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. [email protected] 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]