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Hemoglobinopathy


Key points

  • Normal adult hemoglobins include hemoglobins A (97%), A 2 ( 2%–3%), and F (<1%).

  • Trace quantities of nonfunctional hemoglobins (methemoglobin, carboxyhemoglobin, sulfhemoglobin, and nitrosohemoglobin) are present in normal blood.

  • Specific inherited point mutations of the beta-globin gene lead to abnormal unstable hemoglobin and resultant hemolytic anemia (e.g., hemoglobins S, C, and E).

  • The hemolysis seen with hemoglobins S and C is caused by intraerythrocytic precipitation of the unstable abnormal hemoglobin with increased red blood cell (RBC) rigidity.

  • Thalassemias are anemias caused by defects in globin gene synthesis leading to unbalanced production of globin chains and formation of unstable globin chain homo-tetramers.

  • In alpha thalassemia reduced alpha chains leads to excess beta chains and formation of unstable beta-chain tetramers. In beta thalassemia reduced beta chains leads to excess alpha chains and formation of increased hemoglobin A2, hemoglobin F, and unstable alpha chain tetramers.

  • Some hemoglobin variants with poor solubility (often due to alpha gene mutation) lead to formation of red cells with intracellular aggregates of unstable hemoglobin (Heinz bodies).

Normal hemoglobin types differ in the identity of the non-alpha globin chains—that is, beta chains in hemoglobin A, gamma chains in hemoglobin F, and delta chains in hemoglobin A 2 . The proportions of normal hemoglobin variants in red blood cells (RBCs) vary with age. Synthesis of embryonic hemoglobins Gower and Portland is rapidly followed during the first trimester of pregnancy by synthesis of hemoglobin F. At birth, the predominant hemoglobin is hemoglobin F (fetal hemoglobin) . Composed of two alpha and two gamma-globin chains, hemoglobin F is especially well-suited to meet the needs of fetuses by binding more avidly to oxygen than adult hemoglobin A, thus facilitating oxygen transfer from maternal blood to fetal blood in the placenta. The synthesis of hemoglobin A begins in fetal life, but at birth, it accounts for less than 45% of total hemoglobin. After birth, gamma-chain synthesis rapidly declines, and hemoglobin F levels fall such that by 1 year of age, the proportion of hemoglobin variants reaches adult levels: greater than 95% hemoglobin A, 1% to 3% hemoglobin A 2 , and 0% to 2% hemoglobin F. Hemoglobin A is composed of two alpha- and two beta-globin chains, and hemoglobin A 2 is composed of two alpha- and two delta-globin chains. Hemoglobins A and A 2 bind to oxygen less avidly than hemoglobin F and thus deliver oxygen to tissues at a higher oxygen tension. Poorly controlled diabetes mellitus is characterized by increased amounts of hemoglobin A 1c , a hemoglobin A variant formed by irreversible nonenzymatic glycation of the beta-globin chain.

Nonfunctional hemoglobin variants

Trace amounts of nonfunctional hemoglobin are present in normal blood. These include methemoglobin, carboxyhemoglobin, nitrosohemoglobin, and sulfhemoglobin. Methemoglobin , or oxidized hemoglobin, is formed from hemoglobin by oxidation of heme iron from the ferrous to the ferric form. In nearly all cases, methemoglobinemia is caused by hemoglobin oxidation induced by drugs or toxins. Although methemoglobin itself does not bind oxygen reversibly, the interaction of methemoglobin with normal hemoglobin in the blood of patients with methemoglobinemia leads to increased oxygen affinity and consequent tissue hypoxia. Carboxyhemoglobin results from the binding of carbon monoxide to heme iron. Because carbon monoxide binds to hemoglobin 200 times more strongly than oxygen, exposure to very small amounts of carbon monoxide leads to a large amount of carboxyhemoglobin. Tissue hypoxia is caused not only by the inability of carboxyhemoglobin to carry oxygen but also by the increased oxygen affinity of hybrid oxygen–carbon monoxide tetramers. Nitric oxide binds reversibly to hemoglobin to form nitrosohemoglobin . However, the physiologic and clinical significance of this interaction are unclear at this time. Sulfhemoglobin is formed by heme sulfation, most often by sulfur-containing drugs, leading to reduced oxygen affinity. Low hemoglobin oxygen affinity leads to more rapid oxygen delivery to tissues with reduced erythropoietin production and mild anemia.

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