A 42-year-old woman presents to the emergency department with acute onset dyspnea, chest pain, and syncope. She has a 10-day history of left leg swelling and pain. Vital signs: BP 95/60 mmHg, HR 118/min, RR 28/min, SpO₂ 88% on room air. D-dimer is markedly elevated at 2.8 μg/mL. CT pulmonary angiography (CTPA) confirms bilateral pulmonary emboli. Doppler ultrasound of the left leg shows a deep vein thrombosis (DVT) extending from the popliteal to the femoral vein. She has no prior history of thrombosis, malignancy, or recent surgery. Thrombophilia screening reveals activated protein C (APC) resistance with a normal factor V Leiden gene sequencing. What is the most likely diagnosis?

Explanation

## Clinical Presentation & Key Findings **Key Point:** This patient presents with unprovoked DVT and PE (no recent surgery, malignancy, or immobilization) — a hallmark of inherited or acquired thrombophilia. The critical clue is **APC resistance WITHOUT factor V Leiden mutation** on genetic testing. This dissociation points to an *acquired* cause rather than the inherited factor V Leiden variant (which accounts for ~95% of APC resistance cases). ## Differential Diagnosis of APC Resistance | Feature | Factor V Leiden (Inherited) | Acquired APC Resistance | |---------|----------------------------|------------------------| | **Genetic mutation** | Present (FVL G1691A) | Absent | | **APC resistance** | Positive | Positive | | **Common cause** | Genetic predisposition | Antiphospholipid antibodies (aPL) | | **Associated conditions** | Familial thrombosis | SLE, APS, malignancy, OCP use | | **Reversibility** | Permanent | May resolve with aPL treatment | ## Why Antiphospholipid Syndrome (APS)? 1. **Mechanism:** Antiphospholipid antibodies (anticardiolipin, anti-β₂-glycoprotein I, lupus anticoagulant) interfere with the protein C pathway, causing acquired APC resistance. 2. **Clinical presentation:** Unprovoked thrombosis (DVT/PE) in a young woman with no inherited thrombophilia gene mutation is classic for APS. 3. **Diagnostic approach:** The patient should be tested for: - Lupus anticoagulant (prolonged aPTT that does not correct with normal plasma) - Anticardiolipin IgG/IgM - Anti-β₂-glycoprotein I antibodies **High-Yield:** Acquired APC resistance (without FVL mutation) + unprovoked thrombosis = **suspect antiphospholipid syndrome** until proven otherwise. ## Next Steps - Repeat thrombophilia panel including aPL serology (must be done ≥12 weeks after acute thrombosis to avoid false positives from acute phase response). - Screen for SLE (ANA, anti-dsDNA, complement levels). - Initiate anticoagulation (LMWH or DOAC pending aPL confirmation). **Clinical Pearl:** Patients with APS-related thrombosis require **long-term anticoagulation** (target INR 2–3 if warfarin used), unlike some inherited thrombophilias where duration may be limited. [cite:Harrison 21e Ch 181]