Thrombotic Disorders

Answer: D

Explanation: Although the mutations of factor V Leiden and prothrombin gene are common, in the heterozygous state they are not strong risk factors for thrombosis at a young age. Combined heterozygous prothrombin and factor V Leiden as well as homozygous factor V Leiden may increase this risk substantially. The strength of homozygous prothrombin mutation is not known. The polymorphisms of MTHFR and PAI-1 are of debatable significance. Deficiencies of the natural anticoagulants are very strongly associated with thrombotic events prior to age 40. See table below for additional details.

Inherited thrombophilia	Frequency in population	Risk of thrombosis
Factor V Leiden	Heterozygous state: 3%–8% of Caucasians 1.2% African American Rare in Asian	-Heterozygous state 3–5 X increase over a lifetime -Minimal increased risk of recurrent events -Homozygous 18 X increased risk -Combined with prothrombin gene 30–50 X increased risk
Prothrombin gene mutation	Heterozygous state: 2%–3% of U.S. Caucasians; 0.5% African Americans	-Heterozygous state 3 X increased risk over lifetime -Possible increased risk of recurrent events in children, but not adults -Homozygous increased but unclear -Combined with factor V Leiden 30–50 X increased risk
Antithrombin deficiency	Heterozygous 1 in 500 to 5,000	-50% risk of event prior to age 40 -Increased risk of recurrent events (10%–17% per year) -Homozygous state not compatible with life
Protein S deficiency	Heterozygous state 1 in 800 to 3,000	-Heterozygous 31 X increased risk prior to age 55 -Increased risk of recurrent events (44% in 5 years) -Homozygous state associated with purpura fulminansVTE
Protein C deficiency	Heterozygous state 1 in 500 to 600 Homozygous state 1 in 1,000,000	-Heterozygous 24 X increased risk prior to age 55 -Increased risk of recurrent events (37% in 5 years) -Homozygous state associated with purpura fulminans as neonate
MTHFR polymorphisms: C677T (thermolabile) and A1298C	Heterozygous state 35% of population Homozygous state 12%–20% of population	Debatable significance unless leads to elevated plasma homocysteine
PAI-1 polymorphism	Heterozygous state 12% of population	Debatable significance unless PAI-1 activity also elevated

Question 12