Leiden mutation is of factor:

Explanation

## Correct Answer: C. V The Leiden mutation is a point mutation (G1691A) in the **Factor V gene** that results in a single amino acid substitution (Arg506Gln) in the Factor V protein. This mutation renders Factor V resistant to inactivation by activated protein C (APC), a natural anticoagulant. Normally, APC cleaves Factor V at position 506, inactivating it and preventing excessive thrombin generation. The Leiden variant escapes this proteolytic cleavage, leading to **persistent Factor V activity** and a hypercoagulable state. This is the most common inherited thrombophilia in Caucasian populations (5–7% carrier frequency) and accounts for approximately 20–25% of familial venous thromboembolism cases. In Indian populations, the prevalence is lower but still clinically significant. Heterozygous carriers have a 5–10-fold increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), while homozygous individuals have an even higher risk. The mutation is named after Leiden, Netherlands, where it was first identified in 1994. Diagnosis is confirmed by **APC resistance testing** (prolonged activated partial thromboplastin time [aPTT] ratio) or direct **DNA sequencing** of the Factor V gene. ## Why the other options are wrong **A. VIII** — Factor VIII deficiency causes hemophilia A, an X-linked bleeding disorder with prolonged aPTT and normal PT. While Factor VIII mutations do cause thrombophilia in rare gain-of-function variants, the Leiden mutation is not associated with Factor VIII. This is a distractor that confuses students familiar with Factor VIII as a common coagulation defect. **B. I** — Factor I (fibrinogen) mutations cause dysfibrinogenemia or hypofibrinogenemia, leading to bleeding disorders, not thrombophilia. Fibrinogen defects present with prolonged PT, aPTT, and thrombin time (TT). The Leiden mutation specifically affects Factor V's resistance to APC, not fibrinogen structure or function. **D. X** — Factor X deficiency causes a bleeding disorder with prolonged PT and aPTT (part of the prothrombin complex). Factor X mutations are associated with hemorrhagic disease, not thrombophilia. While Factor X is part of the prothrombinase complex, the Leiden mutation's APC-resistance mechanism is unique to Factor V. ## High-Yield Facts - **Factor V Leiden** is caused by Arg506Gln substitution (G1691A mutation) making Factor V resistant to APC inactivation. - **APC resistance** is the functional hallmark—prolonged aPTT ratio (>2.0) on mixing study with APC indicates Leiden mutation. - **Heterozygous Leiden** confers 5–10-fold increased VTE risk; **homozygous** carriers have >50-fold risk, especially with oral contraceptives or pregnancy. - **Prevalence in India** is lower (~1–2%) compared to Caucasians (5–7%), but still a leading cause of familial thrombophilia in Indian populations. - **Diagnosis** is confirmed by APC resistance testing or direct Factor V gene sequencing; prothrombin time (PT) and platelet count remain normal. - **Combined thrombophilia risk** increases dramatically when Leiden is paired with prothrombin G20210A mutation or antithrombin/protein C/S deficiency. ## Mnemonics **APC-R (Activated Protein C Resistance)** **A**ctivated **P**rotein **C** cannot **R**ecognize (cleave) mutant Factor V → persistent Factor V activity → thrombosis. Use this when remembering why Leiden causes clotting, not bleeding. **LEIDEN = Thrombophilia (not bleeding)** **L**eiden → **E**scapes **I**nactivation → **D**eep vein thrombosis/**E**mbolism → **N**ot bleeding. Helps distinguish from other Factor mutations that cause bleeding. ## NBE Trap NBE often pairs Factor V with bleeding disorders (hemophilia, deficiency states) to trap students who conflate "Factor V mutation = bleeding." Leiden is a **gain-of-function** mutation causing thrombophilia, not a loss-of-function bleeding disorder—this is the critical discriminator. ## Clinical Pearl In Indian clinical practice, a young patient presenting with unprovoked DVT or PE should be screened for Leiden mutation, especially if there is a family history of thrombosis or if the patient is a woman on oral contraceptives—the combination dramatically increases VTE risk and warrants anticoagulation counseling and thrombophilia workup per Indian guidelines. _Reference: Robbins & Cotran Pathologic Basis of Disease, Ch. 4 (Hemostasis and Thrombosis); Harrison's Principles of Internal Medicine, Ch. 139 (Disorders of Coagulation and Thrombosis)_