At least three published studies to date have found that an increased level of factor VIII is associated with venous thrombosis. The mechanism by which this occurs has not been determined. Treatment with oral anticoagulants can lessen the risk of thrombosis, although anticoagulant therapy may increase the risk of bleeding complications. Moreover, the optimal length of anticoagulation therapy has not been determined. Kyrle and colleagues attempted to determine whether an elevated level of factor VIII confers an increased risk of venous thromboembolic disease in patients who have sustained at least one thromboembolic event.
Patients enrolled were adults older than 18 years who had been treated with oral anticoagulants for at least three months after an episode of deep venous thrombosis, pulmonary embolism, or both. Patients whose events were related to cancer, surgery, pregnancy or trauma, and those with a history of protein S or protein C deficiency or hyperhomocystinemia were excluded.
Day 1 of the study was the day oral anticoagulation was discontinued. Three weeks later, patients were screened for deficiency of protein S, protein C and antithrombin, as well as for the presence of lupus anticoagulant. In addition, the level of factor VIII was checked at this time. Patients were seen at three-month intervals for the first year and then every six months. The primary end point was the recurrence of deep venous thrombosis or pulmonary embolism.
A total of 360 patients (189 women) was enrolled in the study. The mean age of the study subjects was 48 years, and the mean follow-up time after cessation of oral anticoagulation was 30 months. Forty-one percent of women in the study sustained the first episode of thromboembolism while they were taking oral contraceptives.
Thirty-eight patients had a recurrent event that included 24 episodes of deep venous thrombosis and 14 cases of pulmonary embolism. These patients had significantly higher levels of factor VIII (182 IU per dL versus 157 IU per dL) than those who did not have a recurrence. This remained a significant risk even after adjustment for age, sex, duration of anticoagulation, the presence of factor V Leiden, and the presence of the G20210A prothrombin mutation. In patients with a factor VIII level above the 90th percentile, the risk of recurrence was almost seven times greater than the risk in patients with normal levels. At two years, these patients had a 37 percent chance of recurrent deep venous thrombosis or pulmonary embolism compared with a 5 percent chance in patients whose level was below the 90th percentile.
The authors conclude that a high plasma level of factor VIII is a significant independent risk factor for recurrent venous thromboembolism. They recommend routine screening for factor VIII levels in patients who are being screened for thrombophilia. The risk of recurrence must be weighed against the risk of bleeding complications with anticoagulant therapy, which is about 1 to 2 percent annually.
editor's note: The number of laboratory studies recommended for evaluating patients as part of a hypercoagulability work-up continues to grow. This study suggests that an assay for factor VIII be added to the panel of tests that includes protein S, protein C, antithrombin III, factor V Leiden and lupus anticoagulant.—j.t.k.