Thromboembolism: More common than we think!
The incidence of thromboembolism in the general population is not known, but it is estimated that the cumulative probability for confirmed thromboembolism ranges from 0.5% before age 50, to almost 11% by age of 80. However, many events are not clinically recognized, which has led some authors to believe that the true cumulative incidence is about 28%.
Risk factors for a thromboembolitic event are many: prolonged immobility, due to a leg fracture, a long car or airplane trip, or paralysis; varicose veins; obesity, with decreased physical activity; cardiac diseases, like congestive heart failure, or atrial fibrillation; increased estrogen, due to oral contraception, estrogen replacement, Tamoxifen, or pregnancy; autoimmune diseases, like Systemic Lupus Erythematosus; and cancer, typically colonic, ovarian, or multiple myeloma. Still, many cases appear without a clear etiologic factor. These cases are most likely associated with congenital abnormalities of coagulation factors, specifically Factor II and Factor V Leiden.
Testing for the presence of mutation of these factors is now available.
The Factor V Leiden gene mutation is the most common genetic risk factor for thrombosis and accounts for 90% of cases with activated protein C (APC) resistance. This mutation is involved in 20-40% of venous thrombosis cases and is present in 5% of the general population. Inherited thrombosis due to APC resistance is considered an autosomal dominant disease. Heterozygous carriers of the Factor 5 Leiden polymorphism have an increased risk of thrombosis of 5 to 10 times the general population. Homozygotes have a 50 to 100 fold increased risk of thrombosis. The presence of this mutation in pregnant women is also associated with higher risk for adverse pregnancy outcomes. Estimated penetrance for homozygotes is close to 80% with a reduced penetrance for heterozygotes (approximately 12 to 20%).
Some indications for Factor V Leiden gene mutation are venous thrombosis, pulmonary embolism, transient ischemic attack or premature stroke, peripheral vascular disease, particularly lower extremity occlusive disease, cerebral vein thrombosis, multiple spontaneous abortions, history of a thrombotic event, family history of venous thrombosis, relative known to have factor V Leiden, presence of another known genetic hypercoagulability in an individual with a history of thrombosis, and prior to major surgery, pregnancy, oral contraceptive use, or estrogen therapy, if there is a personal or family history of thrombosis.
The Factor II (20210A) gene mutation is also a common risk factor for thrombosis and is associated with elevated factor II (Prothrombin) levels in the peripheral blood. It is present in 1-3% of the general population and after the factor V Leiden mutation, it is the most common genetic risk factor for venous thrombosis. Higher concentrations of prothrombin lead to increased rates of thrombin generation, resulting in excessive growth of fibrin clots. It is an autosomal dominant disorder, with heterozygotes being at a 3 to 11 fold increased risk of thrombosis. Although homozygosity is rare, inheritance of two G20210A alleles would increase the risk of developing thrombosis further. If a patient is doubly heterozygous for both the Factor II (G20210A) Mutation and the Factor V Leiden (G1691A) Mutation, the combined heterozygosity leads to an earlier onset of thrombosis and tends to be more severe than single gene heterozygosity.
Some indications for Factor II gene mutation testing are venous thrombosis, pulmonary embolism, premature myocardial infarction in women, premature ischemic stroke in the absence of hypertension, diabetes or hypercholesterolemia, cerebral vein thrombosis, history of a thrombotic event, family history of thrombosis, relative known to have the prothrombin (factor II) mutation, presence of another known genetic hypercoagulability in an individual with a history of thrombosis, and prior to major surgery, pregnancy, oral contraceptive use or estrogen therapy if there is a personal or family history of thrombosis.
Testing for Factor II and Factor V-Leiden gene mutation is available at Ingalls Hospital Molecular Diagnostic Laboratory. These mutations are detected by the Invader Assay (Third Wave Technologies) using Fluorescence Resonance Energy Transfer (FRET) Detection.
Mutations other than the Factor II or V Leiden Gene Mutation that may cause elevated prothrombin and/or increased risk of venous thrombosis are not ruled out by this assay.
Due to the unique nature of genetic susceptibility testing patients should receive pre-test and post-test counseling.
These tests are reported as: negative, heterozygous, or homozygous.
For any questions please call the Department of Pathology and Laboratory Services at Ingalls Hospital (708) 915-5763.
