Role of Fibrin(ogen) in Progression of Liver Disease: Guilt by Association?

Abstract

Strong experimental evidence indicates that components of the hemostatic system, including thrombin, exacerbate diverse features of experimental liver disease. Clinical studies have also begun to address this connection and some studies have suggested that anticoagulants can improve outcome in patients with liver disease. Among the evidence of coagulation cascade activation in models of liver injury and disease is the frequent observation of thrombin-driven hepatic fibrin(ogen) deposition. Indeed, hepatic fibrin(ogen) deposition has long been recognized as a consequence of hepatic injury. Although commonly inferred as pathologic due to protective effects of anticoagulants in mouse models, the role of fibrin(ogen) in acute liver injury and chronic liver disease may not be universally detrimental. The localization of hepatic fibrin(ogen) deposits within the liver is connected to the disease stimulus and in animal models of liver toxicity and chronic disease, fibrin(ogen) deposition may not always be synonymous with large vessel thrombosis. Here, we provide a balanced review of the experimental evidence supporting a direct connection between fibrin(ogen) and liver injury/disease pathogenesis, and suggest a path forward bridging experimental and clinical research to improve our knowledge on the nature and function of fibrin(ogen) in liver disease.

Keywords

fibrin - fibrinogen - liver - coagulation

• References

• 1 Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol 2011; 35 (8–9) 526-533
• 2 Ganey PE, Luyendyk JP, Newport SW , et al. Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice. Hepatology 2007; 46 (4) 1177-1186
• 3 Intagliata NM, Northup PG. Anticoagulant therapy in patients with cirrhosis. Semin Thromb Hemost 2015; 41 (5) 514-519
• 4 Lisman T, Leebeek FW. Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment. Dig Surg 2007; 24 (4) 250-258
• 5 Whipple GH, Hurwitz SH. Fibrinogen of the blood as influenced by the liver necrosis of chloroform poisoning. J Exp Med 1911; 13 (1) 136-161
• 6 Rake MO, Flute PT, Shilkin KB, Williams R. Intravascular coagulation in acute hepatic necrosis: clinical and experimental studies into the deposition of microthrombi and the effect of treatment. Gut 1971; 12 (10) 868-869
• 7 Neubauer K, Knittel T, Armbrust T, Ramadori G. Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver injury. Gastroenterology 1995; 108 (4) 1124-1135
• 8 Fujiwara K, Ogata I, Ohta Y , et al. Intravascular coagulation in acute liver failure in rats and its treatment with antithrombin III. Gut 1988; 29 (8) 1103-1108
• 9 Luyendyk JP, Cantor GH, Kirchhofer D, Mackman N, Copple BL, Wang R. Tissue factor-dependent coagulation contributes to alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice. Am J Physiol Gastrointest Liver Physiol 2009; 296 (4) G840-G849
• 10 Weerasinghe SV, Moons DS, Altshuler PJ, Shah YM, Omary MB. Fibrinogen-γ proteolysis and solubility dynamics during apoptotic mouse liver injury: heparin prevents and treats liver damage. Hepatology 2011; 53 (4) 1323-1332
• 11 Lopez M, Kopec AK, Joshi N , et al. Fas-induced apoptosis increases hepatocyte tissue factor procoagulant activity in vitro and in vivo. Toxicol Sci 2014; 141 (2) 453-464
• 12 Hewett JA, Roth RA. The coagulation system, but not circulating fibrinogen, contributes to liver injury in rats exposed to lipopolysaccharide from gram-negative bacteria. J Pharmacol Exp Ther 1995; 272 (1) 53-62
• 13 Beier JI, Arteel GE. Alcoholic liver disease and the potential role of plasminogen activator inhibitor-1 and fibrin metabolism. Exp Biol Med (Maywood) 2012; 237 (1) 1-9
• 14 Copple BL, Roth RA, Ganey PE. Anticoagulation and inhibition of nitric oxide synthase influence hepatic hypoxia after monocrotaline exposure. Toxicology 2006; 225 (2–3) 128-137
• 15 Okajima K, Harada N, Kushimoto S, Uchiba M. Role of microthrombus formation in the development of ischemia/reperfusion-induced liver injury in rats. Thromb Haemost 2002; 88 (3) 473-480
• 16 Bergheim I, Guo L, Davis MA, Duveau I, Arteel GE. Critical role of plasminogen activator inhibitor-1 in cholestatic liver injury and fibrosis. J Pharmacol Exp Ther 2006; 316 (2) 592-600
• 17 Wang H, Vohra BP, Zhang Y, Heuckeroth RO. Transcriptional profiling after bile duct ligation identifies PAI-1 as a contributor to cholestatic injury in mice. Hepatology 2005; 42 (5) 1099-1108
• 18 Schabbauer G, Tencati M, Pedersen B, Pawlinski R, Mackman N. PI3K-Akt pathway suppresses coagulation and inflammation in endotoxemic mice. Arterioscler Thromb Vasc Biol 2004; 24 (10) 1963-1969
• 19 Beier JI, Luyendyk JP, Guo L, von Montfort C, Staunton DE, Arteel GE. Fibrin accumulation plays a critical role in the sensitization to lipopolysaccharide-induced liver injury caused by ethanol in mice. Hepatology 2009; 49 (5) 1545-1553
• 20 Miyakawa K, Joshi N, Sullivan BP , et al. Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice. Blood 2015; 126 (15) 1835-1843
• 21 Liu W, Pitcher DE, Morris SL , et al. Differential effects of heparin on the early and late phases of hepatic ischemia and reperfusion injury in the pig. Shock 1999; 12 (2) 134-138
• 22 Pearson JM, Schultze AE, Schwartz KA, Scott MA, Davis JM, Roth RA. The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat. J Pharmacol Exp Ther 1996; 278 (1) 378-383
• 23 Luyendyk JP, Copple BL, Barton CC, Ganey PE, Roth RA. Augmentation of aflatoxin B1 hepatotoxicity by endotoxin: involvement of endothelium and the coagulation system. Toxicol Sci 2003; 72 (1) 171-181
• 24 Lisman T, Porte RJ. The role of platelets in liver inflammation and regeneration. Semin Thromb Hemost 2010; 36 (2) 170-174
• 25 Harada N, Okajima K, Uchiba M. Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion-induced liver injury in rats. Crit Care Med 2006; 34 (7) 1883-1891
• 26 Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K. Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood 1999; 93 (1) 157-164
• 27 Liu A, Fang H, Yang Y , et al. The fibrin-derived peptide bβ15-42 attenuates liver damage in a rat model of liver ischemia/reperfusion injury. Shock 2013; 39 (4) 397-403
• 28 Sörensen-Zender I, Rong S, Susnik N , et al. Role of fibrinogen in acute ischemic kidney injury. Am J Physiol Renal Physiol 2013; 305 (5) F777-F785
• 29 Erlich JH, Boyle EM, Labriola J , et al. Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation. Am J Pathol 2000; 157 (6) 1849-1862
• 30 Pawlinski R, Pedersen B, Schabbauer G , et al. Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood 2004; 103 (4) 1342-1347
• 31 Hewett JA, Schultze AE, VanCise S, Roth RA. Neutrophil depletion protects against liver injury from bacterial endotoxin. Lab Invest 1992; 66 (3) 347-361
• 32 Copple BL, Moulin F, Hanumegowda UM, Ganey PE, Roth RA. Thrombin and protease-activated receptor-1 agonists promote lipopolysaccharide-induced hepatocellular injury in perfused livers. J Pharmacol Exp Ther 2003; 305 (2) 417-425
• 33 Luyendyk JP, Maddox JF, Green CD, Ganey PE, Roth RA. Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats. Hepatology 2004; 40 (6) 1342-1351
• 34 Shaw PJ, Fullerton AM, Scott MA, Ganey PE, Roth RA. The role of the hemostatic system in murine liver injury induced by coexposure to lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability. Toxicol Appl Pharmacol 2009; 236 (3) 293-300
• 35 Bergheim I, Guo L, Davis MA , et al. Metformin prevents alcohol-induced liver injury in the mouse: critical role of plasminogen activator inhibitor-1. Gastroenterology 2006; 130 (7) 2099-2112
• 36 Jaeschke H, Bajt ML. Mechanisms of Acetaminophen Hepatotoxicity. In: Comprehensive Toxicology Volume 9. 2nd ed. Oxford: Elsevier; 2010: 457-473
• 37 Sullivan BP, Kopec AK, Joshi N , et al. Hepatocyte tissue factor activates the coagulation cascade in mice. Blood 2013; 121 (10) 1868-1874
• 38 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 (6) 2321-2329
• 39 Bajt ML, Yan HM, Farhood A, Jaeschke H. Plasminogen activator inhibitor-1 limits liver injury and facilitates regeneration after acetaminophen overdose. Toxicol Sci 2008; 104 (2) 419-427
• 40 O'Brien KM, Allen KM, Rockwell CE, Towery K, Luyendyk JP, Copple BL. IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis. Am J Pathol 2013; 183 (5) 1498-1507
• 41 Nakayama T, Sato K, Kotera M, Ishiai S, Sugishita M. [Visual memory in a case of topographical disorientation]. Rinsho Shinkeigaku 1994; 34 (4) 336-340
• 42 Plaa GL, Priestly BG. Intrahepatic cholestasis induced by drugs and chemicals. Pharmacol Rev 1976; 28 (3) 207-273
• 43 Phillips PJ, Thomas DW, Harding PE. Oral hypoglycaemic agents—dangers and contraindications. Med J Aust 1977; 1 (5) 155
• 44 Bailie MB, Pearson JM, Lappin PB, Killam AL, Roth RA. Platelets and alpha-naphthylisothiocyanate-induced liver injury. Toxicol Appl Pharmacol 1994; 129 (2) 207-213
• 45 Sullivan BP, Wang R, Tawfik O, Luyendyk JP. Protective and damaging effects of platelets in acute cholestatic liver injury revealed by depletion and inhibition strategies. Toxicol Sci 2010; 115 (1) 286-294
• 46 Sieghart W, Karobath M. Molecular heterogeneity of benzodiazepine receptors. Nature 1980; 286 (5770) 285-287
• 47 Rautou PE, Tatsumi K, Antoniak S , et al. Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury. J Hepatol 2016; Jan; 64 (1) 53-59
• 48 Guerrero JA, Teruel R, Martínez C , et al. Protective role of antithrombin in mouse models of liver injury. J Hepatol 2012; 57 (5) 980-986
• 49 Wang H, Zhang Y, Heuckeroth RO. Tissue-type plasminogen activator deficiency exacerbates cholestatic liver injury in mice. Hepatology 2007; 45 (6) 1527-1537
• 50 Luyendyk JP, Mackman N, Sullivan BP. Role of fibrinogen and protease-activated receptors in acute xenobiotic-induced cholestatic liver injury. Toxicol Sci 2011; 119 (1) 233-243
• 51 Lisman T, Stravitz RT. Rebalanced hemostasis in patients with acute liver failure. Semin Thromb Hemost 2015; 41 (5) 468-473
• 52 Arshad F, Lisman T, Porte RJ. Hypercoagulability as a contributor to thrombotic complications in the liver transplant recipient. Liver Int 2013; 33 (6) 820-827
• 53 Potze W, Alkozai EM, Adelmeijer J, Porte RJ, Lisman T. Hypercoagulability following major partial liver resection— detected by thrombomodulin-modified thrombin generation testing. Aliment Pharmacol Ther 2015; 41 (2) 189-198
• 54 Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol 2013; 11 (9) 1064-1074
• 55 Groeneveld DJ, Adelmeijer J, Hugenholtz GC, Ariëns RA, 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
• 56 Walton BL, Byrnes JR, Wolberg AS. Fibrinogen, red blood cells, and factor XIII in venous thrombosis. J Thromb Haemost 2015; 13 (Suppl. 01) S208-S215
• 57 Perepelyuk M, Terajima M, Wang AY , et al. Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol 2013; 304 (6) G605-G614
• 58 Tsochatzis EA, Bosch J, Burroughs AK. New therapeutic paradigm for patients with cirrhosis. Hepatology 2012; 56 (5) 1983-1992
• 59 Tsochatzis EA, Bosch J, Burroughs AK. Future treatments of cirrhosis. Expert Rev Gastroenterol Hepatol 2014; 8 (5) 571-581
• 60 Fujimoto J, Iimuro Y. Carbon Tetrachloride-Induced Hepatotoxicity. In: Comprehensive Toxicology Volume 9. 2nd ed. Oxford: Elsevier; 2010: 437-455
• 61 Rake MO, Flute PT, Pannell G, Shilkin KB, Williams R. Experimental hepatic necrosis: studies on coagulation abnormalities, plasma clearance, and organ distribution of 125I-labelled fibrinogen. Gut 1973; 14 (7) 574-580
• 62 Rice CE, Boulanger P, Plummer PJ. Parallel studies of complement and coagulation. IV. Effect of carbon tetrachloride. Can J Med Sci 1951; 29 (2) 48-58
• 63 Abe W, Ikejima K, Lang T , et al. Low molecular weight heparin prevents hepatic fibrogenesis caused by carbon tetrachloride in the rat. J Hepatol 2007; 46 (2) 286-294
• 64 Ronneberger H. Influence of antithrombin III on carbon tetrachloride intoxication of rabbits. Arch Toxicol Suppl 1985; 8: 156-159
• 65 Bezerra JA, Bugge TH, Melin-Aldana H , et al. Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver. Proc Natl Acad Sci U S A 1999; 96 (26) 15143-15148
• 66 Tsujimoto I, Moriya K, Sakai K, Dickneite G, Sakai T. Critical role of factor XIII in the initial stages of carbon tetrachloride-induced adult liver remodeling. Am J Pathol 2011; 179 (6) 3011-3019
• 67 Anstee QM, Wright M, Goldin R, Thursz MR. Parenchymal extinction: coagulation and hepatic fibrogenesis. Clin Liver Dis 2009; 13 (1) 117-126
• 68 Anstee QM, Goldin RD, Wright M, Martinelli A, Cox R, Thursz MR. Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies. J Thromb Haemost 2008; 6 (8) 1336-1343
• 69 Duplantier JG, Dubuisson L, Senant N , et al. A role for thrombin in liver fibrosis. Gut 2004; 53 (11) 1682-1687
• 70 Hugenholtz GC, Meijers JC, Adelmeijer J, Porte RJ, Lisman T. TAFI deficiency promotes liver damage in murine models of liver failure through defective down-regulation of hepatic inflammation. Thromb Haemost 2013; 109 (5) 948-955
• 71 Pohl JF, Melin-Aldana H, Sabla G, Degen JL, Bezerra JA. Plasminogen deficiency leads to impaired lobular reorganization and matrix accumulation after chronic liver injury. Am J Pathol 2001; 159 (6) 2179-2186
• 72 Rullier A, Gillibert-Duplantier J, Costet P , et al. Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2008; 294 (1) G226-G235
• 73 Knight V, Tchongue J, Lourensz D, Tipping P, Sievert W. Protease-activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells. Hepatology 2012; 55 (3) 879-887
• 74 Gaça MD, Zhou X, Benyon RC. Regulation of hepatic stellate cell proliferation and collagen synthesis by proteinase-activated receptors. J Hepatol 2002; 36 (3) 362-369
• 75 Kallis YN, Scotton CJ, Mackinnon AC , et al. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages. PLoS ONE 2014; 9 (1) e86241
• 76 Laschke MW, Dold S, Menger MD, Jeppsson B, Thorlacius H. Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis. Br J Pharmacol 2008; 153 (1) 148-156
• 77 Kodama T, Takehara T, Hikita H , et al. Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice. Gastroenterology 2010; 138 (7) 2487-2498 , 2498.e1–2498.e7
• 78 Katsumi T, Tomita K, Leung PS, Yang GX, Gershwin ME, Ueno Y. Animal models of primary biliary cirrhosis. Clin Rev Allergy Immunol 2015; 48 (2–3) 142-153
• 79 Fickert P, Zollner G, Fuchsbichler A , et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 2002; 123 (4) 1238-1251
• 80 Yoshida S, Ikenaga N, Liu SB , et al. Extrahepatic platelet-derived growth factor-β, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology 2014; 147 (6) 1378-1392
• 81 Luyendyk JP, Kassel KM, Allen K , et al. Fibrinogen deficiency increases liver injury and early growth response-1 (Egr-1) expression in a model of chronic xenobiotic-induced cholestasis. Am J Pathol 2011; 178 (3) 1117-1125
• 82 Joshi N, Kopec AK, O'Brien KM , et al. Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice. J Thromb Haemost 2015; 13 (1) 57-71
• 83 Eliakim M, Eisner M, Ungar H. Experimental intrahepatic obstructive jaundice following ingestion of alphanaphthyl-iso-thiocyanate. Bull Res Counc Isr, Sect E; Exp Med 1959; 8E: 7-17
• 84 Sullivan BP, Weinreb PH, Violette SM, Luyendyk JP. The coagulation system contributes to alphaVbeta6 integrin expression and liver fibrosis induced by cholestasis. Am J Pathol 2010; 177 (6) 2837-2849
• 85 Lesage G, Glaser S, Ueno Y , et al. Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis. Am J Physiol Gastrointest Liver Physiol 2001; 281 (1) G182-G190
• 86 Joshi N, Kopec AK, Towery K, Williams KJ, Luyendyk JP. The antifibrinolytic drug tranexamic acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury. J Pharmacol Exp Ther 2014; 349 (3) 383-392
• 87 Verrijken A, Francque S, Mertens I , et al. Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2014; 59 (1) 121-129
• 88 Barrera F, George J. Prothrombotic factors and nonalcoholic fatty liver disease: an additional link to cardiovascular risk?. Hepatology 2014; 59 (1) 16-18
• 89 Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28 (1) 27-38
• 90 Kassel KM, Owens III AP, Rockwell CE , et al. Protease-activated receptor 1 and hematopoietic cell tissue factor are required for hepatic steatosis in mice fed a Western diet. Am J Pathol 2011; 179 (5) 2278-2289
• 91 Luyendyk JP, Sullivan BP, Guo GL, Wang R. Tissue factor-deficiency and protease activated receptor-1-deficiency reduce inflammation elicited by diet-induced steatohepatitis in mice. Am J Pathol 2010; 176 (1) 177-186
• 92 Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med 2011; 17 (11) 1490-1497
• 93 Kopec AK, Joshi N, Towery KL , et al. Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice. J Pharmacol Exp Ther 2014; 351 (2) 288-297
• 94 Kassel KM, Sullivan BP, Cui W, Copple BL, Luyendyk JP. Therapeutic administration of the direct thrombin inhibitor argatroban reduces hepatic inflammation in mice with established fatty liver disease. Am J Pathol 2012; 181 (4) 1287-1295
• 95 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 (5) 548-555
• 96 Simonetto DA, Yang HY, Yin M , et al. Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces. Hepatology 2015; 61 (2) 648-659