Clinical predictivity of genetic tests for thromboembolism.

Venous thromboembolism (VTE) is a condition in which a thrombus (a solid mass of blood constituents) forms in a vein. VTE represents an extremely common medical problem manifested as either deep venous thrombosis (DVT) or pulmonary embolism (PE) affecting apparently healthy as well as hospitalized patients. Often PE is the physiopathological consequence of the DVT of low extremities vessels, in particular of the calves (1). The pathogenesis of VTE was described over 150 years ago by Rudolph Virchow and summarized in the well-known triad describing the three necessary components for thrombosis: a) blood stasis, b) hypercoagulability, and c) changes in the vessel wall (2). Thrombophilia is a defect in blood coagulation that leads to a predisposition towards thrombosis. It can be heritable (genetic) or acquired (or mixed). Heritable (genetic) thrombophilia is caused most commonly by mutations in the genes for coagulation factors II and V. Factor V Leiden (FVL) is the most common known inherited risk factor for thrombosis, resulting from the G>A substitution at position 1691 of the gene encoding coagulation Factor V (R506Q). FVL causes the Factor V being inactivated more slowly and generating more thrombin. Prothrombin 20210G>A (PT20210A), the second most common known inherited risk factor for thrombosis, produces an amino acid substitution which results in higher circulating prothrombin levels. Therefore, both FVL and PT20210A enhance the potential for clot formation. Acquired thrombophilia refers to conditions in which individuals without genetic defects in coagulation factors are at increased risk of thrombosis, for example those with lupus anticoagulant or anticardiolipin antibodies. Examples of mixed type thrombophilias are elevation of factor VIII or homocysteine levels. As homocysteine level in plasma is in part under control of the methylenetetrahydrofolate reductase, coded by the MTHFR gene, its functional variant C677T has been considered a relevant risk factor for VTE and included in a panel of genetic tests for inherited thrombophilia comprising also FVL and PT20210A (3). Many intrinsic factors, disease-related risk factors and physiological or iatrogenic factors (e.g., pregnancy, oral contraceptives and hormone replacement therapy) can increase the propensity to VTE. Among intrinsic risk factors age, obesity, genetic factors and a previous history of VTE are the main predictors of VTE. Advanced age is associated with an increased risk of VTE with a reported cumulative probability of experiencing a first case of VTE at age 80 years 20-fold higher than at age 50 years (4). Obesity, in particular abdominal obesity, has been found as an independent factor associated with VTE that increases two times the risk in subjects with a body mass index (BMI) greater than 30 kg/m2 (5). A previous event of venous thromboembolism is considered the most important factor associated with VTE, increasing the risk of recurrent events of about 15 times (6). Surgical procedures (in particular orthopedic surgery, surgery for cancer and neurosurgery) are the most relevant diseaserelated risk factors for VTE. It has been found that, under surgical interventions, incidence of thromboembolic events can vary from 15% to 60%, with the higher frequency detected among patients undergoing hip or knee arthroplasty and hip fracture surgery (7). The clinical relevance of VTE is highlighted by the significant rates of recurrence and mortality that, however, are very likely to be underestimated since relevant epidemiological data for the frequency of VTE derive mainly from large community-based studies that reflect symptomatic rather than asymptomatic disease.