Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism

. Background: Inherited deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) are risk factors for venous thromboembolism (VTE). They are usually defined by laboratory cut-offs (in our setting 81, 70 and 63 IU dL-1, respectively), which give only a rough idea of the VTE risk associated with plasma levels of these proteins. Objectives: We investigated whether the risk of VTE associated with the plasma deficiencies of AT, PC or PS has a doseresponse effect, and whether low borderline levels of these proteins are associated with an increased risk of VTE, both in the whole study population and separately in carriers of either factor V Leiden or G20210A prothrombin gene mutation. Patients/Methods: A casecontrol study of 1401 patients with a first objectively-documented VTE and 1847 healthy controls has been carried out. Results: A doseresponse effect on the VTE risk was observed for all the three anticoagulant proteins. Compared with individuals with AT, PC or PS levels > 100 IU/dL, the adjusted odds ratio (95%CI) of VTE was 2.00 (1.442.78) for AT levels between 76 and 85 IUdL-1, 2.21 (1.543.18) and 1.84 (1.312.59) for PC and PS levels between 61 and 75 IUdL-1. The risk of unprovoked VTE in factor V Leiden or prothrombin G20210A carriers appears 2 to 3-fold increased when levels of AT or PS are low borderline. Conclusions: Low borderline plasma levels of AT, PC and PS are associated with a 2-fold increased risk of VTE and should be considered in the assessment of the individual VTE risk.