Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma.
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.
Castoldi
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E
Department of Biochemistry, CARIM, Maastricht University, Maastricht, the Netherlands. e.castoldi@bioch.unimaas.nl
Simioni
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Tormene
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Rosing
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Hackeng
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TM
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D016022:Case-Control Studies; D003276:Contraceptives, Oral / Q000009:adverse effects; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D017293:Protein S / Q000235:genetics / Q000378:metabolism*; D018455:Protein S Deficiency / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D012307:Risk Factors; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
D000925:Anticoagulants; D003276:Contraceptives, Oral; D008074:Lipoproteins; D017293:Protein S; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D013917:Thrombin