What is the management approach for inherited thrombosis?

Management of Inherited Thrombosis

The management of inherited thrombosis requires anticoagulation therapy with duration based on the specific thrombophilia type, with indefinite treatment recommended for patients with severe thrombophilias such as antithrombin, protein C, or protein S deficiencies. 1

Classification of Inherited Thrombophilias

• Inherited thrombophilias can be categorized as either high-risk or low-risk based on the strength of their association with thrombotic events 2
• High-risk thrombophilias include:
  • Antithrombin deficiency
  • Protein C deficiency
  • Protein S deficiency
  • Homozygous factor V Leiden
  • Combined thrombophilias (multiple mutations) 3
• Low-risk thrombophilias include:
  • Heterozygous factor V Leiden
  • Prothrombin G20210A mutation
  • Elevated factor VIII levels 4

Diagnostic Approach

• Inherited thrombophilia is detected in 10-59% of children with venous thromboembolism (VTE) and should be considered in patients with unexplained thrombotic events 1
• Testing for thrombophilia should be performed:
  • After a first unprovoked VTE event
  • In patients with recurrent VTE
  • In those with thrombosis at unusual sites
  • In individuals with a strong family history of thrombosis 5
• Direct oral anticoagulants (DOACs) can interfere with thrombophilia testing, potentially causing overestimation of antithrombin, protein C, and protein S activities, leading to missed diagnoses 3

Anticoagulation Treatment

Initial Management

• For acute venous thromboembolism in patients with inherited thrombophilia:
  • Start with either unfractionated heparin or low molecular weight heparin 6
  • Transition to oral anticoagulation (warfarin or DOACs) after initial parenteral therapy 7

Treatment Duration

• For patients with a first episode of VTE secondary to a transient risk factor:
  • Treat with anticoagulation for 3 months 6
• For patients with a first episode of idiopathic VTE:
  • Treat for 6-12 months 6
• For patients with severe thrombophilias (antithrombin, protein C, or protein S deficiency):
  • Consider indefinite anticoagulation therapy 6, 2
• For patients with factor V Leiden or prothrombin G20210A mutation:
  • Treat for 6-12 months for first idiopathic event
  • Consider indefinite therapy based on individual bleeding risk assessment 6, 2
• For patients with two or more documented VTE episodes:
  • Indefinite anticoagulation is recommended regardless of thrombophilia status 6

Anticoagulation Options

• Vitamin K antagonists (warfarin):
  • Target INR of 2.0-3.0 for most inherited thrombophilias 6
  • Requires regular INR monitoring 6
• Direct oral anticoagulants (DOACs):
  • Apixaban: 10 mg twice daily for 7 days, then 5 mg twice daily for treatment; 2.5 mg twice daily for extended prophylaxis 7
  • Other DOACs (rivaroxaban, dabigatran, edoxaban) are also options 3
  • Limited specific evidence in severe thrombophilias, but growing data support their use 3

Special Considerations

Pregnancy

• Pregnancy in women with congenital fibrinogen disorders is a high-risk situation with increased risk for miscarriages, bleeding, and thrombosis 1
• Management requires a multidisciplinary approach involving hematologists and maternal/fetal medicine experts 1

Pediatric Patients

• Risk factors for pediatric VTE include inherited thrombophilia, central venous access devices, malignancy, and age-related factors 1
• The age distribution of VTE in children is bimodal with peaks in infancy and adolescence 1
• Treatment approaches should be adapted to the pediatric population, with DOACs now approved for some pediatric indications 1

Family Screening

• Consider screening first-degree relatives of patients with high-risk thrombophilias (antithrombin, protein C, or protein S deficiency) 1
• Screening of asymptomatic female relatives is particularly important before starting hormonal contraception or during pregnancy planning 1, 2
• Carriers of inherited thrombophilias have increased risk of thrombosis:
  • Antithrombin deficiency: 1.07 events per 100 patient-years
  • Protein C deficiency: 0.54 events per 100 patient-years
  • Protein S deficiency: 0.50 events per 100 patient-years
  • Factor V Leiden: 0.30-0.56 events per 100 patient-years 1

Risk Assessment and Prevention

• The risk of thrombosis is determined by a complex interplay of genetic, acquired, and circumstantial factors 5
• At least 50% of VTE events in thrombophilic individuals are provoked by predisposing factors such as immobility, surgery, trauma, cancer, hormonal therapy, and pregnancy 5
• Primary prevention strategies should be considered for high-risk situations in patients with known thrombophilias 8
• Risk-benefit assessment for indefinite anticoagulation should be periodically reassessed, weighing thrombosis risk against bleeding risk 6, 2