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Difficulty: HardHematology and Oncology

A 34-year-old man presents to the emergency department with a 4-day history of progressively worsening right upper quadrant abdominal pain and abdominal swelling. Over the past several months, he has experienced profound fatigue and noticed that his first morning urine is often dark, gradually clearing up as the day progresses. He takes no medications and has no significant past medical history. Temperature is 37.2°C (99.0°F), blood pressure is 118/76 mm Hg, and pulse is 98/min. Physical examination shows scleral icterus and a distended abdomen with shifting dullness. The liver edge is markedly tender and palpable 4 cm below the right costal margin.

Laboratory studies show:
TestResult
Hemoglobin8.9 g/dL
Mean corpuscular volume94 fL
Platelets105,000/mm³
Leukocytes3,200/mm³
Total bilirubin3.5 mg/dL
Direct bilirubin0.6 mg/dL
Lactate dehydrogenase1,450 U/L
Haptoglobin< 10 mg/dL

Doppler ultrasonography of the abdomen reveals the absence of blood flow in the hepatic veins. Which of the following is the most appropriate next step in diagnosing the underlying cause of this patient's condition?

  1. Flow cytometry of peripheral bloodAnswer
  2. B
    Direct antiglobulin (Coombs) test
  3. C
    JAK2 V617F mutation analysis
  4. D
    Measurement of ADAMTS13 activity
  5. E
    Bone marrow aspiration and biopsy

Answer

Flow cytometry of peripheral blood
The correct answer is flow cytometry of peripheral blood. This patient's presentation of intravascular hemolysis (dark morning urine, scleral icterus, high LDH, low haptoglobin), pancytopenia (low hemoglobin, platelets, and leukocytes), and atypical venous thrombosis (Budd-Chiari syndrome, diagnosed here via ultrasound showing hepatic vein thrombosis) is classic for Paroxysmal Nocturnal Hemoglobinuria (PNH). PNH is an acquired clonal stem cell disorder caused by a mutation in the PIGA gene, leading to a deficiency of glycosylphosphatidylinositol (GPI) anchors. This results in a lack of complement-regulatory proteins (CD55 and CD59) on the cell surface, rendering red blood cells highly susceptible to complement-mediated lysis. Flow cytometry of peripheral blood is the diagnostic test of choice to demonstrate the absence of these GPI-anchored proteins on red blood cells and white blood cells.

Step-by-Step Solution

1
Analyze the clinical presentation.
The patient has the triad of hemolytic anemia (dark morning urine, elevated indirect bilirubin, high LDH, low haptoglobin), pancytopenia (anemia, thrombocytopenia, leukopenia), and unprovoked atypical venous thrombosis (Budd-Chiari syndrome).
Identifying the classic clinical triad narrows down the differential diagnosis for inherited or acquired hematologic conditions.
2
Formulate a primary diagnosis based on the clinical triad.
The combination of intravascular hemolysis, cytopenias, and atypical venous thrombosis (especially hepatic, portal, or cerebral veins) is highly pathognomonic for Paroxysmal Nocturnal Hemoglobinuria (PNH).
PNH is an acquired hematopoietic stem cell mutation causing a deficiency of glycosylphosphatidylinositol (GPI) anchors, leading to the loss of complement inhibitors (CD55, CD59) on cell surfaces.
3
Select the most appropriate diagnostic test to confirm the suspected condition.
Flow cytometry of peripheral blood is the test of choice.
Flow cytometry definitively identifies the absence or deficiency of GPI-anchored proteins (CD55 and CD59) on the surface of red blood cells and granulocytes, confirming the diagnosis of PNH.

Key Concept

Paroxysmal nocturnal hemoglobinuria (PNH) presentation and diagnosis
Estimated Time:1m 30s
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Topics

Hematology and Oncology

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