USMLE PRACTICE QUESTION #135
TOPIC: Hematology/Pathology
Welcome to USMLE practice question #135! Today’s question covers hematology/pathology.
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A 34-year-old man presents with a history of episodic dark urine, particularly in the mornings, and progressive fatigue. Physical examination reveals pallor and mild hepatosplenomegaly. Laboratory studies show hemoglobin of 8.5 g/dL, elevated lactate dehydrogenase, undetectable haptoglobin, and mild thrombocytopenia. Flow cytometry reveals a deficiency of CD55 and CD59 on red blood cells. Which of the following best explains the underlying mechanism responsible for this patient’s symptoms?
A) IgG-mediated complement activation
B) Defective anchoring of complement regulatory proteins
C) Increased expression of pro-apoptotic factors
D) Loss of structural membrane proteins
E) Formation of antibodies against GPI-anchored proteins
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best explains the underlying mechanism responsible for this patient’s symptoms?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Diagnose the patient’s condition; 2nd: Identify the underlying mechanism responsible for the symptoms.
Step 3: Read the vignette carefully and ask yourself: “Based on this patient’s presentation and history, the underlying mechanism is most likely ______________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 34-year-old man presents with episodic hemoglobinuria, progressive fatigue (anemia), and laboratory findings of hemolytic anemia (low hemoglobin, elevated lactate dehydrogenase, undetectable haptoglobin) and mild thrombocytopenia. Flow cytometry reveals a deficiency of CD55 and CD59 on red blood cells, which are critical complement regulatory proteins. These findings are diagnostic of paroxysmal nocturnal hemoglobinuria.
ANSWER CHOICES:
CHOICE A: IgG-mediated complement activation
Explanation: IgG-mediated complement activation occurs in immune-mediated hemolytic anemia (e.g., warm autoimmune hemolytic anemia). In this process, IgG antibodies bind to red blood cells and activate the classical complement pathway.
CHOICE B: Defective anchoring of complement regulatory proteins
Explanation: PNH is caused by a somatic mutation in the PIGA gene, which impairs the synthesis of GPI anchors. These anchors are necessary for attaching complement regulatory proteins like CD55 (decay-accelerating factor) and CD59 (membrane attack complex inhibitor) to the cell surface. Without these proteins, red blood cells are susceptible to unregulated complement activation and intravascular hemolysis.
CHOICE C: Increased expression of pro-apoptotic factors
Explanation: Increased expression of pro-apoptotic factors leads to programmed cell death (apoptosis). This mechanism is not involved in PNH pathogenesis.
CHOICE D: Loss of structural membrane proteins
Explanation: Loss of structural membrane proteins (e.g., spectrin or ankyrin) occurs in hereditary spherocytosis or elliptocytosis, leading to mechanically fragile red blood cells that are destroyed in the spleen.
CHOICE E: Formation of antibodies against GPI-anchored proteins
Explanation: Antibodies against GPI-anchored proteins can occur in certain autoimmune conditions but are not involved in PNH—PNH is not an autoimmune disorder; it is caused by a somatic mutation in the PIGA gene affecting GPI anchor synthesis.
FINAL VERDICT…
CORRECT ANSWER: B) Defective anchoring of complement regulatory proteins
PNH is caused by a somatic mutation in the PIGA gene, leading to defective synthesis of GPI anchors. This results in loss of complement regulatory proteins like CD55 and CD59 on red blood cells, making them vulnerable to unregulated complement-mediated lysis.
KEY CONCEPTS:
Pathophysiology of PNH:
Caused by a somatic mutation in the PIGA gene.
Impaired synthesis of glycosylphosphatidylinositol (GPI) anchors.
Loss of GPI-tethered complement regulatory proteins:
CD55 (decay-accelerating factor): Prevents C3 convertase formation.
CD59 (membrane attack complex inhibitor): Blocks formation of the membrane attack complex (MAC).
Leads to unregulated complement activation and intravascular hemolysis.
Clinical Features of PNH:
Episodic dark urine due to hemoglobinuria (worse at night due to acidemia during sleep).
Fatigue and pallor due to anemia.
Thrombosis, particularly in unusual sites like hepatic or cerebral veins.
Mild hepatosplenomegaly due to extramedullary hematopoiesis.
Laboratory Findings in PNH:
Hemolytic anemia:
Low hemoglobin.
Elevated lactate dehydrogenase (LDH).
Undetectable haptoglobin.
Flow cytometry: Deficiency of CD55 and CD59 on red blood cells.
Negative Coombs test (distinguishes PNH from autoimmune hemolytic anemia).
Complications of PNH:
Thrombosis: Leading cause of mortality in PNH.
Bone marrow failure syndromes (e.g., aplastic anemia).
Progression to myelodysplastic syndrome or acute leukemia.
Treatment Options for PNH:
Supportive care: Transfusions, iron supplementation.
Eculizumab: A monoclonal antibody that inhibits C5 activation, preventing MAC formation.
Allogeneic stem cell transplantation for severe cases.
