Chapter 099. Disorders of Hemoglobin (Part 5)

Sickle Cell Syndromes The sickle cell syndromes are caused by a mutation in the β-globin gene that changes the sixth amino acid from glutamic acid to valine. HbS (α2β26 Glu→Va1) polymerizes reversibly when deoxygenated to form a gelatinous network of fibrous polymers that stiffen the RBC membrane, increase viscosity, and cause dehydration due to potassium leakage and calcium influx (Fig. 99-3). These changes also produce the sickle shape. Sickled cells lose the pliability needed to traverse small capillaries. They possess altered sticky membranes (especially reticulocytes) that are abnormally adherent to the endothelium of small venules. These abnormalities provoke unpredictable...
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Chapter 099. Disorders of Hemoglobin (Part 5) Chapter 099. Disorders of Hemoglobin (Part 5) Sickle Cell Syndromes The sickle cell syndromes are caused by a mutation in the β-globin genethat changes the sixth amino acid from glutamic acid to valine. HbS (α2β26 Glu→Va1)polymerizes reversibly when deoxygenated to form a gelatinous network offibrous polymers that stiffen the RBC membrane, increase viscosity, and causedehydration due to potassium leakage and calcium influx (Fig. 99-3). Thesechanges also produce the sickle shape. Sickled cells lose the pliability needed totraverse small capillaries. They possess altered sticky membranes (especiallyreticulocytes) that are abnormally adherent to the endothelium of small venules.These abnormalities provoke unpredictable episodes of microvascularvasoocclusion and premature RBC destruction (hemolytic anemia). Hemolysisoccurs because the spleen destroys the abnormal RBC. The rigid adherent cellsalso clog small capillaries and venules, causing tissue ischemia, acute pain, andgradual end-organ damage. This venoocclusive component usually dominates theclinical course. Prominent manifestations include episodes of ischemic pain (i.e.,painful crises) and ischemic malfunction or frank infarction in the spleen, centralnervous system, bones, liver, kidneys, and lungs (Fig. 99-3). Figure 99-3 Pathophysiology of sickle cell crisis. Several sickle syndromes occur as the result of inheritance of HbS from oneparent and another hemoglobinopathy, such as β thalassemia or HbC (α2β26 Glu->Lys ), from the other parent. The prototype disease, sickle cell anemia, is thehomozygous state for HbS (Table 99-2). Table 99-2 Clinical Features of Sickle Hemoglobinopathies Conditio Clinical Hemoglo MC Hemoglon Abnormalities bin Level g/L V, fL bin (g/dL) Electrophoresis Sickle None; rare Normal Nor Hbcell trait painless mal S/A:40/60 hematuria Sickle Vasoocclu 70–100 80– Hbcell anemia sive crises with (7–10) 100 S/A:100/0 infarction of Hb F:2– spleen, brain, marrow, kidney, 25% lung; aseptic necrosis of bone; gallstones; priapism; ankle ulcers S/β° Vasoocclu 70–100 60– Hbthalassemia sive crises; (7–10) 80 S/A:100/0 aseptic necrosis Hb F:1– of bone 10% S/β+ Rare crises 100–140 70– Hbthalassemia and aseptic (10–14) 80 S/A:60/40 necrosis Hemoglo Rare crises 100–140 80– Hbbin SC and aseptic (10–14) 100 S/A:50/0 necrosis; painless Hb hematuriaC:50%