503This is a clinically signifi cant mutation, since it is relatively common (found in
3–6 % of Caucasian subjects) and has been shown to be associated with venous
thrombosis and stroke. It is of special importance in women for the following
reasons:
- It increases the risk of venous thrombosis associated with oral contraceptives
and hormone replacement therapy. - It synergizes with pregnancy which, by itself, increases the risk of venous
thrombosis - It is associated with intrauterine growth restriction, still births and cerebral palsy
in the off-spring - It is associated with myocardial infarction in young women but not in young men
This mutation can be readily detected by molecular diagnostics. The presence of
Factor V mutation is an important consideration for anticoagulant therapy to pre-
vent thromboembolism and should be individualized for each patient. CYP2C9
mutation is a predicator for anticoagulation-related in these patients.
Anticoagulant Therapy
Warfarin is widely used to prevent thromboembolic events in patients with atrial
fi brillation, prosthetic heart valves, and previous cerebrovascular events. Warfarin
is a narrow-therapeutic-index drug; inadequate or excessive anticoagulation may
result in substantial morbidity and potentially in death because of thromboembolic
complications or bleeding. Warfarin therapy is complicated by great interpatient
variability in the dosage needed to achieve optimal anticoagulation.
Several genes play a role in warfarin’s metabolism. The S-isomer of warfarin has
fi ve times the anticoagulant activity of the R-isomer and is metabolized by CYP2C9.
Polymorphisms in CYP2C9, a gene for cytochrome P450, cause about 30 % of
patients to be slow warfarin metabolizers, which could result in high blood concen-
trations. Testing for CYP2C9 polymorphisms provides a better starting point for the
warfarin dose, which would achieve stable blood levels more quickly than trial-and-
error dosing. Many Caucasians (~50 %) possess less active forms of CYP2C9, a key
enzyme in warfarin metabolism: 10-fold interpatient variability in the dose of war-
farin required to attain a therapeutic response. Frequent assessment of anticoagula-
tion status is necessary during warfarin therapy to ensure drug effi cacy and to
prevent or minimize hemorrhagic events. Thus, the identifi cation of factors that
infl uence warfarin dosage requirements would be of great benefi t in the manage-
ment of patients at risk for coagulation disorders. Polymorphisms in the vitamin K
epoxide reductase multiprotein complex (VKOR) also affect warfarin metabolism
in rats. Mutations in one of the complex’s subunits, VKORC1, confer warfarin
resistance in some human disorders. Genotyping for both CYP2C9 and VKORC1
should be considered when prescribing warfarin before surgery.
Heparin is used to prevent and treat thromboembolic diseases. One of the most
serious adverse reactions to heparin is immune-related heparin-induced thrombocy-
topenia (HIT), which can result in severe thromboembolic complications and death.
Role of Diagnostics in Personalized Management of Cardiovascular Disease