Download PDF
Thromb Haemost 2019; 119(02): 246-253
DOI: 10.1055/s-0038-1676954
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Haemostatic Profiles are Similar across All Aetiologies of Cirrhosis

Sarah Bos
1   Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2   Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Bente van den Boom
1   Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Pieter W. Kamphuisen
3   Department of Internal Medicine, Tergooi Hospital, Hilversum, The Netherlands
4   University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Jelle Adelmeijer
1   Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Hans Blokzijl
2   Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Tim Schreuder
2   Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Ton Lisman
1   Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
› Author Affiliations Funding This study was funded in part by the Tekke Huizinga Foundation (The Netherlands).
Further Information

Publication History

28 September 2018

15 November 2018

Publication Date:
04 January 2019 (online)

Also available at
    Permissions and Reprints

Abstract

Background and Aim Patients with cirrhosis may acquire profound changes in haemostasis. Although haemostatic changes in cirrhosis have been extensively studied, most studies were performed in groups of patients with mixed aetiology. As thrombotic events appear more common in some aetiologies of disease, notably non-alcoholic steatohepatitis (NASH) and cholestatic disease, we hypothesized that haemostatic changes might be different across aetiologies.

Patients and Methods We studied 109 patients with cirrhosis (31 cholestatic liver disease, 23 NASH, 37 alcoholic liver disease [ALD], 18 viral hepatitis) and 44 healthy controls. Patients with malignancy were excluded. Routine diagnostic tests of haemostasis, thrombin generation assays, fibrin permeability assays and a plasma-based fibrinolytic assay were performed.

Results All patients had comparable severity of disease according to their Model for End-Stage Liver Disease score (9 [7–11]). Plasma levels of von Willebrand factor were substantially elevated across all aetiologies, with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 levels comparable to controls. Thrombin generation capacity was elevated in all aetiologies, most profoundly in ALD. Fibrin permeability was decreased in all aetiologies, which was accompanied by elevated fibrinogen levels. Clot lysis times were prolonged in NASH and cholestatic disease. Plasma levels of individual proteins were similarly altered in all aetiologies.

Conclusion Our in-depth haemostatic profiling of primary, secondary and tertiary haemostasis in a group of patients with Childs–Turcotte–Pugh A/B cirrhosis showed no large differences between aetiologies, and was consistent with a general hypercoagulable profile in patients with mild cirrhosis. These results suggest that patients with cirrhosis have an increased risk of thrombosis, irrespective of their aetiology.

Keywords

cirrhosis - haemostasis - thrombosis - aetiology
 

  • References

  • 1 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (02) 147-156
    CrossrefPubMedSearch in Google Scholar
  • 2 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (06) 878-885
    CrossrefPubMedSearch in Google Scholar
  • 3 Lisman T, Bongers TN, Adelmeijer J. , et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44 (01) 53-61
    CrossrefPubMedSearch in Google Scholar
  • 4 Hernández Conde M, Llop Herrera E, de la Revilla Negro J. , et al. Prevalence and outcome of portal thrombosis in a cohort of cirrhotic patients undergoing liver transplantation. Rev Esp Enferm Dig 2016; 108 (11) 716-720
    PubMedSearch in Google Scholar
  • 5 Aldawood A, Arabi Y, Aljumah A. , et al. The incidence of venous thromboembolism and practice of deep venous thrombosis prophylaxis in hospitalized cirrhotic patients. Thromb J 2011; 9 (01) 1
    CrossrefPubMedSearch in Google Scholar
  • 6 Groeneveld D, Porte RJ, Lisman T. Thrombomodulin-modified thrombin generation testing detects a hypercoagulable state in patients with cirrhosis regardless of the exact experimental conditions. Thromb Res 2014; 134 (03) 753-756
    CrossrefPubMedSearch in Google Scholar
  • 7 Tripodi A, Salerno F, Chantarangkul V. , et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41 (03) 553-558
    CrossrefPubMedSearch in Google Scholar
  • 8 Gatt A, Riddell A, Calvaruso V, Tuddenham EG, Makris M, Burroughs AK. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost 2010; 8 (09) 1994-2000
    CrossrefPubMedSearch in Google Scholar
  • 9 Kleinegris MC, Habets CAM, Van De Sande AJP. , et al. Liver cirrhosis is associated with hypercoagulability, decreased clot strength and normal fibrinolysis. J Thromb Haemost 2013; 11 (May): 49-50
    PubMedSearch in Google Scholar
  • 10 Vinholt PJ, Alnor AB, Nybo M, Hvas A-M. The primary haemostasis is more preserved in thrombocytopenic patients with liver cirrhosis than cancer. Blood Coagul Fibrinolysis 2018; 29 (03) 307-313
    CrossrefPubMedSearch in Google Scholar
  • 11 Krzanicki D, Sugavanam A, Mallett S. Intraoperative hypercoagulability during liver transplantation as demonstrated by thromboelastography. Liver Transpl 2013; 19 (08) 852-861
    CrossrefPubMedSearch in Google Scholar
  • 12 Pihusch R, Rank A, Göhring P, Pihusch M, Hiller E, Beuers U. Platelet function rather than plasmatic coagulation explains hypercoagulable state in cholestatic liver disease. J Hepatol 2002; 37 (05) 548-555
    CrossrefPubMedSearch in Google Scholar
  • 13 Ben-Ari Z, Panagou M, Patch D. , et al. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J Hepatol 1997; 26 (03) 554-559
    CrossrefPubMedSearch in Google Scholar
  • 14 Hugenholtz GCG, Lisman T, Stravitz RT. Thromboelastography does not predict outcome in different etiologies of cirrhosis. Res Pract Thromb Haemost 2017; 1 (02) 275-285
    CrossrefPubMedSearch in Google Scholar
  • 15 Potze W, Siddiqui MS, Boyett SL. , et al. Preserved hemostatic status in patients with non-alcoholic fatty liver disease. J Hepatol 2016; 65 (05) 980-987
    CrossrefPubMedSearch in Google Scholar
  • 16 Stine JG, Niccum BA, Zimmet AN. , et al. Increased risk of venous thromboembolism in hospitalized patients with cirrhosis due to non-alcoholic steatohepatitis. Clin Transl Gastroenterol 2018; 9 (03) 140
    CrossrefPubMedSearch in Google Scholar
  • 17 Stine JG, Argo CK, Pelletier SJ, Maluf DG, Caldwell SH, Northup PG. Advanced non-alcoholic steatohepatitis cirrhosis: a high-risk population for pre-liver transplant portal vein thrombosis. World J Hepatol 2017; 9 (03) 139-146
    CrossrefPubMedSearch in Google Scholar
  • 18 Hemker HC, Giesen P, Al Dieri R. , et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (01) 4-15
    CrossrefPubMedSearch in Google Scholar
  • 19 Lisman T, de Groot PG, Meijers JCM, Rosendaal FR. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 2005; 105 (03) 1102-1105
    CrossrefPubMedSearch in Google Scholar
  • 20 Ariëns RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96 (03) 988-995
    CrossrefPubMedSearch in Google Scholar
  • 21 Lim BCB, Ariëns RAS, Carter AM, Weisel JW, Grant PJ. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet 2003; 361 (9367): 1424-1431
    CrossrefPubMedSearch in Google Scholar
  • 22 Groeneveld DJ, Adelmeijer J, Hugenholtz GCG, Ariëns RAS, Porte RJ, Lisman T. Ex vivo addition of fibrinogen concentrate improves the fibrin network structure in plasma samples taken during liver transplantation. J Thromb Haemost 2015; 13 (12) 2192-2201
    CrossrefPubMedSearch in Google Scholar
  • 23 Kokame K, Nobe Y, Kokubo Y, Okayama A, Miyata T. FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol 2005; 129 (01) 93-100
    CrossrefPubMedSearch in Google Scholar
  • 24 Eckmann CM, De Laaf RTM, Van Keulen JM, Van Mourik JA, De Laat B. Bilirubin oxidase as a solution for the interference of hyperbilirubinemia with ADAMTS-13 activity measurement by FRETS-VWF73 assay. J Thromb Haemost 2007; 5 (06) 1330-1331
    CrossrefPubMedSearch in Google Scholar
  • 25 Kuboki S, Shimizu H, Ohtsuka M. , et al. Incidence, risk factors, and management options for portal vein thrombosis after hepatectomy: a 14-year, single-center experience. Am J Surg 2015; 210 (05) 878-85.e2
    CrossrefPubMedSearch in Google Scholar
  • 26 Emuakhagbon V, Philips P, Agopian V, Kaldas FM, Jones CM. Incidence and risk factors for deep venous thrombosis and pulmonary embolus after liver transplantation. Am J Surg 2016; 211 (04) 768-771
    CrossrefPubMedSearch in Google Scholar
  • 27 Zhou W, Inada M, Lee T-P. , et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest 2005; 85 (06) 780-788
    PubMedSearch in Google Scholar
  • 28 Uemura M, Tatsumi K, Matsumoto M. , et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood 2005; 106 (03) 922-924
    CrossrefPubMedSearch in Google Scholar
  • 29 Russo FP, Zanetto A, Campello E. , et al. Reversal of hypercoagulability in patients with HCV-related cirrhosis after treatment with direct-acting antivirals. Liver Int 2018; 38 (12) 2210-2218
    CrossrefPubMedSearch in Google Scholar
  • 30 Sinegre T, Duron C, Lecompte T. , et al. Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis. J Thromb Haemost 2018; 16 (06) 1132-1140
    CrossrefPubMedSearch in Google Scholar
  • 31 Lebreton A, Sinegre T, Pereira B, Lamblin G, Duron C, Abergel A. Plasma hypercoagulability in the presence of thrombomodulin but not of activated protein C in patients with cirrhosis. J Gastroenterol Hepatol 2017; 32 (04) 916-924
    CrossrefPubMedSearch in Google Scholar
  • 32 Lisman T, Kamphuisen PW, Northup PG, Porte RJ. Established and new-generation antithrombotic drugs in patients with cirrhosis - possibilities and caveats. J Hepatol 2013; 59 (02) 358-366
    CrossrefPubMedSearch in Google Scholar
  • 33 Violi F, Ferro D, Quintarelli C. , et al. Dilute aPTT prolongation by antiphospholipid antibodies in patients with liver cirrhosis. Thromb Haemost 1990; 63 (02) 183-186
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Quintarelli C, Ferro D, Valesini G, Basili S, Tassone G, Violi F. Prevalence of lupus anticoagulant in patients with cirrhosis: relationship with beta-2-glycoprotein I plasma levels. J Hepatol 1994; 21 (06) 1086-1091
    CrossrefPubMedSearch in Google Scholar
  • 35 Lisman T, Ariëns RAS. Alterations in fibrin structure in patients with liver diseases. Semin Thromb Hemost 2016; 42 (04) 389-396
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Goodpasture EW. Fibrinolysis in chronic hepatic insufficiency. Johns Hopkins Hosp Bull 1914; 25: 330-336
    PubMedSearch in Google Scholar
  • 37 Lisman T, Kleiss S, Patel VC. , et al. In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis. Liver Int 2018; 38 (11) 1988-1996
    CrossrefPubMedSearch in Google Scholar