Semin Thromb Hemost 2015; 41(05): 474-480
DOI: 10.1055/s-0035-1550437
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Fibrinolytic Status in Liver Diseases

Frank W. G. Leebeek
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
,
Dingeman C. Rijken
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Publication Date:
06 June 2015 (online)

Abstract

The liver is the main site of synthesis and/or clearance of proteins involved in fibrinolysis. Therefore, chronic liver disease, including cirrhosis, leads to altered plasma levels of fibrinolytic proteins. Historical studies using in vitro clot lysis assays suggested that patients with chronic liver disease had accelerated fibrinolysis. Subsequent studies measured levels of individual pro- and antifibrinolytic proteins and showed that levels of tissue-type plasminogen activator are elevated. Plasma levels of plasminogen activator inhibitor-1 may also be altered, which leads to a shift in balance in the fibrinolytic system. Despite the fact that a more recent study using a plasma clot lysis assay challenged the existence of hyperfibrinolysis, other recent studies detected hyperfibrinolysis in a considerable number of patients with cirrhosis. Therefore, it is now recognized that hyperfibrinolysis may occur in 30 to 50% of patients with end-stage liver disease. A causal role of hyperfibrinolysis in bleeding is difficult to establish because also other concomitant changes in hemostasis occur. Treatment of hyperfibrinolysis consists of the use of fibrinolysis inhibitors, such as tranexamic acid. In this review we summarize current insights of the role of the liver in fibrinolysis, changes in fibrinolytic proteins, the potential clinical implications, and management of hyperfibrinolysis in liver disease.

 
  • References

  • 1 Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 2009; 7 (1) 4-13
  • 2 Rijken DC, Wijngaards G, Welbergen J. Immunological characterization of plasminogen activator activities in human tissues and body fluids. J Lab Clin Med 1981; 97 (4) 477-486
  • 3 Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982; 257 (6) 2912-2919
  • 4 Declerck PJ, Gils A. Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin. Semin Thromb Hemost 2013; 39 (4) 356-364
  • 5 Aoki N. The past, present and future of plasmin inhibitor. Thromb Res 2005; 116 (6) 455-464
  • 6 Nesheim M, Bajzar L. The discovery of TAFI. J Thromb Haemost 2005; 3 (10) 2139-2146
  • 7 Sakharov DV, Plow EF, Rijken DC. On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. J Biol Chem 1997; 272 (22) 14477-14482
  • 8 Kooistra T, Schrauwen Y, Arts J, Emeis JJ. Regulation of endothelial cell t-PA synthesis and release. Int J Hematol 1994; 59 (4) 233-255
  • 9 Knipe L, Meli A, Hewlett L , et al. A revised model for the secretion of tPA and cytokines from cultured endothelial cells. Blood 2010; 116 (12) 2183-2191
  • 10 Binder BR, Christ G, Gruber F , et al. Plasminogen activator inhibitor 1: physiological and pathophysiological roles. News Physiol Sci 2002; 17: 56-61
  • 11 Otter M, Kuiper J, van Berkel TJ, Rijken DC. Mechanisms of tissue-type plasminogen activator (tPA) clearance by the liver. Ann N Y Acad Sci 1992; 667: 431-442
  • 12 Narita M, Bu G, Herz J, Schwartz AL. Two receptor systems are involved in the plasma clearance of tissue-type plasminogen activator (t-PA) in vivo. J Clin Invest 1995; 96 (2) 1164-1168
  • 13 Mayer EJ, Fujita T, Gardell SJ, Shebuski RJ, Reilly CF. The pharmacokinetics of plasminogen activator inhibitor-1 in the rabbit. Blood 1990; 76 (8) 1514-1520
  • 14 Horn IR, van den Berg BM, Moestrup SK, Pannekoek H, van Zonneveld AJ. Plasminogen activator inhibitor 1 contains a cryptic high affinity receptor binding site that is exposed upon complex formation with tissue-type plasminogen activator. Thromb Haemost 1998; 80 (5) 822-828
  • 15 Hu L, Bovenschen N, Havekes LM, van Vlijmen BJ, Tamsma JT. Plasma plasminogen activator inhibitor-1 level is not regulated by the hepatic low-density lipoprotein receptor-related protein. J Thromb Haemost 2007; 5 (11) 2301-2304
  • 16 Pepperell D, Morel-Kopp MC, Ward C. Clinical application of fibrinolytic assays. In: Kolev K, , ed. Fibrinolysis and Thrombolysis. Rijeka, Croatia: InTech; 2014: 125-162
  • 17 Lisman T, de Groot PG, Meijers JC, Rosendaal FR. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 2005; 105 (3) 1102-1105
  • 18 Talens S, Malfliet JJ, Rudež G , et al. Biological variation in tPA-induced plasma clot lysis time. Thromb Haemost 2012; 108 (4) 640-646
  • 19 He S, Zhu K, Skeppholm M , et al. A global assay of haemostasis which uses recombinant tissue factor and tissue-type plasminogen activator to measure the rate of fibrin formation and fibrin degradation in plasma. Thromb Haemost 2007; 98 (4) 871-882
  • 20 Hartert H. Blutgerinnungsstudien mit der Thrombelastographie; einem neuen Untersuchungsverfahren. Klin Wochenschr 1948; 26 (37-38) 577-583
  • 21 Raza I, Davenport R, Rourke C , et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost 2013; 11 (2) 307-314
  • 22 Rijken DC, Hoegee-de Nobel E, Jie AF, Atsma DE, Schalij MJ, Nieuwenhuizen W. Development of a new test for the global fibrinolytic capacity in whole blood. J Thromb Haemost 2008; 6 (1) 151-157
  • 23 Amiral J, Malmejac A, Gin H , et al. Evaluation of the fibrinolytic potential on plasma: physiological and pathological variations, and associations with cardio-vascular disease risk factors. Fibrinolysis Proteol. 1999; 13 (1) 1-10
  • 24 Goodpasture E. Fibrinolysis in chronic hepatic insufficiency. Bull Johns Hopkins Hosp 1914; 25 (285) 330-336
  • 25 Ratnoff OD. Studies on a proteolytic enzyme in human plasma; the rate of lysis of plasma clots in normal and diseased individuals, with particular reference to hepatic diseases. Bull Johns Hopkins Hosp 1949; 84 (1) 29-42
  • 26 Kwaan HC, McFadzean AJ, Cook J. Plasma fibrinolytic activity in cirrhosis of the liver. Lancet 1956; 270 (6908) 132-136
  • 27 van de Loo J, Schmiesing G. Factors of the fibrinolytic system in liver diseases [in German]. Thromb Diath Haemorrh 1965; 14 (3-4) 580-591
  • 28 Tytgat G, Collen D, De Vreker R, Verstraete M. Investigations on the fibrinolytic system in liver cirrhosis. Acta Haematol 1968; 40 (5) 265-274
  • 29 Brakman P, Mohler ER, Astrup T. Blood fibrinolysis in liver disease. Haemostasis 1974; 2: 209-213
  • 30 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: 681-695
  • 31 Das PC, Cash JD. Fibrinolysis at rest and after exercise in hepatic cirrhosis. Br J Haematol 1969; 17 (5) 431-443
  • 32 Francis Jr RB, Feinstein DI. Clinical significance of accelerated fibrinolysis in liver disease. Haemostasis 1984; 14 (6) 460-465
  • 33 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 (5) 1581-1586
  • 34 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 (5) 1382-1390
  • 35 Aoki N, Yamanaka T. The alpha2-plasmin inhibitor levels in liver diseases. Clin Chim Acta 1978; 84 (1-2) 99-105
  • 36 van Wersch JW, Russel MG, Lustermans FA. The extent of diffuse intravascular coagulation and fibrinolysis in patients with liver cirrhosis. Eur J Clin Chem Clin Biochem 1992; 30 (5) 275-279
  • 37 Booth NA, Anderson JA, Bennett B. Plasminogen activators in alcoholic cirrhosis: demonstration of increased tissue type and urokinase type activator. J Clin Pathol 1984; 37 (7) 772-777
  • 38 Leiper K, Croll A, Booth NA, Moore NR, Sinclair T, Bennett B. Tissue plasminogen activator, plasminogen activator inhibitors, and activator-inhibitor complex in liver disease. J Clin Pathol 1994; 47 (3) 214-217
  • 39 Leebeek FWG, Kluft C, Knot EAR, De Maat MPM. Histidine-rich glycoprotein is elevated in mild liver cirrhosis and decreased in moderate and severe liver cirrhosis. J Lab Clin Med 1989; 113 (4) 493-497
  • 40 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 (1) 230-237
  • 41 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 (1) 131-139
  • 42 Tran-Thang C, Fasel-Felley J, Pralong G, Hofstetter JR, Bachmann F, Kruithof EK. Plasminogen activators and plasminogen activator inhibitors in liver deficiencies caused by chronic alcoholism or infectious hepatitis. Thromb Haemost 1989; 62 (2) 651-653
  • 43 Violi F, Ferro D, Basili S , et al. Hyperfibrinolysis resulting from clotting activation in patients with different degrees of cirrhosis. The CALC Group. Coagulation Abnormalities in Liver Cirrhosis. Hepatology 1993; 17 (1) 78-83
  • 44 Hersch SL, Kunelis T, Francis Jr RB. The pathogenesis of accelerated fibrinolysis in liver cirrhosis: a critical role for tissue plasminogen activator inhibitor. Blood 1987; 69 (5) 1315-1319
  • 45 vanDeWater L, Carr JM, Aronson D, McDonagh J. Analysis of elevated fibrin(ogen) degradation product levels in patients with liver disease. Blood 1986; 67 (5) 1468-1473
  • 46 Bakker CM, Knot EA, Stibbe J, Wilson JH. Disseminated intravascular coagulation in liver cirrhosis. J Hepatol 1992; 15 (3) 330-335
  • 47 Violi F, Ferro D, Basili S , et al. Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastroenterology 1995; 109 (2) 531-539
  • 48 Papatheodoridis GV, Patch D, Webster GJ, Brooker J, Barnes E, Burroughs AK. Infection and hemostasis in decompensated cirrhosis: a prospective study using thrombelastography. Hepatology 1999; 29 (4) 1085-1090
  • 49 Roullet S, Freyburger G, Labrouche S , et al. Hyperfibrinolysis during liver transplantation is associated with bleeding. Thromb Haemost 2015; 113 (5) 1145-1148
  • 50 Jairath V, Hall D, Harrison P , et al. Rotational thromboelastometry in cirrhosis: hypercoagulable and hyperfibrinolytic. Gut 2012; 61: A30
  • 51 Stravitz RT. Potential applications of thromboelastography in patients with acute and chronic liver disease. Gastroenterol Hepatol (N Y) 2012; 8 (8) 513-520
  • 52 Kleinegris MC, Bos MH, Roest M , et al. Cirrhosis patients have a coagulopathy that is associated with decreased clot formation capacity. J Thromb Haemost 2014; 12 (10) 1647-1657
  • 53 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (6) 878-885
  • 54 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
  • 55 Aytac S, Turkay C, Bavbek N, Kosar A. Hemostasis and global fibrinolytic capacity in chronic liver disease. Blood Coagul Fibrinolysis 2007; 18 (7) 623-626
  • 56 Caldwell SH, Hoffman M, Lisman T , et al; Coagulation in Liver Disease Group. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology 2006; 44 (4) 1039-1046
  • 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 (1) 79-86
  • 58 Violi F, Ferro D, Basili S , et al. Hyperfibrinolysis increases the risk of gastrointestinal hemorrhage in patients with advanced cirrhosis. Hepatology 1992; 15 (4) 672-676
  • 59 Violi F, Ferro D, Basili S , et al; CALC Group. Prognostic value of clotting and fibrinolytic systems in a follow-up of 165 liver cirrhotic patients. Hepatology 1995; 22 (1) 96-100
  • 60 Piscaglia F, Siringo S, Hermida RC , et al. Diurnal changes of fibrinolysis in patients with liver cirrhosis and esophageal varices. Hepatology 2000; 31 (2) 349-357
  • 61 Andreotti F, Kluft C. Circadian variation of fibrinolytic activity in blood. Chronobiol Int 1991; 8 (5) 336-351
  • 62 Violi F, Ferro D. Clotting activation and hyperfibrinolysis in cirrhosis: implication for bleeding and thrombosis. Semin Thromb Hemost 2013; 39 (4) 426-433
  • 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 (7) 1312-1319
  • 64 Porte RJ, Knot EA, Bontempo FA. Hemostasis in liver transplantation. Gastroenterology 1989; 97 (2) 488-501
  • 65 Segal H, Cottam S, Potter D, Hunt BJ. Coagulation and fibrinolysis in primary biliary cirrhosis compared with other liver disease and during orthotopic liver transplantation. Hepatology 1997; 25 (3) 683-688