Thrombin Test Detects Low Risk of Recurrent Blood Clots

VIENNA, Austria, July 26 -- Patients with a first venous thromboembolism but a thrombin generation of less than 400 nM had a 60% lower risk of a recurrent leg or lung clot, according to a study here.

Measurement of thrombin generation can help determine which patients with venous thromboembolism (VTE) are at low risk for recurrence and can therefore avoid extensive testing and the bleeding risks of anticoagulant treatment, researchers wrote in the July 26 issue of the Journal of the American Medical Association.

In a study of 914 patients, conducted between 1992 and 2005, patients with either deep-vein thrombosis or pulmonary embolism were followed for an average 47 months after discontinuation of vitamin K antagonist therapy, reported Paul Kyrle, M.D., of the Medical University of Vienna, and colleagues.

Patients were enrolled from the Austrian Study on Recurrent Venous Thromboembolism (AUREC), an ongoing, prospective cohort study at four thrombosis centers in Vienna. A simple global coagulation assay was used to measure thrombin generation, the pivotal step in hemostasis, the researchers said.

Venous thromboembolism recurred in 100 patients (11%): deep-vein thrombosis in 58 and pulmonary embolism in 42. Pulmonary embolism was fatal in three patients, Dr. Kyrle said. Recurrence was spontaneous in 90 patients and secondary to surgery or trauma in 10.

Overall, patients without recurrent thromboembolism had lower thrombin generation values than patients with recurrence (mean 349.2 nM compared with 419.5 nM, P<0.001).

Patients with thrombin generation less than 400 nM, representing two thirds of the patients, had a recurrence risk 60% lower than that of patients with greater values (RR, 0.40; CI, 0.27-0.60; P<0.001), Dr. Kyrle said.

Further analysis showed that compared with patients whose thrombin generation was greater than 400 nM, those with values between 400 nM and 300 nM had a relative risk of recurrence of 0.42 (95% confidence interval 0.26-0.67; P<0.001). For patients with still lower values, the relative risk was 0.37 (CI, 0.21-0.66; P=0.001).

After four years, the probability of recurrence was 6.5% among patients with thrombin generation less than 400 nM (CI, 4.0%-8.9%) compared with 20.0% among patients with higher values (CI, 14.9%-25.1%), (P<0.001).

According to a Kaplan-Meier analysis, the likelihood of recurrent venous thromboembolism in these patients was as low as 7% after four years with an upper 95% CI of 9%, the researchers said.

Most important, Dr. Kryle emphasized, the group of patients with low peak thrombin generation represented more than 60% of the total patient population.

Referring to the study's limitations, the researchers mentioned that their data cannot be applied to several patient groups, including patients with antithrombin or protein C or protein S deficiencies. Also patients with more than one episode of VTE and those with VTE secondary to the lupus anticoagulant routinely receive anticoagulant treatment and were excluded from the study.

In addition, the researchers wrote, the Austrian AUREC study is a hypothesis-generating study, which precluded predefinition of certain cut-off values. The results reported here should serve as the basis for validation in a prospective interventional trial, said the authors.

Identification of patients who might benefit from indefinite anticoagulant therapy (where recurrent thromboembolism risk is greater than the risk of severe bleeding) involves complex laboratory tests, the authors said in summing up. "Over the years, extensive routine thrombophilia screening has become common practice," they said, adding that it is expensive and may be inconclusive.

"Using a simple, inexpensive assay system?to measure thrombin generation, we were able to identify patients in whom the long-term risk of recurrent VTE is almost negligible," the researchers said. "These patients will not likely benefit from indefinite treatment with vitamin K antagonists," they concluded.

Bernd Binder, M.D., a coauthor, reported that he is the chief scientific officer for Technoclone GmbH, of Vienna, maker of the thrombin assay kit.