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Protein C is a naturally occurring anticoagulant that modulates hemostasis. When it is bound to the soluble endothelial protein C receptor (EPCR), protein C is activated by the thrombin-thrombomodulin complex. Activated protein C cleaves activated factors V and VIII and inhibits further thrombin generation. Small amounts of activated protein C and EPCR are found in circulating blood. Recently, autoantibodies against EPCR (aEPCR) have been described, and researchers have suggested that the presence of such antibodies might be a risk factor for venous thromboembolism (VTE).
To examine the relation between aEPCR and VTE, investigators from the Leiden Thrombophilia Study, a European university-based study of risk factors for VTE, reported on 474 VTE patients and an equal number of age- and sex-matched controls. Levels of aEPCR were quantified with an enzyme-linked immunoassay and were characterized as isotypes IgG, IgA, and IgM. Blood samples were obtained from patients at least 6 months after VTE events. Participants also were tested for d-dimer and lupus anticoagulant (LAC). The investigators were able to detect aEPCR in more than 95% of all participants — both patients and controls. The IgG isotype was more prevalent in men than in women, and the level of IgA isotype was age-related, rising with advancing age. Levels of all isotypes were significantly higher in patients than in controls, and levels above the 90th percentile (as measured in control subjects) were associated with approximately twofold increased risk for deep-vein thrombosis. Risk for VTE increased in a dose-dependent fashion with rising levels of IgG and IgA isotypes (P<0.001 for trend).
The investigators examined whether the presence of aEPCR was simply another manifestation of the LAC/antiphospholipid antibody syndrome. They found that high titers of aEPCR often were present in people with LAC but that high-titer aEPCR was an independent risk factor for thrombosis. Patients with LAC plus high-titer aEPCR had an odds ratio for thrombosis of 6.1, compared with 2.4 for people with LAC plus low-titer aEPCR.
van Hylckama Vlieg A et al. Autoantibodies against endothelial protein C receptor and the risk of a first deep vein thrombosis. J Thromb Haemost 2007 Jul; 5:1449-54.
Comment
Autoantibodies against EPCR join a number of other factors that increase risk for VTE. These include mutations in the factor V and prothrombin genes; elevated levels of factors VIII, IX, and XI; decreased concentrations of proteins C and S and antithrombin; and presence of LAC. An unanswered question is why healthy people can have circulating antibodies to EPCR; however, the presence of autoantibodies in healthy people is not unprecedented (e.g., low titers of antiphospholipid antibodies often are detected). This research shows that aEPCR can be present independent of the LAC/antiphospholipid antibody syndrome. More research is needed to determine the relative predictive strengths of the identified factors, but an assay for aEPCR should be included in evaluation of risk for VTE.