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Gregor Hron, MD; Marietta Kollars; Bernd R. Binder, MD; Sabine Eichinger, MD; Paul A. Kyrle, MD

JAMA. 2006;296:397-402.

Context  Screening of patients with venous thromboembolism (VTE) for thrombophilic risk factors is common clinical practice. Because of the large number of risk factors, assessing the risk of recurrence in an individual patient is complex. A method covering multicausal thrombophilia is therefore required.

Objective  To investigate the relationship between recurrence of VTE and a simple global coagulation assay measuring thrombin generation.

Design, Setting, and Participants  Prospective cohort study of 914 patients with first spontaneous VTE who were followed up for an average of 47 months after discontinuation of vitamin K antagonist therapy. The study was conducted at the Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria, between July 1992 and July 2005. Thrombin generation was measured by a commercially available assay system. Patients with a previous or secondary VTE; antithrombin, protein C, or protein S deficiencies; presence of lupus anticoagulant; cancer; or pregnancy were excluded.

Main Outcome Measure  Objectively documented symptomatic recurrent VTE.

Results  Venous thromboembolism recurred in 100 patients (11%). Patients without recurrent VTE had lower thrombin generation than patients with recurrence (mean [SD], 349.2 [108.0] nM vs 419.5 [110.5] nM, respectively; P<.001). Compared with patients who had thrombin generation greater than 400 nM, the relative risk (RR) of recurrence was 0.42 (95% confidence interval [CI], 0.26-0.67; P<.001) in patients with values between 400 nM and 300 nM; for patients with lower values, the RR was 0.37 (95% CI, 0.21-0.66; P = .001). After 4 years, the probability of recurrence was 6.5% (95% CI, 4.0%-8.9%) among patients with thrombin generation less than 400 nM compared with 20.0% (95% CI, 14.9%-25.1%) among patients with higher values (P<.001). Patients with thrombin generation less than 400 nM, representing two thirds of patients, had a 60% lower RR of recurrence than those with greater values (RR, 0.40; 95% CI, 0.27-0.60; P<.001).

Conclusion  Measurement of thrombin generation identifies patients at low risk for recurrent VTE.

Author Affiliations: Departments of Internal Medicine I (Drs Hron, Eichinger, and Kyrle and Ms Kollars) and Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology (Dr Binder), Medical University of Vienna, Austria.

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