A 38-year-old woman with a history of recurrent deep vein thrombosis (DVT) despite adequate anticoagulation presents with a third thrombotic event. Investigations reveal a prolonged activated partial thromboplastin time (aPTT) that does not correct with normal plasma mixing. Which is the most common cause of recurrent thrombosis in this clinical presentation?

## Most Common Cause of Recurrent Thrombosis with Prolonged aPTT ### Clinical Presentation & Diagnostic Clues The combination of **recurrent venous thrombosis despite adequate anticoagulation** and a **prolonged aPTT that does not correct with normal plasma mixing** is pathognomonic for **antiphospholipid syndrome (APS)**. The non-correcting aPTT indicates the presence of a lupus anticoagulant (LA), which is one of the three diagnostic criteria for APS. ### Why Antiphospholipid Syndrome Is Most Common **Key Point:** Antiphospholipid syndrome is the most common **acquired** thrombophilia and the most common cause of recurrent thrombosis in young to middle-aged patients. It accounts for 5–10% of all venous thrombotic events and up to 20% of recurrent thrombosis cases. **High-Yield:** The hallmark feature of APS is the **paradox of prolonged aPTT in vitro but thrombosis in vivo**. This occurs because antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β~2~-glycoprotein I) interfere with phospholipid-dependent coagulation tests but promote thrombosis through endothelial activation and platelet aggregation. ### Diagnostic Criteria for APS | Criterion | Details | |-----------|----------| | **Clinical** | Venous or arterial thrombosis OR pregnancy morbidity | | **Laboratory** | Lupus anticoagulant (LA) OR Anticardiolipin (aCL) IgG/IgM OR Anti-β~2~-glycoprotein I IgG/IgM | | **Timing** | Positive on ≥2 occasions ≥12 weeks apart | **Clinical Pearl:** Recurrent thrombosis **despite therapeutic anticoagulation** is a red flag for APS. Standard warfarin (target INR 2–3) may be inadequate; these patients often require higher INR targets (2.5–3.5) or combination therapy. ### Mnemonic: Features of Antiphospholipid Syndrome **THROMBOSIS**: **T**hrombosis (venous/arterial), **H**emolytic anemia, **T**hrombocytopenia, **R**ecurrent fetal loss, **O**ccult malignancy, **M**igraine, **B**iopsy-proven skin necrosis, **O**rgan involvement, **S**eizures, **I**nterstitial lung disease, **S**Sjögren syndrome ### Comparison with Other Thrombophilias | Feature | APS | Protein S Deficiency | Prothrombin G20210A | HIT | |---------|-----|----------------------|----------------------|-----| | **Inheritance** | Acquired | Inherited (autosomal dominant) | Inherited (autosomal dominant) | Acquired | | **aPTT** | Prolonged, non-correcting | Normal | Normal | Normal | | **Recurrent thrombosis despite anticoagulation** | Yes (common) | No | No | Yes (but with thrombocytopenia) | | **Frequency** | 5–10% of thrombosis | 1–3% | 2–5% | 0.5–1% | **Warning:** Do not confuse the **prolonged aPTT** of APS with a true coagulation factor deficiency. The aPTT prolongation is due to antibody interference with the test, not factor deficiency. Mixing studies will NOT correct the aPTT. [cite:Harrison 21e Ch 181]