A 68-year-old man is evaluated in the emergency department for severe right thigh pain and… — USMLE Step 3

A 68-year-old man is evaluated in the emergency department for severe right thigh pain and swelling that began 48 hours ago without preceding trauma. He has a history of chronic lymphocytic leukemia (CLL), for which he is currently on observation. His other medical problems include hypertension and type 2 diabetes mellitus. He has no personal or family history of bleeding disorders and has undergone several major surgeries in the past without abnormal bleeding. Vital signs show a heart rate of $112/\text{min}$ and blood pressure of $105/65 \text{ mmHg}$ . Physical examination reveals a massive, tense, ecchymotic swelling over the anterior right thigh extending to the knee.

Laboratory studies reveal:
Hemoglobin: $7.4 \text{ g/dL}$
Mean corpuscular volume: $88 \text{ } \mu\text{m}^3$
Platelet count: $310,000/\text{mm}^3$
Prothrombin time (PT): $12.1 \text{ s}$ (Reference: $11-14 \text{ s}$ )
Activated partial thromboplastin time (aPTT): $82 \text{ s}$ (Reference: $25-35 \text{ s}$ )

A 1:1 mixing study of the patient's plasma with normal pooled plasma is performed. Immediately after mixing, the aPTT is $37 \text{ s}$ . After 2 hours of incubation at $37^\circ\text{C}$ , the aPTT is $74 \text{ s}$ .

Which of the following is the most likely diagnosis?

Acquired hemophilia AAnswer
B
Antiphospholipid syndrome
C
Congenital factor VIII deficiency
D
Disseminated intravascular coagulation
E
Von Willebrand disease

Answer

Acquired hemophilia A

The correct diagnosis is acquired hemophilia A. This condition is caused by the development of autoantibodies (inhibitors) against factor VIII. It typically occurs in older adults, often in association with malignancies (like chronic lymphocytic leukemia), autoimmune diseases, or the postpartum state. Patients present with sudden, severe, spontaneous bleeding into soft tissues (e.g., massive muscle hematomas), distinguishing it from congenital hemophilia which frequently involves hemarthroses. The diagnostic hallmark is an isolated prolonged aPTT that exhibits time- and temperature-dependent inhibition on a mixing study. Because the autoantibody often takes time to neutralize the factor VIII provided by the normal pooled plasma, the immediate mixing study may show near-correction, but the aPTT will prolong significantly after 1 to 2 hours of incubation.

Step-by-Step Solution

Analyze the clinical presentation.

The patient is an older adult with a hematologic malignancy (CLL) who presents with sudden, unprovoked severe bleeding (massive muscle hematoma) and no prior bleeding history.

Identifying the onset age and bleeding phenotype is critical to distinguishing acquired from congenital bleeding diatheses.

Interpret the initial coagulation panel.

The patient has an isolated prolongation of the activated partial thromboplastin time (aPTT) with a normal prothrombin time (PT) and normal platelet count.

This isolates the defect to the intrinsic coagulation pathway (factors VIII, IX, XI, XII), ruling out common combined pathway issues like DIC or severe liver disease.

Analyze the mixing study kinetics.

The aPTT nearly corrects immediately after mixing (

37 \text{ s}

) but significantly prolongs again (

74 \text{ s}

) after a 2-hour incubation at

37^\circ\text{C}

A time- and temperature-dependent inhibitor is the hallmark of autoantibodies against Factor VIII, distinguishing it from fast-acting inhibitors (like lupus anticoagulant) and simple factor deficiencies (which show sustained correction).

Synthesize the findings into a diagnosis.

The combination of severe spontaneous bleeding, CLL history, isolated aPTT prolongation, and a time-dependent inhibitor on mixing study points exclusively to Acquired hemophilia A.

This completes the formulation of the most likely differential diagnosis, prioritizing the specific pathophysiology observed in the labs.

Key Concept

Formulating a differential diagnosis for an isolated prolonged aPTT involves using mixing study kinetics to distinguish between factor deficiencies (immediate and sustained correction), fast-acting inhibitors (immediate non-correction), and time-dependent inhibitors (immediate correction followed by prolonged incubation failure, classic for Acquired hemophilia A).

Estimated Time:2m 0s

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