Chapter 14 Pathobiology Clinical Features, And Management Of Sickle Cell Disease
Figure 14-1 SICKLE RED BLOOD CELL (RBC) MORPHOLOGIES.
A, Blood smear from the first patient report on sickle cell disease. B to E, Blood smears prepared under differing conditions from the same sickle cell anemia patient. B, Antecubital venous blood was fixed immediately at a pO2 of approximately 40 mm Hg to document RBC shapes in vivo. Several RBC morphologies are evident, including two granular (raisinlike) cells, five somewhat elongated cells, and two highly elongated and curved cells. C, The mixed venous blood (B) was then fully oxygenated. Most cells have resumed normal shape, but one irreversibly sickled cell is present. D, The oxygenated cells (C) were then partially deoxygenated and assumed classical holly-leaf forms typical of rapid deoxygenation. E, The already partially deoxygenated mixed venous cells (B) were then fully deoxygenated (pO2 = 0 mm Hg) and display the more elongated shape having fewer spikes that is assumed by slowly deoxygenated sickle RBC.
(B to E 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. A from Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med 5:517, 1910.)
Figure 14-2 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 historical, endemic malaria.
(Adapted from Friedman MJ, Trager W: The biochemistry of resistance to malaria. Sci Am 244:154, 1981 and from Nagel RL, Steinberg MH: Genetics of the βS gene: Origins, epidemiology, and epistasis in sickle cell anemia. In Steinberg MH: Forget BG, Higgs DR, Nagel RL, eds: Disorders of hemoglobin: Genetics, pathophysiology, and clinical management, Cambridge, 2001, Cambridge University Press, p 711.)
Relationship of HbS Molecular Behaviors to Disease Features
Dimer assembly → RBC Hb composition
HbS instability → Membrane defects
Figure 14-3 KINETICS OF HEMOGLOBIN S POLYMERIZATION, STUDIED BY NEAR-INSTANTANEOUS AND COMPLETE DEOXYGENATION.
A, Extreme dependence of delay time on hemoglobin concentration. B to D, Kinetic progress curves for polymer formation show that long delay times are highly variable (B), but very short delay times are highly reproducible (D). To the right is a representation of domains and corresponding red blood cell morphology postulated to result from these different scales of polymerization rate (see Fig. 14-1, B to E). E, Delay times for individual red blood cells are influenced by substituent hemoglobins. F, A double nucleation process is hypothesized to underlie polymer formation. G, Physiologically, the finite rate of deoxygenation effectively caps the polymerization rate and eliminates the relevance of delay times that are short relative to deoxygenation rate (<1 sec).
(A to E, Data from Eaton WA, Hofrichter J: Hemoglobin S gelation and sickle cell disease. Blood 70:1245, 1987; F adapted from Ferrone FA, Hofrichter J, Eaton WA: Kinetics of sickle hemoglobin polymerization II. A double nucleation mechanism. J Mol Biol 183:611, 1985; G, Data from Ferrone FA: Oxygen transits and transports. In Embury S, Hebbel RP, Mohandas N, Steinberg MH, eds: Sickle cell disease: basic principles and clinical practice, New York, 1994, Raven Press.)
Major Sickle RBC Membrane Defects
Enhanced mechanosensitivity → ↑ deformability responses →
Abnormal RBC adhesion to endothelium
Figure 14-4 MARKED HETEROGENEITY IN SICKLE RED BLOOD CELL (RBC) HYDRATION.
Compared with normal RBCs (A) studied by discontinuous density-gradient centrifugation, RBCs from a sickle subject with four α genes (D) include cells of unusually low density (usually reticulocytes) and abnormally high density (dehydrated cells). Sickle subjects with three and two α genes are shown in C and B, respectively.
(From Embury SH, Clark MR, Monroy G, Mohandas N: Concurrent sickle cell anemia and a-thalassemia. J Clin Invest 73:116, 1984.)
Figure 14-5 MECHANISMS LEADING TO HEMOLYSIS IN SICKLE CELL DISEASE.
This integrated synthesis shows how the molecular behaviors of hemoglobin S (HbS) (top) cause development of multiple red blood cell (RBC) abnormalities (middle) that lead to the four mechanisms of accelerated RBC destruction (bottom).
(Modified with permission from The American Journal of Hematology from Hebbel RP: Reconstructing sickle cell disease: A data-based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence-based medicine. Am J Hematol