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

Elisabetta Castoldi*, Lisbeth F. A. Maurissen, Daniela Tormene, Luca Spiezia, Sabrina Gavasso, Claudia M. Radu, Tilman M. Hackeng, Jan Rosing, Paolo Simioni

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.
Original languageEnglish
Pages (from-to)1563-1571
JournalHaematologica-the Hematology Journal
Volume95
Issue number9
DOIs
Publication statusPublished - Sep 2010

Keywords

  • protein S
  • Kaplan-Meier analysis
  • activated protein C
  • tissue factor pathway inhibitor
  • thrombin generation

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