Similar hypercoagulable state and thrombosis risk in type I and type III proteinS-deficient individuals from mixed type I/III families.

Haematologica. 2010 Sep;95(9):1563-71. Epub 2010 Apr 26. 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. Castoldi E, Maurissen LF, Tormene D, Spiezia L, Gavasso S, Radu C, Hackeng TM, Rosing J, Simioni P. Department of Biochemistry, Maastricht University P.O. Box 616, 6200 Maastricht, The Netherlands. e.castoldi@bioch.unimaas.nl BACKGROUND: Protein S, which circulates in plasma in both free and bound forms, is an anticoagulant protein that stimulates activated protein C and tissue factor pathway inhibitor. Hereditary type I protein S deficiency (low total and low free protein S) is a well-established risk factor for venous thrombosis, whereas the thrombosis risk associated with type III deficiency (normal total and low free protein S) has been questioned. DESIGN AND METHODS: Kaplan-Meier analysis was performed on 242 individuals from 30 families with protein S deficiency. Subjects were classified as normal, or having type I or type III deficiency according to their total and free protein S levels. Genetic and functional studies were performed in 23 families (132 individuals). RESULTS: Thrombosis-free survival was not different between type I and type III protein S-deficient individuals. Type III deficient individuals were older and had higher protein S, tissue factor pathway inhibitor and prothrombin levels than type I deficient individuals. Thrombin generation assays sensitive to the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S revealed similar hypercoagulable states in type I and type III protein S-deficient plasma. Twelve PROS1 mutations and two large deletions were identified in the genetically characterized families. CONCLUSIONS: Not only type I, but also type III protein S deficiency is associated with a hypercoagulable state and increased risk of thrombosis. These findings may, however, be restricted to type III deficient individuals from families with mixed type I/III protein S deficiency, as these represented 80% of type III deficient individuals in our cohort. PMCID: PMC2930959 PMID: 20421270 [PubMed - in process]