Makindo Medical Notes

Related Subjects: Thrombophilia testing |Antiphospholipid syndrome |Protein C Deficiency |Protein S Deficiency |Prothrombin 20210A mutation |Factor V Leiden Deficiency |Antithrombin III deficiency (AT3) |Cerebral Venous Sinus thrombosis |Budd-Chiari syndrome

Introduction

Clotting risk is often cumulative and additive. The Factor V Leiden (FVL) mutation is the most common hereditary thrombophilia, characterized by a genetic variant of coagulation factor V that results in resistance to activated protein C (APC). This resistance leads to an increased tendency for thrombosis, particularly in the venous system. While the association between FVL and venous thromboembolism (VTE) is well-established, its role in arterial thrombosis, including ischemic stroke, is less clear but may be significant in certain populations, such as children and young adults.

Genetics and Epidemiology

The Factor V Leiden mutation is a single point mutation (G1691A) in the gene coding for coagulation factor V, leading to the substitution of arginine with glutamine at position 506 (Arg506Gln). This mutation renders factor V resistant to inactivation by activated protein C.

• Prevalence:
  • Heterozygous FVL mutation is present in approximately 3-7% of individuals of European descent.
  • Less common in African, Asian, and Indigenous populations.
  • Homozygous FVL mutation is rare, occurring in about 1 in 5,000 individuals.
• Inheritance Pattern: Autosomal dominant with incomplete penetrance.

Pathophysiology

The normal function of activated protein C is to inactivate factors Va and VIIIa, thus regulating coagulation. In individuals with the FVL mutation:

• Factor V becomes resistant to inactivation by activated protein C.
• This leads to prolonged activity of factor Va, promoting thrombin generation and fibrin formation.
• The hypercoagulable state increases the risk of venous thrombosis.

Clinical Features

The clinical manifestations of Factor V Leiden mutation are primarily related to an increased risk of venous thromboembolism (VTE). Key clinical features include:

• Venous Thromboembolism:
  • Deep Vein Thrombosis (DVT): Swelling, pain, and redness in the affected limb.
  • Pulmonary Embolism (PE): Shortness of breath, chest pain, tachycardia, and potentially life-threatening complications.
  • Cerebral Venous Sinus Thrombosis (CVST): Headache, seizures, focal neurological deficits, and increased intracranial pressure.
  • Superficial Vein Thrombosis: Painful induration along superficial veins.
  • Budd-Chiari Syndrome: Hepatic vein thrombosis leading to hepatomegaly, ascites, and liver dysfunction.
• Risk in Heterozygotes:
  • Approximately 3-8 fold increased risk of initial VTE compared to the general population.
  • Risk is further elevated in the presence of additional risk factors (e.g., surgery, immobilization, pregnancy).
• Risk in Homozygotes:
  • Up to 80 fold increased risk of VTE.
  • Higher likelihood of recurrent thrombosis.
• Arterial Thrombosis:
  • The association with arterial events like stroke is less clear but may be relevant in young individuals without traditional risk factors.
  • Some studies suggest a modest increase in risk for ischemic stroke and myocardial infarction in carriers.
• Pregnancy Complications:
  • Increased risk of miscarriage, stillbirth, preeclampsia, placental abruption, and intrauterine growth restriction.
  • Pregnant women with FVL mutation are at higher risk of developing VTE.
• Family History: A family history of thrombosis at a young age may suggest the presence of FVL mutation.

Risk Factors and Triggers

The risk of thrombosis in individuals with FVL mutation is influenced by additional acquired and genetic factors:

• Acquired Risk Factors:
  • Surgery and trauma
  • Immobilization
  • Obesity
  • Hormone therapy: Oral contraceptives and hormone replacement therapy increase VTE risk synergistically.
  • Pregnancy and postpartum period
  • Malignancy
  • Antiphospholipid antibody syndrome
  • Smoking
• Other Thrombophilias: Co-inheritance of other genetic mutations (e.g., prothrombin G20210A mutation, protein C or S deficiency) can compound the risk.

Diagnosis

Diagnostic evaluation includes:

• Clinical Assessment: Evaluation of personal and family history of thrombosis.
• Laboratory Tests:
  • Activated Protein C Resistance (APCR) Assay: Functional test measuring the prolongation of clotting time in response to activated protein C.
  • Genetic Testing: DNA analysis using polymerase chain reaction (PCR) to detect the G1691A mutation in the factor V gene.
• Additional Thrombophilia Screening: Especially in patients with unprovoked VTE or strong family history.
  • Antithrombin III levels
  • Protein C and Protein S activity
  • Prothrombin gene mutation testing
  • Antiphospholipid antibodies
  • Homocysteine levels

Differential Diagnosis

Other hereditary and acquired thrombophilias to consider include:

Management

Management strategies aim to prevent thrombosis and manage acute events:

Prevention

• Lifestyle Modifications:
  • Avoid prolonged immobilization; encourage mobility during travel.
  • Maintain healthy weight and engage in regular exercise.
  • Smoking cessation.
• Avoidance of Hormonal Risk Factors:
  • Use non-estrogen-containing contraceptives when possible.
  • Careful consideration of hormone replacement therapy risks and benefits.
• Prophylactic Anticoagulation:
  • Considered in high-risk situations (e.g., surgery, pregnancy) especially in homozygous individuals or those with prior VTE.
  • Low molecular weight heparin (LMWH) is commonly used during pregnancy.

Treatment of Acute Thrombosis

• Anticoagulation Therapy:
  • Initial treatment with LMWH or unfractionated heparin, followed by transition to oral anticoagulants.
  • Vitamin K antagonists (e.g., warfarin) have been traditionally used.
  • Direct oral anticoagulants (DOACs) such as apixaban, rivaroxaban, and dabigatran are alternatives with ease of use.
• Duration of Therapy:
  • Typically 3-6 months for a first episode of provoked VTE.
  • Extended or indefinite anticoagulation may be considered in cases of recurrent thrombosis or high-risk profiles.
• Monitoring and Follow-Up:
  • Regular assessment for bleeding complications and efficacy of anticoagulation.
  • Patient education on signs of thrombosis and bleeding.

Pregnancy Management

• Risk Assessment: Individualized based on personal and family history.
• Prophylactic Anticoagulation:
  • Consider LMWH during pregnancy and postpartum period in women with prior VTE or additional risk factors.
  • Monitoring of anti-Xa levels may be necessary in some cases.
• Antenatal Surveillance: Close monitoring for signs of placental insufficiency and fetal growth restriction.

Arterial Thrombosis and Stroke

The role of FVL mutation in arterial thrombosis is less clear:

• Evidence suggests a possible association with ischemic stroke in children and young adults, particularly in the presence of other risk factors.
• Routine screening for FVL mutation in all patients with arterial thrombosis is not currently recommended.
• Management focuses on standard stroke prevention strategies and addressing modifiable risk factors.

Genetic Counseling and Family Screening

• Discuss implications of genetic testing with patients and families.
• Family members may consider testing, especially if there is a strong history of thrombosis.
• Provide education on recognizing symptoms of VTE and preventive measures.

Prognosis

The risk of thrombosis in individuals with FVL mutation varies widely. Many carriers remain asymptomatic throughout life. The prognosis is favorable with appropriate management and preventive strategies. Awareness and early intervention reduce morbidity and mortality associated with thrombotic events.

References

• Connors JM. Thrombophilia Testing and Venous Thrombosis. N Engl J Med. 2017;377(12):1177-1187.
• Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008;112(1):19-27.
• De Stefano V, Rossi E, Paciaroni K, Leone G. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood. 2016;128(9):109-116.
• Franchini M, Mannucci PM. Factor V Leiden and thrombophilia. Clin Chem Lab Med. 2008;46(6):733-736.
• Martinelli I, De Stefano V, Taioli E, et al. Increased risk of cerebral vein thrombosis in carriers of prothrombin gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338(25):1793-1797.
• Hypercoagulability in stroke. In: Caplan LR, Biller J, Leary MC, Lo EH, Thomas AJ, Yenari MA, Zhang JH, eds. Caplan's Stroke: A Clinical Approach. 5th ed. Elsevier; 2016:819-837.