A 65-year-old man comes to the office due to 4 months of worsening fatigue. The patient feels tired with simple household chores. He has a 15-pack-year smoking history and drinks 2 or 3 beers daily. Temperature is 37 C (98.6 F), blood pressure is 134/86 mm Hg, and pulse is 76/min. Physical examination reveals a late systolic ejection murmur with a soft S2. The lungs are clear to auscultation. The abdomen is soft and nontender with no hepatosplenomegaly. There are no focal neurological deficits. Laboratory testing reveals hemoglobin is 9 g/dL and mean corpuscular volume is 93 µm³. Peripheral blood smear is shown below: Which of the following best explains the observed erythrocyte findings in this patient?

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11ec160b_398a_2a1d_9249_993c1961cb06_MD0001_00 This patient's peripheral blood smear shows rows of erythrocytes stacked on one another like coins (rouleaux formation). This occurs due to elevated levels of circulating proteins, which disrupts the repulsive electrostatic charge on the erythrocyte surface and causes stacked aggregation. Although rouleaux formation can be seen with inflammatory conditions (eg, infection, rheumatic disease) that increase acute-phase reactants (eg, fibrinogen), it is classically linked to lymphoproliferative/plasma cell disorders such as multiple myeloma and Waldenstrom macroglobulinemia, which generate high levels of monoclonal paraprotein (immunoglobulins). Multiple myeloma is a plasma cell malignancy often associated with normocytic anemia, osteolytic bone lesions, and hypercalcemia due to proliferation of neoplastic cells in the bone marrow. Patients also frequently have renal insufficiency (due to immunoglobulin light-chain cast nephropathy) and nonspecific symptoms (eg, fatigue). Diagnosis is generally made using serum/urine protein electrophoresis (monoclonal M-spike) and bone marrow biopsy. (Choice A) Chronic gastrointestinal blood loss is a leading cause of iron-deficiency anemia, which usually results in microcytosis and hypochromia on peripheral smear (sometimes with target cells). Rouleaux formation and normocytic erythrocytes would be atypical. (Choice B) Cold agglutinins are cross-reactive IgM antibodies that form with some infections (particularly Mycoplasma pneumoniae) and hematologic malignancies. Cold agglutinins typically cause clumping agglutination (not stacked-coin agglutination) and hemolysis. (Choice D) Mechanical erythrocyte injury is common in patients with damaged or artificial heart valves. Although this patient has a cardiac murmur that indicates possible aortic stenosis, mechanical erythrocyte injury is usually associated with schistocytes on peripheral blood smear, not rouleaux formation. (Choice E) Vitamin B₁₂ deficiency causes abnormal hematologic cell nuclear maturation, which leads to macrocytic anemia and hypersegmented neutrophils on peripheral blood smear. Educational objective: Multiple myeloma is associated with elevated circulating paraproteins (monoclonal immunoglobulins), which causes erythrocytes to stack like coins (rouleaux formation). Patients classically have normocytic anemia, hypercalcemia, bone pain, and renal insufficiency.

A 65-Year-Old Man Comes to the Office Due to 4