Are most inherited clotting disorders autosomal dominant or autosomal recessive?

Inheritance Patterns of Clotting Disorders

Most inherited clotting disorders are autosomal dominant, while severe bleeding disorders are typically autosomal recessive. 1

Autosomal Dominant Clotting Disorders

The majority of inherited thrombophilias (hypercoagulable states) follow an autosomal dominant inheritance pattern:

• Factor V Leiden mutation - most common inherited thrombophilia 1, 2
• Prothrombin G20210A mutation - second most common inherited thrombophilia 3
• Protein C deficiency 4
• Protein S deficiency 4
• Antithrombin III deficiency 4

These disorders primarily predispose individuals to venous thrombosis rather than arterial events 1, 4. Factor V Leiden is carried in heterozygous form by approximately 5% of the Caucasian population and increases venous thrombosis risk about 7-fold in heterozygotes and 80-fold in homozygotes 1.

Autosomal Recessive Clotting Disorders

In contrast, most severe bleeding disorders follow an autosomal recessive inheritance pattern:

• Deficiencies of factors V, VII, X, XI, and XIII 1, 5
• These can lead to cerebral hemorrhage in childhood or neonatal period 1
• Factor X deficiency is a rare autosomal recessive disorder with worldwide prevalence of approximately 1:1,000 1

The only exceptions to this pattern are hemophilia A and B, which are X-linked recessive bleeding disorders 2.

Clinical Implications

The inheritance pattern has important implications for:

1. Risk assessment: Autosomal dominant disorders like Factor V Leiden can manifest clinically in heterozygotes, while autosomal recessive disorders typically require homozygosity or compound heterozygosity for clinical manifestation 1

2. Family screening: For autosomal dominant disorders, first-degree relatives have a 50% chance of inheriting the mutation, while for autosomal recessive disorders, siblings have a 25% chance of being affected 5

3. Prevalence in certain populations: Autosomal recessive disorders are more common in populations with high rates of consanguineous marriages (e.g., Iran, southern India, Pakistan) 1, 5

Genetic Testing Considerations

When considering genetic testing for clotting disorders:

• Testing should be guided by clinical presentation and family history
• For thrombophilias, Factor V Leiden and prothrombin G20210A are the most common mutations to test for 1, 3
• Patients should be informed about the genetic nature of testing and implications for family members 1
• Formal informed consent may not be required for Factor V Leiden testing, but patients should understand the familial implications 1

Common Pitfalls and Caveats

1. Heterogeneity in presentation: The clinical manifestations of these disorders vary widely, even within families with the same mutation

2. Multifactorial nature: Most thrombotic events require both genetic and environmental triggers

3. Incomplete penetrance: Not all individuals with thrombophilia mutations will develop thrombosis

4. Acquired vs. inherited: Some coagulopathies that appear acquired (like lupus anticoagulant) can have a familial component in approximately 10% of cases 1

5. Population differences: Factor V Leiden is common in Caucasians but rare in Africans and Asians 1

Understanding the inheritance pattern of clotting disorders is essential for proper genetic counseling, risk assessment, and management of affected individuals and their families.