A 9-year-old boy with a history of sickle cell disease is brought to the office due to fatigue. The patient takes penicillin, hydroxyurea, and folic acid daily. Temperature is 37.1 C (98.8 F), blood pressure is 102/68 mm Hg, pulse is 130/min, and respirations are 20/min. Examination shows conjunctival pallor. The oropharynx is clear and the neck is supple. The lungs are clear to auscultation bilaterally, and the abdomen is soft with normal bowel sounds; there is no organomegaly. Skin examination is unremarkable. Laboratory results are as follows: Which of the following is the most likely cause of this patient's findings?

Question

A 9-year-old boy with a history of sickle cell disease is brought to the office due to fatigue.  The patient takes penicillin, hydroxyurea, and folic acid daily.  Temperature is 37.1 C (98.8 F), blood pressure is 102/68 mm Hg, pulse is 130/min, and respirations are 20/min.  Examination shows conjunctival pallor.  The oropharynx is clear and the neck is supple.  The lungs are clear to auscultation bilaterally, and the abdomen is soft with normal bowel sounds; there is no organomegaly.  Skin examination is unremarkable.  Laboratory results are as follows:  Which of the following is the most likely cause of this patient's findings?

Quizplus · Accepted Answer

11ec160b_3be9_c4a5_9249_6fb130603825_MD0001_00 This patient with sickle cell disease (SCD) has pancytopenia, a decrease in all 3 blood cell lineages. Pancytopenia is caused by hematopoietic stem cell dysfunction, bone marrow infiltration, or peripheral destruction of mature blood cells. Important clues in this case include: Low reticulocyte count: Patients with severe anemia usually have increased reticulocytes due to enhanced bone marrow erythropoiesis. The presence of pancytopenia with an inappropriately low reticulocyte count usually indicates the bone marrow is impaired and is unable to adequately generate new cells despite strong growth signals (eg, increased erythropoietin). Macrocytosis: Although macrocytosis can be seen in a wide range of pathologies, the presence of pancytopenia plus macrocytosis usually indicates a vitamin deficiency (eg, vitamin B₁₂, folate) or a medication (eg, hydroxyurea) is impairing DNA synthesis in hematopoietic cells. Hydroxyurea inhibits ribonucleoside reductase, an enzyme that generates deoxyribonucleoside triphosphates for DNA synthesis/repair. A lack of deoxyribonucleoside triphosphates slows erythrocyte nuclear development, leading to decreased cellular division with an overall increase in erythrocyte size. High doses of hydroxyurea also impair nuclear development in precursors of leukocytes and thrombocytes, leading to pancytopenia. Hydroxyurea is the major disease-modifying medication in SCD; it reduces production of the mutated beta globulin gene and increases production of the fetal hemoglobin gene, which increases fetal hemoglobin (HbF). Because HbF functions normally, erythrocytes with increased HbF are less likely to sickle in the microvasculature. (Choice A) Autoimmune hemolytic anemia is associated with high (not low) reticulocytes due to increased erythropoiesis. Because reticulocytes are larger (MCV 125-135 µm³) than mature erythrocytes, reticulocytosis can cause macrocytosis; however, leukopenia and thrombocytopenia would not be seen. (Choice B) Folate is a methyl group donor for the synthesis of purines and pyrimidines. Folate deficiency impairs DNA synthesis, which can lead to pancytopenia and macrocytosis. However, this patient is taking folic acid, making deficiency unlikely. (Choice C) Paroxysmal nocturnal hemoglobinuria is an acquired disorder of hematopoietic stem/progenitor cells marked by lack of complement inhibitor on the erythrocyte surface. Hemolytic anemia is the primary manifestation; reticulocytosis is common, and pancytopenia rarely occurs. (Choice E) SCD can cause hypersplenism due to splenic congestion with damaged erythrocytes. Although this can occasionally cause pancytopenia, patients with hypersplenism usually have splenomegaly and normocytic (not macrocytic) anemia. Educational objective: Hydroxyurea increases fetal hemoglobin production, which reduces erythrocyte sickling in patients with sickle cell disease. It also inhibits ribonucleoside reductase, which decreases deoxynucleoside triphosphates available for DNA synthesis; this leads to macrocytosis and, with high doses, pancytopenia.

A 9-Year-Old Boy with a History of Sickle Cell Disease