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?

Question

Accepted Answer

C. Factor V Leiden. ## 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).

Answer

A. Homocysteinemia

Answer

B. Protein S deficiency

Answer

D. Antithrombin deficiency

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)

Molecular Basis

Inheritance Pattern

Clinical Features

Laboratory Diagnosis

Comparison of Common Inherited Thrombophilias

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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