A 28-year-old man with no prior medical history presents with sudden-onset deep vein thrombosis of the lower limb. Thrombophilia workup is initiated. What is the most common inherited cause of thrombophilia in this patient?

Explanation

## Diagnosis: Factor V Leiden (FVL) **Key Point:** Factor V Leiden is the most common inherited thrombophilia worldwide, present in 3–7% of Caucasians and 1–2% of other populations. It accounts for approximately 50% of inherited thrombophilias. ### Molecular Basis Factor V Leiden is caused by a point mutation (G1691A) in the Factor V gene that results in substitution of arginine 506 with glutamine. This mutation renders Factor V resistant to inactivation by activated protein C (APC), leading to persistent Factor Va activity and hypercoagulability. **High-Yield:** The key mechanism is **APC resistance** — the mutant Factor V cannot be cleaved by APC, so Factor Va remains active longer, promoting thrombin generation. ### Inheritance Pattern - Autosomal dominant with incomplete penetrance - Heterozygotes: ~5-fold increased thrombotic risk - Homozygotes: ~50-fold increased thrombotic risk ### Clinical Features 1. **Age of presentation:** Usually 20–40 years (younger than acquired thrombophilias) 2. **Type of thrombosis:** Predominantly venous (DVT, PE), not arterial 3. **Recurrence:** High risk of recurrent thrombosis if untreated 4. **Pregnancy:** Increased risk of thrombosis and pregnancy complications ### Laboratory Diagnosis - **Activated Protein C Resistance (APCR) assay:** Prolonged aPTT ratio when Factor V is added - **Genetic testing:** PCR-based detection of G1691A mutation (confirmatory) - **Routine coagulation studies:** Normal PT, aPTT, and platelet count **Clinical Pearl:** FVL is often discovered incidentally during thrombophilia workup or when a young patient presents with unprovoked VTE. Many carriers never develop thrombosis (incomplete penetrance). ### Comparison of Common Inherited Thrombophilias | Feature | Factor V Leiden | Antithrombin Deficiency | Protein S Deficiency | Homocysteinemia | |---------|-----------------|------------------------|----------------------|-----------------| | **Prevalence** | 3–7% (Caucasians) | 0.02–0.1% | 0.03–0.13% | 1–2% | | **Inheritance** | Autosomal dominant | Autosomal dominant | Autosomal dominant | Autosomal recessive (homozygous) | | **Mechanism** | APC resistance | ↓ Anticoagulant activity | ↓ Anticoagulant activity | ↑ Homocysteine (prothrombotic) | | **Thrombotic Risk** | Moderate (5–50×) | High (10–50×) | Moderate to high | Moderate | | **Most Common Inherited Cause** | **YES** | No | No | No | | **Frequency Among Inherited Thrombophilias** | ~50% | ~3% | ~5% | Variable | **Mnemonic: FVL = Factor V Leiden = Frequent, Venous, Leiden** — Frequent (most common), Venous thrombosis (not arterial), Leiden (where it was first described).