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Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma
Author(s) -
CASTOLDI E.,
SIMIONI P.,
TORMENE D.,
ROSING J.,
HACKENG T. M.
Publication year - 2010
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2009.03712.x
Subject(s) - tissue factor pathway inhibitor , protein s , protein c , thrombin generation , medicine , endocrinology , tissue factor , protein s deficiency , thrombin , coagulation , blood proteins , thromboplastin , platelet
Summary. 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.