A 72-year-old woman is evaluated in the emergency department for severe right thigh pain a… — USMLE Step 3

A 72-year-old woman is evaluated in the emergency department for severe right thigh pain and swelling that began spontaneously 2 days ago. She also reports easy bruising over her trunk and arms for the past 3 weeks. She has no prior history of abnormal bleeding, even during three uncomplicated vaginal deliveries and an open cholecystectomy at age 55. She takes no medications and has no family history of bleeding disorders. Physical examination reveals a massive, tense hematoma over the right anterior thigh and multiple large ecchymoses on the abdomen.

Laboratory studies are as follows:

Laboratory Parameter	Patient Value	Reference Range
Hemoglobin	$8.2 \text{ g/dL}$	$12.0-15.5 \text{ g/dL}$
Platelet count	$250,000/\text{mm}^3$	$150,000-400,000/\text{mm}^3$
Prothrombin time (PT)	$12.1 \text{ seconds}$	$11.0-15.0 \text{ seconds}$
Activated partial thromboplastin time (aPTT)	$86 \text{ seconds}$	$25-40 \text{ seconds}$
Thrombin time	$14 \text{ seconds}$	$< 15 \text{ seconds}$

A 1:1 mixing study with normal pooled plasma is performed to further evaluate the prolonged aPTT:

Parameter	Patient Value
Immediate aPTT	$37 \text{ seconds}$
Incubated aPTT (2 hours at $37^\circ\text{C}$ )	$74 \text{ seconds}$

Which of the following is the most likely underlying mechanism for this patient's clinical and laboratory findings?

Autoantibody directed against factor VIIIAnswer
B
Phospholipid-binding antibodies
C
Congenital deficiency of factor VIII
D
Qualitative defect in von Willebrand factor
E
Systemic activation of the coagulation cascade

Answer

Autoantibody directed against factor VIII

The correct answer explains the pathophysiology of acquired hemophilia A. The patient has an isolated prolonged aPTT and severe, spontaneous, deep-tissue bleeding despite a negative bleeding history, which strongly points to an acquired inhibitor. The 1:1 mixing study is the critical differentiating test: factor deficiencies will correct immediately and remain corrected, while most inhibitors (like lupus anticoagulant) will fail to correct immediately. However, autoantibodies directed against factor VIII (acquired hemophilia A) are distinctively time- and temperature-dependent. They may initially appear to correct the aPTT immediately after mixing, but the aPTT will progressively prolong after a 1- to 2-hour incubation at

37^\circ\text{C}

as the autoantibodies bind and neutralize the factor VIII in the normal pooled plasma.

Step-by-Step Solution

Analyze the basic coagulation panel.

The patient has an isolated prolonged aPTT with a normal PT, normal platelet count, and normal thrombin time.

An isolated prolonged aPTT narrows the differential to an intrinsic pathway issue (factor VIII, IX, XI, XII deficiency or an inhibitor like lupus anticoagulant or specific factor autoantibody).

Interpret the 1:1 mixing study results.

The immediate mix corrected the aPTT to normal (37 seconds), but the incubated mix became prolonged again (74 seconds).

Immediate correction suggests a factor deficiency, but subsequent prolongation after incubation at body temperature is the hallmark of a time- and temperature-dependent inhibitor, classic for factor VIII autoantibodies.

Synthesize laboratory findings with the clinical presentation.

An elderly patient with no prior bleeding history who suddenly develops life-threatening deep tissue bleeding (muscle hematoma) and a time-dependent factor VIII inhibitor.

This combination definitively establishes the diagnosis of acquired hemophilia A (autoantibody directed against factor VIII).

Key Concept

Interpretation of time-dependent inhibitors on mixing studies (Acquired Hemophilia A)

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