last revised December 20, 2000 Management of Patients with Sickle Cell Disease An Overview Contents Background Nature of the Problem Modulators of SCD Severity Origin of the Sickle Mutation Management of Acute Problems Pain Acute chest syndrome Infection Bone marrow necrosis Stroke Splenic sequestration crisis Aplastic crisis Hepatic sequestration crisis Priapism Management of Chronic Problems Pain Anemia infection prophylaxis Avascular bone necrosis Osteomyelitis skin ulcers Renal dysfunction Retinopathy Heart Pregnancy Newer Therapies Hydroxyurea Erythropoietin Butyrate Clotrimazole Nitric Oxide FluocorTM Bone marrow transplantation Gene replacement therapy References Background Nature of the Problem Sickle cell disease (SCD) results from the substitution of a valine residue for glutamic acid at position 6 in the beta-subunit of hemoglobin (Ingram, 1956). With a few minor exceptions, people with only one gene for hemoglobin S (Hb S) are phenotypically normal (sickle trait). People who inherit two Hb S genes from their parents have sickle cell disease. Deoxygenated Hb S tends to polymerize non-covalently into long strands that deform the erythrocyte, giving the characteristic "sickle cell" morphology (Eaton and Hofrichter, 1990). Hb S with bound oxygen (e.g., in the arterial circulation) does not polymerize.

The mechanism by which these changes in the physical properties of the hemoglobin molecule produce the clinical manifestations of the disease is not unequivocally proven. The most widely accepted hypothesis is that erythrocytes deform as they release their oxygen in the capillaries and are trapped in the microcirculation (Eaton et al., 1976) (Kaul et al., 1989). The blockade of blood flow produces areas of tissue ischemia, leading to the myriad of clinical problems seen with sickle cell disease. Although a good deal of indirect evidence supports this theory, definitive proof that this is the pathophysiologic mechanism in sickle cell disease is lacking.

Recently, investigators have focused on other factors outside the red cell that could contribute to the manifestations of sickle cell disease. Hebbel and colleagues first showed that sickle erythrocytes adhere abnormally to vascular endothelial cells. Their observations were confirmed and extended by other workers. The endothelial cells may abnormally express adhesion receptors, perhaps in response to activators released from sickle red cells (e.g., reactive oxygen species). Other investigators have focused on leucocytes and platelets which might also contribute to disturbed blood flow in sickle cell disease. The involvement of multiple components of the blood in the manifestations of sickle cell disease makes understanding the pathophysiology more difficult. On the other hand, these additional modulators could be targeted by new therapies, with diminution in the severity of sickle cell symptoms.

Sickle cell disease is extremely varied in its manifestations (Ballas, 1991) (Wethers, 1982). This includes both the organ systems that are affected as well as the severity of the affliction. A study of the natural history of sickle cell disease indicated that about 5% of patients account for nearly one-third of hospital admissions (Platt et al., 1991). A significant number of patients with the disease have few admissions and live productive and relatively healthy lives. The average life-span of people with sickle cell disease is shorter than normal, however, reflecting increased mortality due to the complications of the disease.

Patients with sickle cell disease who also have hereditary persistence of fetal hemoglobin (HPFH) often have few if any symptoms (Stamatoyannopoulos et al., 1975). In these individuals, Hb F usually comprises greater than 20% of the hemoglobin in the erythrocytes. Patients may be partially protected from the ravages of sickle cell disease with even lower levels of Hb F. Unfortunately, few patients with SCD have Hb F levels of greater than 10 or 11% in the absence of HPFH.

Fetal Hb disrupts the polymerization of deoxy-Hb-S (Goldberg et al., 1977). Since polymerization of deoxy-Hb-S is the signal event in the pathogenesis of SCD, fetal Hb effectively prevents disease manifestation. The distribution of Hb F among RBCs is also important. In hereditary persistence of fetal hemoglobin (HPFH), Hb F exists at high levels in all red cells. All red cells are equally protected from sickling. In the absence of HPFH, patients with high levels of Hb F have a heterogeneous distribution of fetal hemoglobin between cells. An over simplified example is a patient in whom half the cells have 30% Hb F and half have 0%. The patient would have 15% Hb F overall. However, half the cells would sickle and occlude flow through the microcirculation. These deformed cells would block the flow of the normally shaped high Hb F cells. The patient would experience all the manifestations of sickle cell disease.

The relationship of stroke risk to high blood velocity in the intracranial arteries is discussed below.

No clear explanation exists for the differences in average severity between the haplotypes. The mutations in the flanking region could secondarily affect severity by altering Hb F expression in the cells. This is only a hypothesis, however. The patterns of severity apply only to populations. Broad overlap in the clinical patterns prevents the use of haplotypes to predict the clinical course in a particular person. Usually, people with sickle cell disease outside Africa (e.g., blacks in the United States) or India have mixed haplotypes for their sickle cell genes. Analysis of haplotype in this setting is even less likely to provide clinically useful information.

Hb S is common in some areas of the Mediterranean basin, including regions of Italy, Greece, Albania and Turkey (Boletini et al., 1994) (Schiliro et al., 1990). Haplotype analysis shows that the Hb S in these areas originated in Africa. The genes probably moved along ancient trading routes between wealthy kingdoms in western Africa and the trade centers in the Mediterranean basin. The high levels of Hb S attained in some areas reflects partial protection against protection against malaria provided by sickle cell trait (see below).

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Management of sickle cell disease

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