Decreased tissue factor pathway inhibitor (TFPI)-dependent anticoagulant capacity in patients with cirrhosis who have decreased protein S but normal TFPI plasma levels

Br J Haematol. 2013 Sep;162(6):819-26. doi: 10.1111/bjh.12462. Epub 2013 Jul 11.


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.

Keywords: cirrhosis; coagulation; protein S; thrombin generation; tissue factor pathway inhibitor.

MeSH terms

  • Case-Control Studies
  • Female
  • Humans
  • Lipoproteins / blood*
  • Lipoproteins / deficiency
  • Lipoproteins / genetics
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / genetics
  • Male
  • Middle Aged
  • Protein S / metabolism*
  • Protein S Deficiency / blood*
  • Thrombin / metabolism*


  • Lipoproteins
  • Protein S
  • lipoprotein-associated coagulation inhibitor
  • Thrombin