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Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis

  • Armando Tripodi
    Correspondence
    Corresponding author. Address: Via Pace 9, 20122 Milano, Italy. Tel.: +39 02 503 20725; fax: +39 02 503 20723.
    Affiliations
    Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy

    IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
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  • Massimo Primignani
    Affiliations
    First Division of Gastroenterology, IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy

    IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
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  • Laura Lemma
    Affiliations
    Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy

    IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
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  • Veena Chantarangkul
    Affiliations
    Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy

    IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
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  • Pier Mannuccio Mannucci
    Affiliations
    Scientific Direction, IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy

    IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
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Published:April 12, 2013DOI:https://doi.org/10.1016/j.jhep.2013.03.036

      Background & Aims

      Cirrhosis is associated with a plasmatic procoagulant imbalance, detected in vitro by thrombin generation tests performed in the presence vs. absence of such activators of protein C as thrombomodulin or Protac®. This imbalance is thought to be due to decreased protein C and increased factor VIII, but this has never been directly demonstrated. To test this hypothesis we analyzed plasma from 50 patients with cirrhosis before and after in vitro addition of purified protein C meant to restore normal levels.

      Methods

      Results for two thrombin generation assays were expressed as ratios of endogenous thrombin potential (ETP) with-to-without thrombomodulin or as Protac®-induced coagulation inhibition (PICI%). By definition, high ETP ratios or low PICI% reflect a resistance to the anticoagulant action of thrombomodulin or Protac®, respectively, and can be taken as indexes of in vitro procoagulant imbalance.

      Results

      The median (range) protein C level before addition was 40% (4–101%) and increased to 156% (110–305) after addition (p <0.001). The procoagulant imbalance, which was high before protein C addition [ETP ratio = 0.83 (0.44–1.00)], was reduced after addition [ETP ratio = 0.60 (0.14–0.84)], p <0.001. ETP-ratios were inversely correlated with protein C activity (rho = –0.46, p <0.001). Similar results were obtained with the Protac® assay.

      Conclusions

      The results provide evidence that low protein C contributes to the procoagulant imbalance in plasma from patients with cirrhosis. The findings may have clinical implications for the treatment or prophylaxis of thrombosis in these patients.

      Abbreviations:

      PICI (Protac®-induced-coagulation inhibition), ETP (endogenous thrombin potential)

      Keywords

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