Chapter 099. Disorders of Hemoglobin (Part 5)

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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) 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 episodes of microvascular
vasoocclusion and premature RBC destruction (hemolytic anemia). Hemolysis occurs because the spleen destroys the abnormal RBC. The rigid adherent cells also clog small capillaries and venules, causing tissue ischemia, acute pain, and gradual end-organ damage. This venoocclusive component usually dominates the clinical course. Prominent manifestations include episodes of ischemic pain (i.e., painful crises) and ischemic malfunction or frank infarction in the spleen, central nervous 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 one parent and another hemoglobinopathy, such as β thalassemia or HbC (α2β26 Glu- >Lys ), from the other parent. The prototype disease, sickle cell anemia, is the homozygous state for HbS (Table 99-2). Table 99-2 Clinical Features of Sickle Hemoglobinopathies Conditio Clinical Hemoglo MC Hemoglo n Abnormalities bin Level g/L V, fL bin (g/dL) Electrophoresis Sickle None; rare Normal Nor Hb cell trait painless mal S/A:40/60 hematuria Sickle Vasoocclu 70–100 80– Hb cell 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– Hb thalassemia sive crises; (7–10) 80 S/A:100/0 aseptic necrosis Hb F:1– of bone 10% S/β+ Rare crises 100–140 70– Hb thalassemia and aseptic (10–14) 80 S/A:60/40 necrosis Hemoglo Rare crises 100–140 80– Hb bin SC and aseptic (10–14) 100 S/A:50/0 necrosis; painless Hb hematuria
C:50%