Test your medicine knowledge with the MKSAP challenge, in partnership with the American College of Physicians.

A 48-year-old woman is evaluated for fatigue and intermittent abdominal discomfort of 2 months’ duration and occasional dark urine. Medical and family histories are unremarkable. Her only medication is an oral contraceptive pill.

On physical examination, temperature is 37.2 °C (99.0 °F), blood pressure is 125/74 mm Hg, pulse rate is 68/min, and respiration rate is 13/min. Pallor is observed, and abdominal tenderness is present on palpation. No icterus, bruising, or splenomegaly is noted.

Laboratory studies:

Hemoglobin	7.2 g/dL (72 g/L)
Leukocyte count	3000/µL (3 × 109/L) with a normal differential
Platelet count	125,000/µL (125 × 109/L)
Reticulocyte count	8% of erythrocytes
Bilirubin, total	Normal
Direct antiglobulin (Coombs) test	Negative

A bone marrow biopsy shows 20% cellularity. Flow cytometry reveals erythrocytes lacking CD55 and CD59. Abdominal ultrasonography shows portal vein thrombosis.

Which of the following is the most likely diagnosis?

A: Aplastic anemia
B: Myelodysplastic syndrome
C: Myeloproliferative neoplasm
D: Paroxysmal nocturnal hemoglobinuria

MKSAP Answer and Critique

The correct answer is D. Paroxysmal nocturnal hemoglobinuria.

The most likely diagnosis is paroxysmal nocturnal hemoglobinuria (PNH). PNH is an acquired clonal stem cell disorder that should be considered in patients presenting with hemolytic anemia, pancytopenia, or unprovoked atypical thrombosis. Mutations in the PIG-A gene lead to the reduction or absence of glycosylphosphatidylinositol, an important erythrocyte-anchoring protein. Hemolysis is caused by the absence of decay-accelerating factor (CD55) and the membrane inhibitor of reactive lysis (CD59), which are glycosylphosphatidylinositol-dependent complement regulatory proteins. Diagnosis of PNH is based on flow cytometry results, which can detect CD55 and CD59 deficiency on the surface of peripheral erythrocytes or leukocytes.

The patient does not have aplastic anemia (AA). Although AA often has small PNH clones present, thrombosis and hemolysis are not features of this disease. In patients with AA, however, annual screening for the presence of PNH clones by flow cytometry is recommended.

The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis. Although MDS may present with a hypocellular bone marrow approximately 10% of the time, thrombosis and hemolysis are not typical symptoms. MDS usually presents with anemia or pancytopenia and a hypercellular marrow with dysplastic changes in cell precursors.

Myeloproliferative neoplasms (MPNs) can present with splanchnic thrombosis and should be considered in the differential diagnosis of unusual blood clots. However, the peripheral blood counts do not suggest MPN (no cell lines are elevated), and hemolysis is not a prominent clinical feature. Additionally, the marrow in MPNs is typically hypercellular or fibrotic.

Key Point

• Findings diagnostic of paroxysmal nocturnal hemoglobinuria include hemolytic anemia, hypocellular bone marrow, and lack of CD55 and CD59.

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