A 23-year-old man comes to the clinic for a follow-up appointment. Laboratory results from his wellness visit 6 weeks ago included a hemoglobin level of 12.3 g/dL, suggesting mild anemia. The patient has otherwise been well. He feels that his energy level is normal, and he has run several half-marathons in the past 2 years. Today's laboratory results are as follows:
| Hemoglobin | 12.2 g/dL |
| Erythrocytes | 5.8 million/mm3 |
| Mean corpuscular volume | 74 µm3 |
| Leukocytes | 6,500/mm3 |
| Platelets | 180,000/mm3 |
| Hemoglobin A2 | 6% (normal: 1%-3%) |
The patient's blood smear is shown below.
Show Explanatory Sources
Which of the following is the most likely initial pathologic defect leading to this patient's current condition?
Show Explanatory Sources
This patient has a mild microcytic (mean corpuscular volume <80 µm3) anemia and an elevated hemoglobin (Hb) A2 (alpha-2 delta-2) concentration. These findings, in addition to peripheral smear revealing poikilocytes (spherocytes and target cells), suggest beta-thalassemia trait.
Patients with beta-thalassemia trait have 1 normal beta-globin allele and 1 mutated beta-globin allele. Most mutations are point mutations leading to faulty mRNA processing (eg, splicing error) or premature translation termination. Decreased production of normal beta-globin chains results in limited formation of normal adult hemoglobin (Hb A) and increased production of hemoglobin subtypes (eg, Hb A2) from pairing of excess alpha-globin chains with non–beta-globin chains. The imbalance in the ratio of alpha-/beta-globin chains also results in unpaired excess alpha-globin chains, which are insoluble (precipitating adjacent to the red blood cell [RBC] membrane) and susceptible to oxidation. This causes cell membrane instability and destruction of some early RBC precursors within the bone marrow (ineffective erythropoiesis).
Because patients with beta-thalassemia trait have 1 normal beta-globin allele, their anemia is usually mild and often discovered on routine laboratory evaluation. Peripheral smear may reveal target cells, which are formed when reduced cell volume from decreased hemoglobin allows a relative excess of membrane to sink in. Spherocytes may also be present and are due to cell membrane damage and injury to cytoskeletal components in more mature RBCs. Because hemoglobin levels are low, the marrow attempts to compensate by increasing erythrocyte production, resulting in a normal to slightly high erythrocyte count, as seen in this patient.
(Choices A, C, and F) Although insoluble protein (ie, alpha-globin chain) formation, elevated oxidative stress, and cell membrane instability occur in beta-thalassemia, a genetic mutation affecting the transcription, processing, or translation of beta-globin mRNA is the initial pathologic defect.
(Choice B) Complete gene deletion is the most common mechanism causing alpha-thalassemia, which is associated with decreased (not elevated) hemoglobin A2 due to impaired alpha chain production. In contrast, most cases of beta-thalassemia occur due to point mutations.
(Choice E) Hemoglobin contains 2 components, an iron-containing heme component and a globin component. Impaired heme synthesis results in porphyria. Thalassemia is due to disruption to the globin component.
Educational objective:
Patients with beta-thalassemia trait have 1 normal beta-globin allele and 1 mutated beta-globin allele. The gene mutation most commonly impairs mRNA processing (eg, splicing) or translation, resulting in reduced production of normal beta-globin chains. Patients are typically asymptomatic with laboratory findings of mild microcytic anemia, target cells, and increased hemoglobin A2 concentration.