Hereditary Predisposition to Thrombosis in Children

Topic Name Introduction Genetic Risk Factors Clinical Presentation Diagnosis Management

Introduction to Hereditary Predisposition to Thrombosis in Children

Hereditary thrombophilia refers to genetic conditions that increase the risk of thrombosis (blood clot formation) in children. While thrombotic events are less common in children compared to adults, they can have significant morbidity and mortality. Understanding the genetic factors contributing to thrombosis is crucial for proper diagnosis, management, and prevention of thrombotic events in pediatric patients.

Genetic Risk Factors for Thrombosis in Children

Several genetic mutations have been identified as risk factors for thrombosis in children:

1. Factor V Leiden mutation (FVL):
   • Most common inherited thrombophilia
   • Causes resistance to activated protein C
   • Heterozygous mutation increases thrombosis risk 3-8 fold
   • Homozygous mutation increases risk 50-80 fold
2. Prothrombin G20210A mutation:
   • Second most common inherited thrombophilia
   • Leads to increased prothrombin levels
   • Heterozygous mutation increases thrombosis risk 2-3 fold
3. Protein C deficiency:
   • Reduces anticoagulant activity
   • Can be quantitative (type I) or qualitative (type II)
   • Heterozygous deficiency increases thrombosis risk 10-fold
4. Protein S deficiency:
   • Cofactor for activated protein C
   • Can be quantitative or qualitative
   • Increases thrombosis risk similarly to protein C deficiency
5. Antithrombin deficiency:
   • Most potent inherited thrombophilia
   • Can be quantitative (type I) or qualitative (type II)
   • Increases thrombosis risk 20-50 fold
6. Other less common genetic factors:
   • Dysfibrinogenemia
   • Plasminogen deficiency
   • Elevated levels of factors VIII, IX, or XI

It's important to note that the presence of these genetic factors doesn't necessarily lead to thrombosis. Often, a combination of genetic and acquired risk factors triggers a thrombotic event.

Clinical Presentation of Hereditary Thrombophilia in Children

The clinical manifestations of hereditary thrombophilia in children can vary widely:

• Venous thromboembolism (VTE): Most common presentation
  • Deep vein thrombosis (DVT), often in lower extremities
  • Pulmonary embolism (PE)
  • Cerebral sinovenous thrombosis (CSVT)
• Arterial thrombosis: Less common, but can occur
  • Stroke
  • Myocardial infarction (rare in children)
  • Peripheral arterial thrombosis
• Neonatal purpura fulminans: Severe presentation in homozygous protein C or S deficiency
• Recurrent pregnancy loss: In adolescent females
• Asymptomatic: Many children with hereditary thrombophilia remain asymptomatic until adulthood or when exposed to additional risk factors

The age of onset and severity can vary depending on the specific genetic defect and the presence of additional risk factors such as immobility, surgery, trauma, or use of oral contraceptives.

Diagnosis of Hereditary Thrombophilia in Children

Diagnosing hereditary thrombophilia in children involves a combination of clinical assessment, family history, and laboratory testing:

1. Clinical evaluation:
   • Detailed personal and family history of thrombotic events
   • Physical examination
2. Imaging studies: To confirm thrombosis
   • Doppler ultrasound for DVT
   • CT angiography or MR venography for CSVT
   • CT pulmonary angiography for PE
3. Laboratory testing:
   • Complete blood count
   • Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
   • D-dimer levels
4. Thrombophilia panel:
   • Factor V Leiden mutation analysis
   • Prothrombin G20210A mutation analysis
   • Protein C activity and antigen levels
   • Protein S activity and antigen levels
   • Antithrombin activity
   • Homocysteine levels
   • Lipoprotein(a) levels

It's important to note that testing should be performed at least 6 weeks after an acute thrombotic event and off anticoagulation therapy to avoid false results. The decision to test asymptomatic children with a family history of thrombophilia is controversial and should be made on an individual basis.

Management of Hereditary Thrombophilia in Children

The management of hereditary thrombophilia in children focuses on prevention and treatment of thrombotic events:

1. Acute thrombosis management:
   • Anticoagulation therapy: Usually with low molecular weight heparin (LMWH) or unfractionated heparin, followed by oral anticoagulants
   • Duration of therapy depends on the site and extent of thrombosis, and the underlying thrombophilia
   • Thrombolysis may be considered in severe cases
2. Long-term management:
   • Risk assessment and counseling
   • Avoidance of additional risk factors (e.g., oral contraceptives in FVL mutation carriers)
   • Consideration of long-term anticoagulation in severe thrombophilias or recurrent thrombosis
3. Prophylaxis:
   • Short-term prophylaxis during high-risk situations (e.g., surgery, prolonged immobilization)
   • Consideration of long-term prophylaxis in severe cases
4. Management of specific deficiencies:
   • Protein C concentrate for severe protein C deficiency
   • Fresh frozen plasma or protein C concentrate for neonatal purpura fulminans
5. Family screening:
   • Genetic counseling
   • Consideration of testing first-degree relatives

Management should be individualized based on the specific thrombophilia, personal and family history of thrombosis, and presence of additional risk factors. Collaboration between hematologists, geneticists, and other specialists is often necessary for optimal care.

Hereditary Predisposition to Thrombosis in Children

1. What is hereditary thrombophilia?
   Hereditary thrombophilia refers to inherited conditions that increase the risk of abnormal blood clot formation
2. Which genetic mutation is most commonly associated with hereditary thrombophilia in children?
   Factor V Leiden mutation is the most common inherited thrombophilia
3. What is the inheritance pattern of Factor V Leiden mutation?
   Autosomal dominant inheritance with variable penetrance
4. How does prothrombin G20210A mutation increase thrombosis risk?
   It leads to increased prothrombin levels, enhancing thrombin generation and clot formation
5. What is the significance of homozygous vs. heterozygous mutations in hereditary thrombophilia?
   Homozygous mutations generally confer a higher thrombosis risk compared to heterozygous mutations
6. Which natural anticoagulant deficiencies are associated with hereditary thrombophilia?
   Deficiencies of antithrombin, protein C, and protein S
7. How does antithrombin deficiency affect thrombosis risk in children?
   Antithrombin deficiency is associated with a high risk of both venous and arterial thrombosis, even in childhood
8. What is the role of protein C in normal hemostasis?
   Protein C is a natural anticoagulant that inactivates factors Va and VIIIa
9. How does protein S deficiency manifest in children?
   Protein S deficiency can cause venous thromboembolism, with increased risk during adolescence and in the presence of additional risk factors
10. What is the significance of elevated factor VIII levels in pediatric thrombophilia?
    Persistently elevated factor VIII levels are an independent risk factor for thrombosis in children
11. How does hyperhomocysteinemia contribute to thrombosis risk?
    Elevated homocysteine levels can damage endothelium and activate coagulation, increasing thrombosis risk
12. What is the role of MTHFR mutations in pediatric thrombophilia?
    MTHFR mutations alone do not significantly increase thrombosis risk but may contribute in combination with other risk factors
13. How does the presence of multiple thrombophilic defects affect thrombosis risk in children?
    The presence of multiple thrombophilic defects has a synergistic effect, significantly increasing thrombosis risk
14. What is the most common site of thrombosis in children with hereditary thrombophilia?
    Deep veins of the lower extremities are the most common site, followed by cerebral venous sinuses
15. How does oral contraceptive use affect thrombosis risk in adolescents with hereditary thrombophilia?
    Oral contraceptives significantly increase thrombosis risk, especially in those with Factor V Leiden or prothrombin mutations
16. What is the role of genetic testing in asymptomatic children with a family history of thrombophilia?
    Routine genetic testing is controversial in asymptomatic children and should be considered on a case-by-case basis
17. How does obesity interact with hereditary thrombophilia in children?
    Obesity compounds thrombosis risk in children with hereditary thrombophilia through various mechanisms, including inflammation and stasis
18. What is the significance of antiphospholipid antibodies in children with hereditary thrombophilia?
    The presence of antiphospholipid antibodies can further increase thrombosis risk in children with hereditary thrombophilia
19. How does hereditary thrombophilia affect the risk of catheter-related thrombosis in children?
    Hereditary thrombophilia increases the risk of catheter-related thrombosis, particularly with central venous catheters
20. What is the role of thromboelastography in assessing children with hereditary thrombophilia?
    Thromboelastography can provide a global assessment of hemostasis but is not specific for diagnosing hereditary thrombophilia
21. How does hereditary thrombophilia affect the risk of stroke in children?
    Certain thrombophilias, particularly antithrombin deficiency and protein C deficiency, increase the risk of arterial ischemic stroke in children
22. What is the significance of elevated lipoprotein(a) levels in pediatric thrombophilia?
    Elevated lipoprotein(a) is an independent risk factor for arterial thrombosis in children
23. How does the presence of hereditary thrombophilia affect the management of Legg-Calvé-Perthes disease in children?
    Hereditary thrombophilia may increase the risk and severity of Legg-Calvé-Perthes disease, potentially influencing treatment decisions
24. What is the role of D-dimer testing in children with hereditary thrombophilia?
    D-dimer testing can be useful in acute thrombosis evaluation but is not diagnostic of hereditary thrombophilia
25. How does hereditary thrombophilia affect the risk of pregnancy complications in adolescents?
    Hereditary thrombophilia increases the risk of pregnancy-related complications such as recurrent miscarriage and placental abruption
26. What is the significance of a positive family history in assessing thrombosis risk in children?
    A positive family history of thrombosis, especially in first-degree relatives, significantly increases a child's thrombosis risk
27. How does hereditary thrombophilia affect the choice of contraception in adolescents?
    Non-hormonal or progestin-only contraceptives are generally preferred in adolescents with hereditary thrombophilia
28. What is the role of thromboprophylaxis in asymptomatic children with hereditary thrombophilia?
    Routine thromboprophylaxis is not recommended for asymptomatic children but may be considered in high-risk situations
29. How does the presence of hereditary thrombophilia affect the management of pediatric inflammatory bowel disease?
    It may influence decisions regarding thromboprophylaxis during disease flares and hospitalization
30. What is the significance of JAK2 mutations in pediatric thrombophilia?
    JAK2 mutations are associated with myeloproliferative neoplasms and can increase thrombosis risk in affected children
31. How does hereditary thrombophilia affect the risk of cerebral sinovenous thrombosis in neonates?
    Certain thrombophilias, particularly Factor V Leiden, increase the risk of cerebral sinovenous thrombosis in neonates
32. What is the role of global coagulation assays in assessing children with hereditary thrombophilia?
    Global assays like thrombin generation tests can provide insight into overall thrombotic potential but are not routinely used
33. How does the presence of hereditary thrombophilia affect the management of pediatric nephrotic syndrome?
    It may influence decisions regarding thromboprophylaxis, especially during periods of severe hypoalbuminemia
34. What is the significance of protein Z deficiency in pediatric thrombophilia?
    Protein Z deficiency may contribute to thrombosis risk, particularly in combination with other thrombophilic factors
35. How does hereditary thrombophilia affect the risk of portal vein thrombosis in children?
    Hereditary thrombophilia increases the risk of portal vein thrombosis, particularly in children with underlying liver disease
36. What is the role of thrombophilia testing in children with arterial ischemic stroke?
    Thrombophilia testing is often performed in children with arterial ischemic stroke, but its impact on management remains controversial
37. How does the presence of hereditary thrombophilia affect the management of sickle cell disease in children?
    It may increase the risk of vaso-occlusive events and influence decisions regarding chronic transfusion therapy
38. What is the significance of plasminogen activator inhibitor-1 (PAI-1) polymorphisms in pediatric thrombophilia?
    PAI-1 polymorphisms may contribute to thrombosis risk by impairing fibrinolysis, particularly in combination with other risk factors

Further Reading

• How I treat thrombophilia in children - ASH Education Book
• Pediatric Hereditary Thrombophilia - Blood Research
• Recommendations for the management of pediatric venous thromboembolism - Journal of Thrombosis and Haemostasis