Genetics, Epidemiology, and Biochemical Basis
What mutation in the F5 gene causes Factor V Leiden?
G1691A point mutation causing an Arg506Gln (R506Q) substitution.
FVL is a point mutation substituting glutamine for arginine at position 506, the primary activated protein C (APC) cleavage site.
What is the hallmark functional abnormality in Factor V Leiden?
Answer: APC resistance.
Explanation: Factor Va is not degraded efficiently.
What is the first-line imaging modality for suspected lower-limb DVT?
Answer: Doppler ultrasound.
Explanation: Non-invasive, sensitive for detecting thrombi.
How is an acute DVT treated in a patient with Factor V Leiden?
Answer: Same as in noncarriers: DOACs or LMWH/warfarin.
Explanation: Mutation does not alter acute management.
What is the most common presentation of symptomatic FVL?
Answer: DVT.
Explanation: Classic venous thromboembolism.
What is the inheritance pattern of Factor V Leiden?
Autosomal dominant with incomplete penetrance.
One mutant allele is enough to increase risk, but not all carriers develop thrombosis.
Which thrombotic disorders most commonly present in FVL carriers?
Answer: Deep vein thrombosis (DVT) and pulmonary embolism (PE).
Explanation: These are venous clots, consistent with the pathophysiology.
What is the initial laboratory screening test for Factor V Leiden?
Answer: APC resistance assay.
Explanation: Measures clotting time after APC is added.
Why are estrogen-containing contraceptives contraindicated in FVL carriers?
Answer: They synergistically increase VTE risk.
Explanation: Safer alternatives are progestin-only or nonhormonal.
Name one provoking factor for thrombosis in FVL carriers related to surgery.
Answer: Postoperative immobility.
Explanation: Enhances venous stasis.
What is the approximate prevalence of heterozygous Factor V Leiden in Northern Europeans?
3–8% (≈5%)
It’s the most common inherited thrombophilia in this population; rare elsewhere.
Why does Factor V Leiden predispose more strongly to venous than arterial thrombosis?
Answer: Venous clots are coagulation-driven; arterial clots are platelet-driven.
Explanation: FVL alters the coagulation cascade, not platelet activation.
What confirmatory test is used to establish FVL diagnosis?
Answer: Genetic testing (PCR for G1691A mutation).
Explanation: Determines mutation and zygosity.
Compare warfarin with newer DOACs (dabigatran, rivaroxaban) in terms of mechanism.
Answer: Warfarin: inhibits vitamin K–dependent factors.
Dabigatran: direct thrombin inhibitor.
Rivaroxaban: factor Xa inhibitor.
Explanation: Different sites of anticoagulation, similar end goal.
A heterozygous carrier undergoes knee arthroscopy. What preventive strategy should be used?
Answer: Standard VTE prophylaxis (mechanical ± pharmacologic).
Explanation: Carrier status alone doesn’t mandate long-term anticoagulation.
Compare VTE risk between heterozygous and homozygous carriers.
Answer: 3–8× risk in heterozygotes; 50–80× in homozygotes.
Explanation: A dose-response relationship exists.
A 22-year-old woman with heterozygous FVL develops a DVT after starting OCPs. Which risk factor triggered the event?
Answer: Exogenous estrogen.
Explanation: OCPs increase clotting risk, synergizing with FVL.
Why can anticoagulants interfere with functional thrombophilia assays?
Answer: They prolong clotting times, leading to false positives/negatives.
Explanation: Genetic testing avoids this issue.
When is long-term anticoagulation indicated for FVL carriers?
Answer: After unprovoked or recurrent VTE; not for isolated provoked VTE.
Explanation: Risk/benefit must be balanced.
How do obesity and hypertension interact with Factor V Leiden in terms of thrombosis risk?
Answer: They cause venous stasis, endothelial dysfunction, and hypercoagulability.
Explanation: Risk is additive with genetic predisposition.
Relate the genetic defect of Factor V Leiden to the clinical presentation of unprovoked venous thrombosis in young adults.
Answer: The mutation causes persistent procoagulant activity, explaining why otherwise healthy young adults present with DVT/PE without triggers.
Explanation: This links the genetic defect directly to clinical phenotype (LO1 integration).
Discuss how comorbidities such as obesity and hypertension contribute to thrombotic risk in FVL carriers.
Answer: They increase venous stasis, endothelial dysfunction, and hypercoagulability, compounding the inherited defect.
Explanation: This illustrates multifactorial thrombosis risk.
Outline when it is clinically appropriate to test for FVL after a thrombotic event.
Answer: In cases of young age (<50), recurrent thrombosis, strong family history, or unusual clot sites.
Explanation: Testing is targeted, not universal (LO2 critical thinking).
What lifestyle modifications reduce thrombosis risk in asymptomatic carriers?
Answer: Weight control, blood pressure management, hydration, mobility on long flights, avoidance of smoking and estrogen.
Explanation: Non-pharmacologic strategies are critical in prevention (LO3 integration).
A pregnant woman with heterozygous FVL and a history of unprovoked DVT—what prophylaxis is appropriate?
Answer: LMWH during pregnancy and postpartum.
Explanation: Both pregnancy and prior clot history justify pharmacologic prevention.