Cleaved Protein S (PS), Total PS, Free PS, and Activated Protein C Cofactor Activity as Risk Factors for Venous Thromboembolism

Abstract

Background: Although hereditary protein S (PS) deficiency is clearly associated with venous thromboembolism (VTE), the importance of low PS concentrations as a risk factor for VTE in other patients is still a matter of debate. To clarify this issue, we designed a case-control study to evaluate the role of different molecular forms of plasma PS. Methods: We quantified plasma cleaved, total, and free PS and activated protein C (APC) cofactor activity in 87 VTE patients and 174 controls matched for age, sex, and hormonal treatment. Free PS was measured by ELISA or by enzyme-linked ligand sorbent assay (ELSA). Cleaved and total PS were measured by ELISA. Results: In controls, the mean (SD) concentration of circulating cleaved PS was 39 (14) nmol/L, corresponding to 10% (3.5%) of total PS. Concentrations of cleaved PS and total PS were not significantly different in patients with VTE compared with controls. However, in our population, low free PS measured by ELISA or ELSA, as well as APC cofactor activity values were significantly associated with VTE with odds ratios (95% confidence intervals) of 2.9 (1.3-6.3), 2.5 (1.1-5.6), and 2.9 (1.3-6.4), respectively, in multivariate analyses. Conclusion: Phenotypic low PS detected by APC cofactor activity assay or by an assay specific for free PS should be considered a risk factor for VTE.

Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies

“…The average portion of cleaved protein S that we observed (ǠFig. 1) in our Dutch population of 106 healthy control subjects (25 ± 8%), is more than twice as high as the 10% reported by Borgel et al (26). The cause of this apparent discrepancy is unclear, but it might be a methodological issue.…”

Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency

“…This type of PS deficiency is often, but not always, 16 associated with the PROS1 Ser 460 →Pro (Heerlen) mutation. 17 Although PS deficiency and, particularly, low levels of free PS 18,19 are an established risk factor for venous thrombosis, risk estimates differ widely among studies, possibly reflecting the different severity of the underlying molecular defects. 20 Moreover, the few epidemiological studies that distinguish between type I and type III deficiencies are rather contradictory with respect to the risk of thrombosis associated with type III deficiency, which was found to be none, 21 the same as in type I deficiency 22 or intermediate.…”

Genetic correlation between plasma levels of C4BP isoforms containing chains and susceptibility to thrombosis

“…The risk of thrombosis associated with PS deficiency is a controversial issue. [31][32][33][34] In this respect, it should be remembered that because the GAIT Project attempted to identify genetic factors underlying idiopathic thrombophilia, PS deficient families were excluded from the sample. 6 16 This explains the lack of correlations among the PS plasma phenotypes and the thrombotic liability in the present study.…”