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

• Published in: Haematologica (Roma) 2010-09, Vol.95 (9), p.1563-1571
• Main Authors: CASTOLDI, Elisabetta, MAURISSEN, Lisbeth F. A, TORMENE, Daniela, SPIEZIA, Luca, GAVASSO, Sabrina, RADU, Claudia, HACKENG, Tilman M, ROSING, Jan, SIMIONI, Paolo
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Disease-Free Survival; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Family; Female; Hematologic and hematopoietic diseases; Humans; Kaplan-Meier Estimate; Male; Medical sciences; Middle Aged; Original; Platelet diseases and coagulopathies; Protein S Deficiency - blood; Protein S Deficiency - classification; Protein S Deficiency - genetics; Thrombophilia - etiology; Thrombosis - etiology; Young Adult
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2010.021923

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. 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). 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. 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.