Molecular diversity and thrombotic risk in protein S deficiency: The PROSIT study

Eugenia Biguzzi, Cristina Razzari, David A. Lane, Giancarlo Castaman, Antonio Cappellari, Paolo Bucciarelli, Gessica Fontana, Maurizio Margaglione, Giovanna D'Andrea, Rachel E. Simmonds, Suely M. Rezende, Roger Preston, Domenico Prisco, Elena M. Faioni, G. Finazzi, C. Legnani, F. Iannaccaro, A. Rogolino, M. Mori, U. ArmaniE. Rossi, V. Brancaccio, M. L. Papa, M. De Caterina, L. Castori, M. Berrettini, V. De Stefano, F. Faillace, G. Barillari, G. Lippi

Research output: Contribution to journalArticlepeer-review

Abstract

The Protein S Italian Team (PROSIT) enrolled 79 protein S (PS) deficient families and found 38 PROS1 variations (19 novel) in 53 probands. Of these, 23 variants were selected for expression in vitro, to evaluate their role as possible causative variants. Transient expression showed high secretion levels (> 75%) for three variants, which were considered neutral. Seven missense and five nonsense variants showed low (≤ 11%) expression levels and were classified as severe defects. Intermediate expression was observed for eight variants, which were evaluated by factor Va inactivation assay in order to be globally classified as severe or intermediate. Based on the cumulative data, the hazard ratio associated with causative variants was 4.9 (95% CI: 1.4-17.7) for deep vein thrombosis and/or pulmonary embolism, 5.1 (95% CI: 1.1-23.9) for superficial thrombophlebitis, and 4.8 (95% CI: 1.8-13.0) for any venous thrombosis. The hazard ratio for deep vein thrombosis and/or pulmonary embolism in carriers of severe defects only was 7.4 (95% CI: 1.6-24.1). PROSIT showed that dysfunctional variants causing PS deficiency are more common than expected and confirmed that PS deficiency is associated with increased thrombotic risk, although risk assessment is complicated by molecular heterogeneity.

Original languageEnglish
Pages (from-to)259-269
Number of pages11
JournalHuman Mutation
Volume25
Issue number3
DOIs
Publication statusPublished - 2005

Keywords

  • Expression studies
  • PROS1
  • Protein S
  • Thrombophilia
  • Thrombotic risk

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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