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

The Prothrombin G20210A mutation, also known as the prothrombin 20210A mutation, is a genetic variation associated with an increased risk of thrombosis. This mutation leads to elevated levels of prothrombin (factor II), a key protein in the coagulation cascade, resulting in a hypercoagulable state. While the mutation is primarily linked to venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), it may also contribute to cerebral venous sinus thrombosis (CVST) and has been studied in relation to ischemic stroke in children and young adults.

Genetics and Epidemiology

The Prothrombin G20210A mutation involves a guanine (G) to adenine (A) substitution at nucleotide position 20210 in the 3'-untranslated region of the prothrombin gene (F2) on chromosome 11.

• Prevalence:
  • Approximately 1-2% of the general white population are heterozygous for the mutation.
  • Less common in African, Asian, and Indigenous populations.
  • Homozygosity is rare, occurring in about 1 in 10,000 individuals.
• Inheritance Pattern: Autosomal dominant with incomplete penetrance.

Pathophysiology

The mutation leads to increased prothrombin levels due to enhanced gene expression:

• The 3'-untranslated region mutation increases the stability of prothrombin mRNA.
• Elevated prothrombin levels result in increased thrombin generation.
• Excess thrombin promotes fibrin formation, leading to a hypercoagulable state.

Clinical Features

Individuals with the Prothrombin G20210A mutation may present with:

• Venous Thromboembolism (VTE):
  • Deep Vein Thrombosis (DVT): Swelling, pain, and redness in the affected limb.
  • Pulmonary Embolism (PE): Sudden shortness of breath, chest pain, tachycardia.
  • Cerebral Venous Sinus Thrombosis (CVST): Headache, visual disturbances, seizures, focal neurological deficits.
  • Increased Risk: Heterozygotes have a 2-3 fold increased risk of VTE; homozygotes have a higher risk.
• Arterial Thrombosis:
  • The association with arterial events like ischemic stroke is less clear but may be significant in children and young adults.
• Pregnancy Complications:
  • Higher risk of miscarriage, stillbirth, preeclampsia, placental abruption.
  • Increased risk of VTE during pregnancy and postpartum period.
• Interaction with Other Risk Factors:
  • Oral contraceptive use significantly increases VTE risk in carriers.
  • Hormone replacement therapy also elevates risk.
  • Co-inheritance with other thrombophilic mutations (e.g., Factor V Leiden) amplifies the risk.

Risk Factors and Triggers

The risk of thrombosis is influenced by additional acquired factors:

• Surgery or trauma
• Immobilization
• Obesity
• Smoking
• Cancer
• Antiphospholipid antibody syndrome
• Advanced age

Diagnosis

Evaluation involves:

• Clinical Assessment: Personal and family history of thrombotic events.
• Laboratory Testing:
  • Genetic Testing: Polymerase chain reaction (PCR) to detect the G20210A mutation in the prothrombin gene.
  • Prothrombin Levels: May show mildly elevated plasma prothrombin activity.
• Thrombophilia Screen: To identify other inherited or acquired thrombophilias.

Differential Diagnosis

Other thrombophilic conditions to consider include:

Management

Management focuses on preventing thrombotic events and mitigating risk factors:

Preventive Measures

• Lifestyle Modifications:
  • Maintain healthy weight and engage in regular physical activity.
  • Smoking cessation.
  • Avoid prolonged immobilization; encourage movement during long travel.
• Avoid Hormonal Risk Factors:
  • Use non-estrogen contraceptives if possible.
  • Evaluate risks before initiating hormone replacement therapy.
• Risk Assessment during Pregnancy:
  • Consider prophylactic anticoagulation in high-risk women.
  • Close monitoring for obstetric complications.

Treatment of Thrombotic Events

• Anticoagulation Therapy:
  • Initial treatment with low molecular weight heparin (LMWH) or unfractionated heparin.
  • Transition to oral anticoagulants such as warfarin or direct oral anticoagulants (DOACs).
  • Duration of therapy depends on the event and risk profile; often at least 3-6 months.
• Long-Term Anticoagulation:
  • May be considered in patients with recurrent VTE or additional risk factors.
  • Regular monitoring for efficacy and adverse effects.

Considerations for Ischemic Stroke

While the Prothrombin G20210A mutation is primarily associated with venous thrombosis, its role in arterial thrombosis such as ischemic stroke is less definitive:

• Some studies suggest an increased risk in children and young adults, particularly when combined with other risk factors.
• Routine screening for the mutation in arterial stroke is not universally recommended.
• Management should focus on standard stroke prevention strategies.

Genetic Counseling and Family Screening

• Discuss the implications of genetic findings with patients.
• Family members may consider testing, especially if there is a strong history of thrombotic events.
• Educate on recognizing signs of thrombosis and preventive measures.

Prognosis

Many individuals with the Prothrombin G20210A mutation remain asymptomatic. The risk of thrombosis is influenced by additional genetic and environmental factors. With appropriate management and risk mitigation, the prognosis is generally favorable.

References

• Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographical distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998;79(4):706-708.
• Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88(10):3698-3703.
• De Stefano V, Rossi E, Paciaroni K, et al. Prothrombin G20210A mutation and the risk of cerebral vein thrombosis. Stroke. 2006;37(9):2317-2320.
• Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338(25):1793-1797.
• National Institute for Health and Care Excellence (NICE). Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. NICE guideline [NG158]; 2020.