A 5-year-old girl is brought to the emergency department for evaluation of a rash. Her mother noticed a few red spots on the child's cheeks this morning, which subsequently spread to the neck and trunk as the day progressed. The patient has a history of partial complex seizures, which have been well controlled with carbamazepine. Vital signs are normal. The lips are slightly pale, and the oropharynx is clear. There is no lymphadenopathy. The abdomen is soft with no palpable masses or hepatosplenomegaly. Skin examination shows flat, red, pinpoint lesions that do not blanch on the face, neck, trunk, and extremities. Neurological examination is unremarkable. Laboratory results are as follows: Peripheral smear reveals a paucity of cells with normal morphologic appearance of all cell lines. Which of the following mechanisms is most likely responsible for this patient's current condition?

Question

A 5-year-old girl is brought to the emergency department for evaluation of a rash.  Her mother noticed a few red spots on the child's cheeks this morning, which subsequently spread to the neck and trunk as the day progressed.  The patient has a history of partial complex seizures, which have been well controlled with carbamazepine.  Vital signs are normal.  The lips are slightly pale, and the oropharynx is clear.  There is no lymphadenopathy.  The abdomen is soft with no palpable masses or hepatosplenomegaly.  Skin examination shows flat, red, pinpoint lesions that do not blanch on the face, neck, trunk, and extremities.  Neurological examination is unremarkable.  Laboratory results are as follows:  Peripheral smear reveals a paucity of cells with normal morphologic appearance of all cell lines.  Which of the following mechanisms is most likely responsible for this patient's current condition?

Quizplus · Accepted Answer

11ec160b_3bdc_cc43_9249_953073064b27_MD0001_00 This patient who takes carbamazepine developed pancytopenia with morphologically normal peripheral blood cells, indicating likely drug-induced aplastic anemia (AA). AA is a form of bone marrow failure caused by damage to multipotent hematopoietic stem cells. Most cases are induced by direct toxicity to hematopoietic stem cells or an alteration to stem cell surface antigens, which leads to their subsequent destruction by cytotoxic lymphocytes. Although AA can be idiopathic, it is often triggered by ionizing radiation, toxic chemicals, viral infections, or medications. Drug-induced AA is typically categorized as follows: Dose-dependent reactions are caused by medications (eg, chemotherapy, immunosuppressives) that are toxic to the bone marrow when drug levels exceed a certain concentration for a certain period. They tend to be predictable in onset. Idiosyncratic reactions are often caused by antiseizure medications (eg, carbamazepine, valproic acid), sulfonamides, or nifedipine. They are unpredictable, unrelated to the dose of the drug, and may occur at any point during or after therapy. Although the mechanism is unclear, patients often have genetic mutations in drug-metabolizing enzymes or efflux pumps, which may promote toxicity. Because multipotent hematopoietic cells generate all mature blood cells, patients with AA usually have signs of thrombocytopenia (eg, petechiae, bleeding), anemia (eg, pale mucous membranes), and/or leukopenia (eg, infections). Bone marrow biopsy will reveal a hypocellular marrow with increased lipids. (Choice A) AA is primarily caused by toxic injury to hematopoietic stem cells or cytotoxic T-cell-mediated stem cell destruction; autoantibodies are not a major part of the pathogenesis. (Choice B) Vitamin B₁₂ and folate deficiencies impair DNA synthesis in hematopoietic stem cells, which leads to hypersegmented neutrophils and macrocytic erythrocytes (not normal morphologic cells) on peripheral smear because of delayed nuclear (relative to cytoplasmic) maturation. (Choice D) Hypersplenism can cause sequestration with increased destruction of blood cells in the splenic sinusoids. Most cases arise in those with portal hypertension (eg, liver disease, portal vein thrombosis), which leads to an increase in splenic volume and activity. Although cytopenias can occur, they are typically mild and do not cause symptoms; in addition, most patients have splenomegaly. (Choice E) Thrombotic microangiopathic hemolysis is associated with clot formation in the microvasculature and shearing of red blood cells, leading to thrombocytopenia (eg, petechiae) and anemia. However, peripheral blood smear would reveal schistocytes. Educational objective: Aplastic anemia (AA) is bone marrow failure due to multipotent hematopoietic stem cell destruction. Cases are often triggered by medications, radiation, toxins, or viruses. Medication-induced AA can be due to dose-dependent bone marrow damage (eg, chemotherapy, immunosuppressive drugs) or idiosyncratic reactions (eg, antiseizure medicines, sulfonamides, nifedipine) that may occur at any point during or after therapy.

A 5-Year-Old Girl Is Brought to the Emergency Department for Evaluation