, Cambridge University Press, p 711.)

largely corroborates predictions of gene flow derived from historical Relationship of HbS Molecular Behaviors to Disease Features
records. As a generalization, it spread on the Benin haplotype to
North Africa and then across the Mediterranean. All three major Altered dimer assembly → RBC Hb composition
African haplotypes are present in the western Arabian Peninsula; but Hb phenotype and diagnosis
on the eastern side, the sickle gene tends to be on the Arab-India Polymerization risk
haplotype. This is also true in India, although sub-Saharan haplotypes HbS instability → Membrane defects
S
are represented as well. In the Americas, the β gene is mostly found RBC dehydration
on the Benin, Senegal, and Bantu haplotypes. Hemolysis
Malaria resistance
HbS polymerization → Sickling
ABNORMAL MOLECULAR BEHAVIORS OF Vasoocclusion
SICKLE HEMOGLOBIN Hemolysis

Because the β 6Glu→Val substitution entails a loss of negative charge and
gain in hydrophobicity, HbS exhibits three abnormal molecular
behaviors of direct relevance to pathophysiology.