Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma

E. Castoldi*, Paolo Simioni, D. Tormene, J. Rosing, T. M. Hackeng

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

56 Citations (Web of Science)

Abstract

Background: Protein S and tissue factor pathway inhibitor (TFPI) act together in down-regulating coagulation. Objective: To investigate the TFPI/protein S system in hereditary and acquired protein S deficiency. Methods: Plasma antigen levels of protein S and full-length TFPI were determined in heterozygous type I protein S-deficient individuals (n = 35), patients on oral anticoagulant treatment (OAT) (n = 29), oral contraceptive (OC) users (n = 10) and matched controls. Thrombin generation was determined using calibrated automated thrombography. Results: Full-length TFPI levels were lower in type I protein S-deficient individuals (76.8 +/- 33.8%) than in age-and sex-matched controls (128.0 +/- 59.4%, P <0.001). Among protein S-deficient individuals with thrombosis, those on OAT had not only lower total protein S levels (25.7 +/- 8.2% vs. 54.7 +/- 8.2%, P <0.001), but also lower full-length TFPI levels (52.6 +/- 15.0% vs. 75.4 +/- 22.9%, P = 0.009) than those not on OAT. Similarly, OC users had lower protein S (73.8 +/- 11.5% vs. 87.9 +/- 10.8%, P = 0.005) and full-length TFPI levels (73.7 +/- 27.7% vs. 106.4 +/- 29.2%, P = 0.007) than non-users. When triggered with tissue factor, plasma from protein S-deficient individuals generated 3-5-fold more thrombin than control plasma. The difference was only partially corrected by normalization of the protein S level, full correction requiring additional normalization of the TFPI level. Protein S-immunodepletion experiments indicated that free protein S and full-length TFPI form a complex in plasma, and the protein S/TFPI interaction was confirmed by surface plasmon resonance analysis. Conclusions: Full-length TFPI binds to protein S in plasma and is reduced in genetic and acquired protein S deficiency. The concomitant TFPI deficiency substantially contributes to the hypercoagulable state associated with protein S deficiency.
Original languageEnglish
Pages (from-to)294-300
JournalJournal of Thrombosis and Haemostasis
Volume8
Issue number2
DOIs
Publication statusPublished - Feb 2010

Keywords

  • oral anticoagulant therapy
  • oral contraceptives
  • protein S deficiency
  • TFPI
  • thrombosis

Cite this