title: Decreased tissue factor pathway inhibitor (TFPI)-dependent anticoagulant capacity in patients with cirrhosis who have decreased protein S but normal TFPI plasma levels.
abstract: Protein S acts as a cofactor for tissue factor pathway inhibitor (TFPI) in the down regulation of thrombin generation, and acquired and congenital protein S deficiencies are associated with a concomitant TFPI deficiency. In contrast, in patients with liver diseases, decreased protein S, but normal or increased levels of TFPI have been reported. We compared TFPI and protein S plasma levels between 26 patients with cirrhosis and 20 healthy controls and found that TFPI levels were comparable between patients (111 ± 38%) and controls (108 ± 27%), despite reduced protein S levels (74 ± 23% in patients vs. 98 ± 10% in controls). Subsequently, we quantified the activity of the TFPI-protein S system by measuring thrombin generation in the absence and presence of neutralizing antibodies to protein S or TFPI. Ratios of peak thrombin generation in the absence and presence of these antibodies were calculated. Both the protein S and the TFPI ratios were increased in patients with cirrhosis compared to controls. Protein S ratios were (0·62 [0·08-0·93] in patients vs. 0·32 [0·20-0·54] in controls; TFPI ratios were 0·50 [0·05-0·90] in patients vs. 0·18 [0·11-0·49] in controls). Thus, although the acquired protein S deficiency in patients with cirrhosis is not associated with decreased TFPI levels, the TFPI/protein S anticoagulant system is functionally impaired.
authors.affiliation: Surgical Research Laboratory, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Wilma
authors.initials: W
authors.lastname: Potze
authors.forename: Freeha
authors.initials: F
authors.lastname: Arshad
authors.forename: Jelle
authors.initials: J
authors.lastname: Adelmeijer
authors.forename: Hans
authors.initials: H
authors.lastname: Blokzijl
authors.forename: Arie P
authors.initials: AP
authors.lastname: van den Berg
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Porte
authors.forename: Ton
authors.initials: T
authors.lastname: Lisman
mesh_terms: D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D008103:Liver Cirrhosis / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017293:Protein S / Q000378:metabolism*; D018455:Protein S Deficiency / Q000097:blood*; D013917:Thrombin / Q000378:metabolism*
chemical_list: D008074:Lipoproteins; D017293:Protein S; C051928:lipoprotein-associated coagulation inhibitor; D013917:Thrombin
keywords: cirrhosis; coagulation; protein S; thrombin generation; tissue factor pathway inhibitor