Porth's Essentials of Pathophysiology, 4e

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Hematopoietic Function

U N I T 3

with two HbS genes). Approximately 8% of African Americans are heterozygous for HbS and 0.1% to 0.2% are homozygous. 5 In parts of Africa, where malaria is endemic, the gene frequency approaches 30%, attrib- uted to the slight protective effect it confers against Plasmodium falciparum malaria. 5 The abnormal structure of HbS results from a point mutation in the β chain of the hemoglobin molecule, with an abnormal substitution of a single amino acid, valine, for glutamic acid (Fig. 13-9). In the heterozygote, only approximately 40% of the hemoglobin is HbS, but in the homozygote, 80% to 95% of the hemoglobin is HbS. 5 Variations in proportions exist, and the concen- tration of HbS correlates with the risk of sickling. HbS polymerizes when deoxygenated, creating a semisolid gel that makes the erythrocyte rigid, distorts its shape, and causes structural damage to the red cell membrane (see Figure 13-8C). The sickled cell may return to its normal shape with oxygenation in the lungs. However, after repeated episodes of deoxygenation, the cells remain permanently sickled. The person with sickle cell trait who has less HbS has little tendency to sickle and is virtually asymptomatic. Fetal hemoglobin (HbF) inhib- its the polymerization of HbS; therefore, most infants with sickle cell disease do not begin to experience the

effects of the sickling until after 8 to 10 weeks of age, when the HbF has been replaced by HbS. 6 There are two major consequences of red blood cell sickling—chronic hemolytic anemia and blood vessel occlusion. Premature destruction of the cells due to the rigid, nondeformable membrane occurs in the spleen, causing hemolysis and anemia from a decrease in red cell numbers. Overall, the mean life span of red cells in persons with sickle cell disease averages only 20 days (one sixth of normal). 5 Vessel occlusion disrupts blood flow, causing tissue ischemia and a pain crisis. Recent evidence suggests that vessel occlusion is a complex pro- cess involving an interaction among the sickled cells, vessel endothelial cells, platelets, and other blood com- ponents. 7 The process is initiated by the adherence of sickled cells to the vessel endothelium, causing endo- thelial cell activation with liberation of inflammatory mediators and substances that increase platelet activa- tion and promote blood coagulation. 5–7 Factors associated with sickling and vessel occlusion include cold, stress, physical exertion, infection, and ill- nesses that cause hypoxia, dehydration, or acidosis. The rate of HbS polymerization is affected by the concentra- tion of hemoglobin in the cell. Dehydration increases the hemoglobin concentration and contributes to the polymerization and resultant sickling. Acidosis reduces the affinity of hemoglobin for oxygen, resulting in more deoxygenated hemoglobin and increased sickling. Even such trivial incidents as reduced oxygen tension induced by sleep may contribute to the sickling process. Clinical Course. Persons who are homozygous for the HbS gene experience severe hemolytic anemia, chronic hyperbilirubinemia, and vaso-occlusive crises. The hyperbilirubinemia that results from the breakdown products of hemoglobin often leads to jaundice and the formation of pigment gallstones. The complications of sickle cell disease are numerous, with two of the most common being vaso-occlusive pain crisis and acute chest syndrome. 7–9 An acute pain episode results from tissue hypoxia due to vessel occlusion and can occur suddenly in almost any part of the body. 7–12 Common sites obstructed by sickled cells include the abdomen, chest, bones, and joints. Many areas may be affected simultaneously. Infarctions caused by sluggish blood flowmay cause chronic damage to the liver, spleen, heart, kidneys, retinas, and other organs (Fig. 13-10). Acute chest syndrome is an atypical pneumonia result- ing from pulmonary infarction. It is the second lead- ing cause of hospitalization in persons with sickle cell disease and is characterized by pulmonary infiltrates, shortness of breath, fever, chest pain, and cough. The syndrome can cause chronic respiratory insufficiency and is a leading cause of death in sickle cell disease. Children may experience growth retardation and sus- ceptibility to osteomyelitis. Painful bone crises may be caused by marrow infarcts of the bones of the hands and feet, resulting in swelling of those extremities. Another major complication is stroke. Approximately 25% of persons with sickle cell disease have neurologic compli- cations, including stroke, related to vessel occlusion. 10

C

C

A T

T A

C G

C G

Point mutation

G

G

Glutamic acid

Valine

HbS

HbA

Oxygenated

Deoxygenated

Reversibly sickled

Irreversibly sickled

Increased red cell adhesiveness and adherence to vessel wall

Hemolysis

Vessel occlusion

Tissue ischemia and infarction

FIGURE 13-9. Mechanism of sickling and its consequences in sickle cell disease.