Fibrinolysis in Patients with Liver Disease

Fien A. von Meijenfeldt; Ton Lisman

doi:10.1055/s-0040-1718924

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2021; 47(05): 601-609
DOI: 10.1055/s-0040-1718924

Review Article

Fibrinolysis in Patients with Liver Disease

Fien A. von Meijenfeldt

¹Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

,

Ton Lisman

¹Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

› Author Affiliations

Abstract

Patients with liver disease acquire complex changes in their hemostatic system. Historically, these patients were considered to have a bleeding tendency related, in part, to a hyperfibrinolytic state. However, studies using more modern fibrinolysis tests have questioned the presence of a hyperfibrinolytic state in patients with liver disease and its association with bleeding risk. It may be that the sickest patients with liver disease do have fibrinolytic abnormalities. However, the debate on the fibrinolytic state of patients with (decompensated) cirrhosis or critically ill liver disease is complicated by the fact that hypo- and hyperfibrinolysis have been poorly defined. This could, in part, be explained by the lack of reliable tests that assess a patient's fibrinolytic status. Moreover, large clinical studies on the relationship between bleeding and fibrinolysis in patients with liver disease are scarce. Here, we provide an overview of the current knowledge on fibrinolysis in various types of liver diseases and possible implications as a target for therapeutic strategies in liver disease. As antifibrinolytic therapy has been shown to be safe and effective during liver transplantation, it could potentially be of use in patients with (either laboratory-established or suspected) hyperfibrinolysis-related bleeding.

Keywords

liver disease - coagulation - fibrinolysis - cirrhosis - acute liver failure - acute-on-chronic liver failure - antifibrinolytic therapy - liver transplantation

Full Text

References

References
1 Lisman T, Leebeek FW, de Groot PG. Haemostatic abnormalities in patients with liver disease. J Hepatol 2002; 37 (02) 280-287
2 Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost 2017; 1 (02) 150-161
3 Ferro D, Quintarelli C, Lattuada A. et al. High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia. Hepatology 1996; 23 (06) 1377-1383
4 Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012; 129 (03) 290-295
5 van Deventer SJ, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76 (12) 2520-2526
6 Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrombocytopenia. J Clin Invest 1966; 45 (05) 645-657
7 Afdhal N, McHutchison J, Brown R. et al. Thrombocytopenia associated with chronic liver disease. J Hepatol 2008; 48 (06) 1000-1007
8 Bakker CM, Knot EA, Stibbe J, Wilson JH. Disseminated intravascular coagulation in liver cirrhosis. J Hepatol 1992; 15 (03) 330-335
9 Ferro D, Angelico F, Caldwell SH, Violi F. Bleeding and thrombosis in cirrhotic patients: what really matters?. Dig Liver Dis 2012; 44 (04) 275-279
10 Schepis F, Turco L, Bianchini M, Villa E. Prevention and management of bleeding risk related to invasive procedures in cirrhosis. Semin Liver Dis 2018; 38 (03) 215-229
11 Stravitz RT, Ellerbe C, Durkalski V. et al; Acute Liver Failure Study Group. Bleeding complications in acute liver failure. Hepatology 2018; 67 (05) 1931-1942
12 Massicotte L, Thibeault L, Roy A. Classical notions of coagulation revisited in relation with blood losses, transfusion rate for 700 consecutive liver transplantations. Semin Thromb Hemost 2015; 41 (05) 538-546
13 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (06) 878-885
14 Fisher C, Patel VC, Stoy SH. et al. Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure. J Crit Care 2018; 43: 54-60
15 Northup PG, McMahon MM, Ruhl AP. et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol 2006; 101 (07) 1524-1528 , quiz 1680
16 Goodpasture E. Fibrinolysis in chronic hepatic insufficiency. Johns Hopkins Hosp Bull 1914; 25: 330-336
17 Violi F, Ferro D, Basili S. et al. Hyperfibrinolysis increases the risk of gastrointestinal hemorrhage in patients with advanced cirrhosis. Hepatology 1992; 15 (04) 672-676
18 Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001; 345 (09) 669-681
19 Turon F, Casu S, Hernández-Gea V, Garcia-Pagán JC. Variceal and other portal hypertension related bleeding. Best Pract Res Clin Gastroenterol 2013; 27 (05) 649-664
20 Cerini F, Gonzalez JM, Torres F. et al. Impact of anticoagulation on upper-gastrointestinal bleeding in cirrhosis. A retrospective multicenter study. Hepatology 2015; 62 (02) 575-583
21 Intagliata NM, Henry ZH, Shah N, Lisman T, Caldwell SH, Northup PG. Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding. Liver Int 2014; 34 (01) 26-32
22 Jain S, Acharya SS. Inherited disorders of the fibrinolytic pathway. Transfus Apheresis Sci 2019; 58 (05) 572-577
23 Schuster V, Hügle B, Tefs K. Plasminogen deficiency. J Thromb Haemost 2007; 5 (12) 2315-2322
24 Kolev K, Longstaff C. Bleeding related to disturbed fibrinolysis. Br J Haematol 2016; 175 (01) 12-23
25 Franchini M, Mannucci PM. Primary hyperfibrinolysis: facts and fancies. Thromb Res 2018; 166: 71-75
26 Dietrich K, Ball GD, Mitchell LG. Increased plasminogen activator inhibitor results in a hypofibrinolytic state in adolescents with obesity: in vivo and ex vivo evidence. Br J Haematol 2016; 175 (02) 300-307
27 Yamamoto K, Takeshita K, Kojima T, Takamatsu J, Saito H. Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Cardiovasc Res 2005; 66 (02) 276-285
28 Meltzer ME, Lisman T, de Groot PG. et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116 (01) 113-121
29 Moore HB, Moore EE, Huebner BR. et al. Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity to tissue plasminogen activator. J Trauma Acute Care Surg 2017; 83 (06) 1014-1022
30 Kassis J, Hirsh J, Podor TJ. Evidence that postoperative fibrinolytic shutdown is mediated by plasma factors that stimulate endothelial cell type I plasminogen activator inhibitor biosynthesis. Blood 1992; 80 (07) 1758-1764
31 Pepperell D, Morel-Kopp M, Ward C. Clinical application of fibrinolytic assays. In: Kolev K. ed. InTech: Fibrinolysis and Thrombolysis. Rijeka, Croatia: InTechOpen; 2014: 125-162
32 Blasi A, Calvo A, Prado V. et al. Coagulation failure in patients with acute-on-chronic liver failure and decompensated cirrhosis: beyond the international normalized ratio. Hepatology 2018; 68 (06) 2325-2337
33 Moore HB, Moore EE, Gonzalez E. et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg 2014; 77 (06) 811-817 , discussion 817
34 Lisman T. Decreased fibrinolytic capacity in cirrhosis and liver transplantation outcomes. Liver Transpl 2019; 25 (03) 359-361
35 Kuiper GJ, Kleinegris MC, van Oerle R. et al. Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity. Thromb J 2016; 14: 1
36 Lisman T. Decreased plasma fibrinolytic potential as a risk for venous and arterial thrombosis. Semin Thromb Hemost 2017; 43 (02) 178-184
37 Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev 2015; 29 (01) 17-24
38 Johnson ED, Schell JC, Rodgers GM. The D-dimer assay. Am J Hematol 2019; 94 (07) 833-839
39 Lisman T, Leebeek FW, Mosnier LO. et al. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 2001; 121 (01) 131-139
40 Saes JL, Schols SEM, van Heerde WL, Nijziel MR. Hemorrhagic disorders of fibrinolysis: a clinical review. J Thromb Haemost 2018
41 Hrafnkelsdottir T, Gudnason T, Wall U, Jern C, Jern S. Regulation of local availability of active tissue-type plasminogen activator in vivo in man. J Thromb Haemost 2004; 2 (11) 1960-1968
42 Francis Jr RB, Feinstein DI. Clinical significance of accelerated fibrinolysis in liver disease. Haemostasis 1984; 14 (06) 460-465
43 Hu KQ, Yu AS, Tiyyagura L, Redeker AG, Reynolds TB. Hyperfibrinolytic activity in hospitalized cirrhotic patients in a referral liver unit. Am J Gastroenterol 2001; 96 (05) 1581-1586
44 Leebeek FW, Kluft C, Knot EA, de Maat MP, Wilson JH. A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis. Gastroenterology 1991; 101 (05) 1382-1390
45 Mizuno A, Isobe J, Shima K. Simplification of a venous occlusion test. Thromb Res 1991; 62 (1-2): 83-92
46 Tornai I, Hársfalvi J, Boda Z, Udvardy M, Pfliegler G, Rak K. Endothelium releases more von Willebrand factor and tissue-type plasminogen activator upon venous occlusion in patients with liver cirrhosis than in normals. Haemostasis 1993; 23 (01) 58-64
47 Fletcher AP, Biederman O, Moore D, Alkjaersig N, Sherry S. Abnormal plasminogen-plasmin system activity (fibrinolysis) in patients with hepatic cirrhosis: its cause and consequences. J Clin Invest 1964; 43 (04) 681-695
48 Kwaan HC, McFadzean AJS, Cook J. On plasma fibrinolytic activity in cryptogenetic splenomegaly. Scott Med J 1957; 2 (04) 137-150
49 Das PC, Cash JD. Fibrinolysis at rest and after exercise in hepatic cirrhosis. Br J Haematol 1969; 17 (05) 431-443
50 Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T. Fibrinolysis and the risk of venous and arterial thrombosis. Curr Opin Hematol 2007; 14 (03) 242-248
51 Rijken DC, Kock EL, Guimarães AH. et al. Evidence for an enhanced fibrinolytic capacity in cirrhosis as measured with two different global fibrinolysis tests. J Thromb Haemost 2012; 10 (10) 2116-2122
52 Colucci M, Binetti BM, Branca MG. et al. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 2003; 38 (01) 230-237
53 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
54 Bos S, van den Boom B, Kamphuisen PW. et al. Haemostatic profiles are similar across all aetiologies of cirrhosis. Thromb Haemost 2019; 119 (02) 246-253
55 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
56 Krzanicki D, Sugavanam A, Mallett S. Intraoperative hypercoagulability during liver transplantation as demonstrated by thromboelastography. Liver Transpl 2013; 19 (08) 852-861
57 Boks AL, Brommer EJ, Schalm SW, Van Vliet HH. Hemostasis and fibrinolysis in severe liver failure and their relation to hemorrhage. Hepatology 1986; 6 (01) 79-86
58 Joist JH. AICF and DIC in liver cirrhosis: expressions of a hypercoagulable state. Am J Gastroenterol 1999; 94 (10) 2801-2803
59 O'Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA clinical practice update: Coagulation in cirrhosis. Gastroenterology 2019; 157 (01) 34-43.e1
60 Drolz A, Horvatits T, Roedl K. et al. Coagulation parameters and major bleeding in critically ill patients with cirrhosis. Hepatology 2016; 64 (02) 556-568
61 Cho J, Choi SM, Yu SJ. et al. Bleeding complications in critically ill patients with liver cirrhosis. Korean J Intern Med (Korean Assoc Intern Med) 2016; 31 (02) 288-295
62 Blasi A, Patel VC, Adelmeijer J. et al. Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival. Hepatology 2020; 71 (04) 1381-1390
63 Lisman T, Bakhtiari K, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure. J Thromb Haemost 2012; 10 (07) 1312-1319
64 Driever EG, Stravitz RT, Zhanf J. et al. VWF/ADAMTS13 imbalance, but not global coagulation or fibrinolysis, is associated with outcome and bleeding in acute liver failure. Hepatology 2020. DOI: 10.1002/hep.31507
65 Ganey PE, Luyendyk JP, Newport SW. et al. Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice. Hepatology 2007; 46 (04) 1177-1186
66 Villa E, Cammà C, Marietta M. et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143 (05) 1253-1260.e4
67 Sullivan BP, Kassel KM, Jone A, Flick MJ, Luyendyk JP. Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury. Am J Pathol 2012; 180 (06) 2321-2329
68 Pant A, Kopec AK, Baker KS, Cline-Fedewa H, Lawrence DA, Luyendyk JP. Plasminogen activator inhibitor-1 reduces tissue-type plasminogen activator-dependent fibrinolysis and intrahepatic hemorrhage in experimental acetaminophen overdose. Am J Pathol 2018; 188 (05) 1204-1212
69 Porte RJ, Bontempo FA, Knot EA, Lewis JH, Kang YG, Starzl TE. Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation. Transplantation 1989; 47 (06) 978-984
70 Dzik WH, Arkin CF, Jenkins RL, Stump DC. Fibrinolysis during liver transplantation in humans: role of tissue-type plasminogen activator. Blood 1988; 71 (04) 1090-1095
71 Porte RJ, Molenaar IQ, Begliomini B. et al; EMSALT Study Group. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. Lancet 2000; 355 (9212): 1303-1309
72 Molenaar IQ, Warnaar N, Groen H, Tenvergert EM, Slooff MJ, Porte RJ. Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2007; 7 (01) 185-194
73 Fergusson DA, Hébert PC, Mazer CD. et al; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358 (22) 2319-2331
74 Arshad F. Pathophysiology and management of hemostatic alterations in cirrhosis and liver transplantation. Groningen: Rijksuniversiteit Groningen; 2016
75 Schofield N, Sugavanam A, Thompson K, Mallett SV. No increase in blood transfusions during liver transplantation since the withdrawal of aprotinin. Liver Transpl 2014; 20 (05) 584-590
76 Heijdra JM, Cnossen MH, Leebeek FWG. Current and emerging options for the management of inherited von willebrand disease. Drugs 2017; 77 (14) 1531-1547
77 Roberts I, Shakur-Still H, Afolabi A. et al; HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020; 395 (10241): 1927-1936
78 Roberts I, Shakur H, Coats T. et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess 2013; 17 (10) 1-79
79 WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 2017; 389 (10084): 2105-2116
80 Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2014; 2014 (11) CD006640
81 Twum-Barimah E, Abdelgadir I, Gordon M, Akobeng AK. Systematic review with meta-analysis: the efficacy of tranexamic acid in upper gastrointestinal bleeding. Aliment Pharmacol Ther 2020; 51 (11) 1004-1013
82 Warnaar N, Lisman T, Porte RJ. The two tales of coagulation in liver transplantation. Curr Opin Organ Transplant 2008; 13 (03) 298-303