Which of the following statements regarding hemoglobinopathies is MOST correct?A. Deoxygenation of sickle hemoglobin (HbS) results in polymerization that produces sickling of the red cell which is reversible
Correct Answer: A
Hemoglobin is the major protein responsible for oxygen transport and is usually composed of two alpha-globin chains and two beta-globin chains. The synthesis of alpha and beta chains must also be closely matched as free globin units are toxic to red cells. Hemoglobinopathies arise from either (1) a quantitative defect (either reduction or total absence) in the production of one of the globin chains or (2) a structural defect in one of the globin chains. Quantitative disorders of globin chain synthesis result in the thalassemia syndromes. Most mutations that result in structural defects in the one of the globin chains are clinically silent and are discovered as an incidental finding. Those that are clinically relevant can cause the sickle cell disorders, anemia due to hemolysis, changes in oxygen affinity resulting in polycythemia or cyanosis, or methemoglobinemia.
The thalassemia syndromes are inherited disorders that result in either decreased or absence of either the alpha- or beta-globin chains. Under normal circumstances, the synthesis of alpha- and beta-globin chains is highly regulated to prevent excess of one or the other chain. If synthesis of one globin chain is decreased or absent, there is accumulation of the unaffected globin chain that precipitates and leads to hemolysis and decreased red cell survival. The clinical manifestations of the thalassemia syndromes range from asymptomatic carrier status to profound abnormalities including severe anemia, extramedullary hematopoiesis, and skeletal and growth deficits.
The alpha-thalassemias are usually caused by the deletion of one or more alpha-globin genes. Deletion of one or two alpha-globin genes is not associated with severe hematologic abnormalities; a mild hypochromic, microcytic anemia is seen with deletion of two alpha-globin genes. Deletion of three alpha-globin genes (eg, hemoglobin H [HbH] disease) results in a microcytic, hypochromic anemia with hemoglobin levels between 8 and 10 g/dL. The anemia can be exacerbated by acute infections, oxidative stress, and pregnancy and is treated with transfusions as needed. Deletion of all four alpha-globin chains results in hydrops fetalis and is usually fatal during late pregnancy or shortly after birth.
There are two beta-globin genes and beta-thalassemias are usually caused by point mutations in one or both genes. The mutations can result in decreased production or absence of beta-globin. Severity of disease depends on how much beta-globin is made with the most severe disease in homozygotes that make no beta-globin (TM). These patients have severe anemia (Hb range 1-7 g/dL), hemolysis, and ineffective erythropoiesis, resulting in skeletal abnormalities due to expanded marrow cavities and extramedullary hematopoiesis. Iron overload occurs because of increased intestinal iron uptake secondary to ineffective erythropoiesis and from transfusions. Excess iron stores can cause toxicity in the liver, heart, and endocrine organs, with resulting organ dysfunction. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation.
HbS results from an amino acid substitution on the beta-globin chain. Patients with sickle cell disease are homozygous for HbS. Deoxygenation of HbS results in polymerization that distorts the shape of the red cell, which is reversible with reoxygenation of HbS. Sickled RBCs increase blood viscosity and obstruct capillary flow causing vaso-occlusion and pain. Furthermore, repeated cycles of sickling damage the RBC membrane, resulting in premature destruction of RBCs and a chronic hemolytic anemia. The polymerization of deoxygenated HbS is inhibited by HbF. Treatment of sickle cell disease includes pain medications to treat pain associated with vaso-occlusive crises, transfusions, hydroxyurea to increase HbF concentrations, and hematopoietic stem cell transplantation.