A 38-year-old woman is brought to the emergency department by her husband due to confusion… — USMLE Step 3

A $38$ -year-old woman is brought to the emergency department by her husband due to confusion and difficulty speaking that began earlier today. Her husband reports that for the past three days, she has complained of extreme fatigue, headaches, and a low-grade fever. She has not had any recent diarrhea, nausea, or abdominal pain. Her medical history is unremarkable, and she takes no prescription medications. Her temperature is $38.3^\circ\text{C}$ ( $100.9^\circ\text{F}$ ), pulse is $115$ /min, respirations are $18$ /min, and blood pressure is $142/88$ mmHg. Physical examination reveals scleral icterus and scattered petechiae over her bilateral lower extremities. She is disoriented to time and place, and her speech is intermittently slurred, though she moves all extremities with full strength.

Laboratory results:

Test	Result	Reference Range
Hemoglobin	$7.8$ g/dL	$12.0-16.0$ g/dL
Mean corpuscular volume	$88$ fL	$80-100$ fL
Platelets	$18,000/\text{mm}^3$	$150,000-400,000/\text{mm}^3$
Leukocytes	$8,400/\text{mm}^3$	$4,500-11,000/\text{mm}^3$
Blood urea nitrogen	$34$ mg/dL	$7-20$ mg/dL
Serum creatinine	$1.9$ mg/dL	$0.6-1.2$ mg/dL
Total bilirubin	$4.5$ mg/dL	$0.1-1.2$ mg/dL
Direct bilirubin	$0.8$ mg/dL	$0.0-0.3$ mg/dL
Lactate dehydrogenase	$1,450$ U/L	$100-250$ U/L
Prothrombin time	$12$ seconds	$11-14$ seconds
Partial thromboplastin time	$28$ seconds	$25-35$ seconds
Fibrinogen	$320$ mg/dL	$150-400$ mg/dL

A peripheral blood smear demonstrates numerous fragmented red blood cells. Which of the following is the most likely diagnosis?

A
Disseminated intravascular coagulation
B
Hemolytic uremic syndrome
C
Immune thrombocytopenic purpura
Thrombotic thrombocytopenic purpuraAnswer
E
Evans syndrome

Answer

Thrombotic thrombocytopenic purpura

The correct diagnosis is Thrombotic thrombocytopenic purpura (TTP). This patient presents with the classic pentad of TTP: microangiopathic hemolytic anemia (schistocytes, high LDH, anemia), severe thrombocytopenia, neurological symptoms (confusion, slurred speech), renal impairment (elevated BUN and creatinine), and fever. Importantly, the coagulation studies (PT, PTT, and fibrinogen) are perfectly normal, which confirms a primary thrombotic microangiopathy rather than a consumptive process like DIC. TTP is a medical emergency caused by severely decreased activity of the ADAMTS13 protease, leading to the accumulation of ultra-large von Willebrand factor multimers that shear red blood cells and consume platelets in the microvasculature.

Step-by-Step Solution

Analyze the patient's primary hematologic and laboratory abnormalities.

The patient has severe thrombocytopenia and microangiopathic hemolytic anemia (MAHA), evidenced by low hemoglobin, markedly elevated lactate dehydrogenase (LDH), indirect hyperbilirubinemia, and schistocytes on the peripheral blood smear.

Identifying the core pathophysiologic syndrome (MAHA with thrombocytopenia) narrows the differential diagnosis down to thrombotic microangiopathies (TMAs) and consumptive coagulopathies.

Evaluate the coagulation profile to differentiate between primary TMAs and consumptive coagulopathies.

Prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen levels are all within normal limits.

A normal coagulation profile rules out Disseminated Intravascular Coagulation (DIC), which characteristically presents with prolonged PT/PTT and low fibrinogen due to the systemic consumption of clotting factors.

Differentiate among the primary TMAs based on the clinical presentation and extent of organ involvement.

The patient exhibits prominent neurological symptoms (confusion, aphasia), fever, and mild renal impairment, without any preceding diarrheal illness.

The presence of the classic pentad (fever, neurologic changes, renal failure, MAHA, and thrombocytopenia) strongly indicates Thrombotic Thrombocytopenic Purpura (TTP), distinguishing it from Hemolytic Uremic Syndrome (HUS), which typically features a bloody diarrheal prodrome and more severe acute kidney injury.

Key Concept

Formulating a differential diagnosis for microangiopathic hemolytic anemia (MAHA) and thrombocytopenia using coagulation profiles and clinical presentation.

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