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Semin Thromb Hemost 2022; 48(05): 596-606
DOI: 10.1055/s-0042-1742438
Review Article

Effects of Inflammation on Hemostasis in Acutely Ill Patients with Liver Disease

Ellen G. Driever
1   Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Ton Lisman
1   Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Abstract

Patients with liver diseases are in a rebalanced state of hemostasis, due to simultaneous decline in pro- and anticoagulant factors. This balance seems to remain even in the sickest patients, but is less stable and might destabilize when patients develop disease complications. Patients with acute decompensation of cirrhosis, acute-on-chronic liver failure, or acute liver failure often develop complications associated with changes in the hemostatic system, such as systemic inflammation. Systemic inflammation causes hemostatic alterations by adhesion and aggregation of platelets, release of von Willebrand factor (VWF), enhanced expression of tissue factor, inhibition of natural anticoagulant pathways, and inhibition of fibrinolysis. Laboratory tests of hemostasis in acutely-ill liver patients may indicate a hypocoagulable state (decreased platelet count, prolongations in prothrombin time and activated partial thromboplastin time, decreased fibrinogen levels) due to decreased synthetic liver capacity or consumption, or a hypercoagulable state (increased VWF levels, hypofibrinolysis in global tests). Whether these changes are clinically relevant and should be corrected with antithrombotic drugs or blood products is incompletely understood. Inflammation and activation of coagulation may cause local ischemia, progression of liver disease, and multiorgan failure. Anti-inflammatory treatment in acutely-ill liver patients may be of potential interest to prevent thrombotic or bleeding complications and halt progression of liver disease.

Keywords

hemostasis - coagulation - inflammation - acute-on-chronic liver failure - acute liver failure


Publication History

Article published online:
08 February 2022

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  • References

  • 1 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (06) 878-885
    CrossrefPubMedGoogle Scholar
  • 2 Lisman T, Stravitz RT. Rebalanced hemostasis in patients with acute liver failure. Semin Thromb Hemost 2015; 41 (05) 468-473
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Lisman T, Arefaine B, Adelmeijer J. et al. Global hemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease. J Thromb Haemost 2021; 19 (01) 85-95
    CrossrefPubMedGoogle Scholar
  • 4 Lisman T, Hernandez-Gea V, Magnusson M. et al. The concept of rebalanced hemostasis in patients with liver disease: communication from the ISTH SSC working group on hemostatic management of patients with liver disease. J Thromb Haemost 2021; 19 (04) 1116-1122
    CrossrefPubMedGoogle Scholar
  • 5 Moreau R, Jalan R, Gines P. et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (07) 1426-1437 , 1437.e1–1437.e9
    CrossrefPubMedGoogle Scholar
  • 6 Olson JC, Kamath PS. Acute-on-chronic liver failure: concept, natural history, and prognosis. Curr Opin Crit Care 2011; 17 (02) 165-169
    CrossrefPubMedGoogle Scholar
  • 7 Lee WM. Acute liver failure. Semin Respir Crit Care Med 2012; 33 (01) 36-45
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 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
    CrossrefPubMedGoogle Scholar
  • 9 Arroyo V, Angeli P, Moreau R. et al; investigators from the EASL-CLIF Consortium, Grifols Chair and European Foundation for the Study of Chronic Liver Failure (EF-Clif). The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol 2021; 74 (03) 670-685
    CrossrefPubMedGoogle Scholar
  • 10 Lisman T, Luyendyk JP. Systemic inflammation and disorders of hemostasis in the AD-ACLF syndrome. J Hepatol 2021; 74 (05) 1264-1265
    CrossrefPubMedGoogle Scholar
  • 11 Stravitz RT, Ellerbe C, Durkalski V, Reuben A, Lisman T, Lee WM. Acute Liver Failure Study Group. Thrombocytopenia is associated with multi-organ system failure in patients with acute liver failure. Clin Gastroenterol Hepatol 2016; 14 (04) 613-620.e4
    CrossrefPubMedGoogle Scholar
  • 12 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (2, Suppl): S26-S34
    CrossrefPubMedGoogle Scholar
  • 13 Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw 2018; 18 (04) e27 DOI: 10.4110/in.2018.18.e27.
    CrossrefPubMedGoogle Scholar
  • 14 Fernández J, Acevedo J, Wiest R. et al; European Foundation for the Study of Chronic Liver Failure. Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis. Gut 2018; 67 (10) 1870-1880
    CrossrefPubMedGoogle Scholar
  • 15 Bernsmeier C, Pop OT, Singanayagam A. et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology 2015; 148 (03) 603-615.e14
    CrossrefPubMedGoogle Scholar
  • 16 Borzio M, Salerno F, Piantoni L. et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33 (01) 41-48
    CrossrefPubMedGoogle Scholar
  • 17 Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000; 32 (4 Pt 1): 734-739
    CrossrefPubMedGoogle Scholar
  • 18 Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol 2014; 60 (01) 197-209
    CrossrefPubMedGoogle Scholar
  • 19 Strnad P, Tacke F, Koch A, Trautwein C. Liver - guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol 2017; 14 (01) 55-66
    CrossrefPubMedGoogle Scholar
  • 20 Bernsmeier C, van der Merwe S, Périanin A. Innate immune cells in cirrhosis. J Hepatol 2020; 73 (01) 186-201
    CrossrefPubMedGoogle Scholar
  • 21 Dong V, Nanchal R, Karvellas CJ. Pathophysiology of acute liver failure. Nutr Clin Pract 2020; 35 (01) 24-29
    CrossrefPubMedGoogle Scholar
  • 22 Philips CA, Ahamed R, Rajesh S, George T, Mohanan M, Augustine P. Update on diagnosis and management of sepsis in cirrhosis: current advances. World J Hepatol 2020; 12 (08) 451-474
    CrossrefPubMedGoogle Scholar
  • 23 Lippi G, Plebani M. Cytokine “storm”, cytokine “breeze”, or both in COVID-19?. Clin Chem Lab Med 2020; 59 (04) 637-639
    CrossrefPubMedGoogle Scholar
  • 24 Levi M, van der Poll T, Büller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109 (22) 2698-2704
    CrossrefPubMedGoogle Scholar
  • 25 Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118 (09) 1392-1408
    CrossrefPubMedGoogle Scholar
  • 26 Iba T, Levy JH. Derangement of the endothelial glycocalyx in sepsis. J Thromb Haemost 2019; 17 (02) 283-294
    CrossrefPubMedGoogle Scholar
  • 27 Esmon CT. Crosstalk between inflammation and thrombosis. Maturitas 2004; 47 (04) 305-314
    CrossrefPubMedGoogle Scholar
  • 28 Margetic S. Inflammation and haemostasis. Biochem Med (Zagreb) 2012; 22 (01) 49-62
    CrossrefPubMedGoogle Scholar
  • 29 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 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
    CrossrefPubMedGoogle Scholar
  • 31 Driever EG, Stravitz RT, Zhang J. et al. VWF/ADAMTS13 imbalance, but not global coagulation or fibrinolysis, is associated with outcome and bleeding in acute liver failure. Hepatology 2021; 73 (05) 1882-1891
    CrossrefPubMedGoogle Scholar
  • 32 Lisman T, Bakhtiari K, Adelmeijer J, Meijers JCM, 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
    CrossrefPubMedGoogle Scholar
  • 33 von Meijenfeldt FA, van den Boom BP, Adelmeijer J, Roberts LN, Lisman T, Bernal W. Prophylactic fresh frozen plasma and platelet transfusion have a prothrombotic effect in patients with liver disease. J Thromb Haemost 2021; 19 (03) 664-676
    CrossrefPubMedGoogle Scholar
  • 34 Campello E, Zanetto A, Bulato C. et al. Coagulopathy is not predictive of bleeding in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. Liver Int Off J Int Assoc Study Liver 2021; 41 (10) 2455-2466
    PubMedGoogle Scholar
  • 35 Zermatten MGG, Fraga M, Moradpour D. et al. Hemostatic alterations in patients with cirrhosis: from primary hemostasis to fibrinolysis. Hepatology 2020; 71 (06) 2135-2148
    Google Scholar
  • 36 Peck-Radosavljevic M. Thrombocytopenia in chronic liver disease. Liver Int 2017; 37 (06) 778-793
    Google Scholar
  • 37 Seeßle J, Löhr J, Kirchner M, Michaelis J, Merle U. Rotational thromboelastometry (ROTEM) improves hemostasis assessment compared to conventional coagulation test in ACLF and Non-ACLF patients. BMC Gastroenterol 2020; 20 (01) 271
    CrossrefPubMedGoogle Scholar
  • 38 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
    CrossrefPubMedGoogle Scholar
  • 39 Goyal S, Jadaun S, Kedia S. et al. Thromboelastography parameters in patients with acute on chronic liver failure. Ann Hepatol 2018; 17 (06) 1042-1051
    CrossrefPubMedGoogle Scholar
  • 40 Pradella P, Bonetto S, Turchetto S. et al. Platelet production and destruction in liver cirrhosis. J Hepatol 2011; 54 (05) 894-900
    CrossrefPubMedGoogle Scholar
  • 41 Smith TL, Weyrich AS. Platelets as central mediators of systemic inflammatory responses. Thromb Res 2011; 127 (05) 391-394
    CrossrefPubMedGoogle Scholar
  • 42 Vardon-Bounes F, Ruiz S, Gratacap M-P, Garcia C, Payrastre B, Minville V. Platelets are critical key players in sepsis. Int J Mol Sci 2019; 20 (14) 3494
    CrossrefPubMedGoogle Scholar
  • 43 Kaser A, Brandacher G, Steurer W. et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood 2001; 98 (09) 2720-2725
    CrossrefPubMedGoogle Scholar
  • 44 Zakynthinos SG, Papanikolaou S, Theodoridis T. et al. Sepsis severity is the major determinant of circulating thrombopoietin levels in septic patients. Crit Care Med 2004; 32 (04) 1004-1010
    CrossrefPubMedGoogle Scholar
  • 45 Schiødt FV, Balko J, Schilsky M, Harrison ME, Thornton A, Lee WM. Acute Liver Failure Study Group. Thrombopoietin in acute liver failure. Hepatology 2003; 37 (03) 558-561
    CrossrefPubMedGoogle Scholar
  • 46 Premkumar M, Saxena P, Rangegowda D. et al. Coagulation failure is associated with bleeding events and clinical outcome during systemic inflammatory response and sepsis in acute-on-chronic liver failure: an observational cohort study. Liver Int 2019; 39 (04) 694-704
    CrossrefPubMedGoogle Scholar
  • 47 Nieuwland R, Berckmans RJ, McGregor S. et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95 (03) 930-935
    CrossrefPubMedGoogle Scholar
  • 48 Ohuchi M, Fujino K, Kishimoto T. et al. Association of the plasma platelet-derived microparticles to platelet count ratio with hospital mortality and disseminated intravascular coagulopathy in critically ill patients. J Atheroscler Thromb 2015; 22 (08) 773-782
    CrossrefPubMedGoogle Scholar
  • 49 Stravitz RT, Bowling R, Bradford RL. et al. Role of procoagulant microparticles in mediating complications and outcome of acute liver injury/acute liver failure. Hepatology 2013; 58 (01) 304-313
    CrossrefPubMedGoogle Scholar
  • 50 Hugenholtz GCG, Lisman T, Stravitz RTT. Thromboelastography does not predict outcome in different etiologies of cirrhosis. Res Pract Thromb Haemost 2017; 1 (02) 275-285
    CrossrefPubMedGoogle Scholar
  • 51 Stravitz RT, Lisman T, Luketic VA. et al. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography. J Hepatol 2012; 56 (01) 129-136
    CrossrefPubMedGoogle Scholar
  • 52 Lisman T, Luyendyk JPP. Platelets as modulators of liver diseases. Semin Thromb Hemost 2018; 44 (02) 114-125
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 De Ceunynck K, De Meyer SF, Vanhoorelbeke K. Unwinding the von Willebrand factor strings puzzle. Blood 2013; 121 (02) 270-277
    CrossrefPubMedGoogle Scholar
  • 54 Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98 (09) 2730-2735
    CrossrefPubMedGoogle Scholar
  • 55 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
    Google Scholar
  • 56 Hugenholtz GCG, Adelmeijer J, Meijers JCM, Porte RJ, Stravitz RT, Lisman T. An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for hemostasis and clinical outcome. Hepatology 2013; 58 (02) 752-761
    CrossrefPubMedGoogle Scholar
  • 57 Reiter RA, Varadi K, Turecek PL, Jilma B, Knöbl P. Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 2005; 93 (03) 554-558
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Chen J, Chung DW. Inflammation, von Willebrand factor, and ADAMTS13. Blood 2018; 132 (02) 141-147
    CrossrefPubMedGoogle Scholar
  • 59 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
    CrossrefPubMedGoogle Scholar
  • 60 Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 2008; 135 (01) 41-60
    CrossrefPubMedGoogle Scholar
  • 61 Larsen JB, Hvas A-M. Predictive value of whole blood and plasma coagulation tests for intra- and postoperative bleeding risk: a systematic review. Semin Thromb Hemost 2017; 43 (07) 772-805
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 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
    CrossrefPubMedGoogle Scholar
  • 63 Habib M, Roberts LN, Patel RK, Wendon J, Bernal W, Arya R. Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation. Liver Int 2014; 34 (05) 672-678
    CrossrefPubMedGoogle Scholar
  • 64 Stravitz RTT. Potential applications of thromboelastography in patients with acute and chronic liver disease. Gastroenterol Hepatol (N Y) 2012; 8 (08) 513-520
    PubMedGoogle Scholar
  • 65 Tripodi A, Primignani M, Chantarangkul V. et al. The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters. Thromb Res 2009; 124 (01) 132-136
    CrossrefPubMedGoogle Scholar
  • 66 Raeven P, Baron-Stefaniak J, Simbrunner B. et al. Thromboelastometry in patients with advanced chronic liver disease stratified by severity of portal hypertension. Hepatol Int 2020; 14 (06) 1083-1092
    CrossrefPubMedGoogle Scholar
  • 67 Bihari C, Patil A, Shasthry SM, Baweja S, Kumar G, Sarin SK. Viscoelastic test-based bleeding risk score reliably predicts coagulopathic bleeding in decompensated cirrhosis and ACLF patients. Hepatol Int 2020; 14 (04) 597-608
    CrossrefPubMedGoogle Scholar
  • 68 Agarwal B, Wright G, Gatt A. et al. Evaluation of coagulation abnormalities in acute liver failure. J Hepatol 2012; 57 (04) 780-786
    CrossrefPubMedGoogle Scholar
  • 69 Stravitz RT, Fontana RJ, Meinzer C. et al; ALF Study Group. Coagulopathy, bleeding events, and outcome according to rotational thromboelastometry in patients with acute liver injury/failure. Hepatology 2021; 74 (02) 937-949
    CrossrefPubMedGoogle Scholar
  • 70 Lisman T. Interpreting hemostatic profiles assessed with viscoelastic tests in patients with cirrhosis. J Clin Gastroenterol 2020; 54 (04) 389-391
    CrossrefPubMedGoogle Scholar
  • 71 Davis JPE, Northup PG, Caldwell SH, Intagliata NM. Viscoelastic testing in liver disease. Ann Hepatol 2018; 17 (02) 205-213
    CrossrefPubMedGoogle Scholar
  • 72 Theoharides TC, Alysandratos K-D, Angelidou A. et al. Mast cells and inflammation. Biochim Biophys Acta 2012; 1822 (01) 21-33
    CrossrefPubMedGoogle Scholar
  • 73 Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK. Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study. J Hepatol 2002; 37 (04) 463-470
    CrossrefPubMedGoogle Scholar
  • 74 Rizzo K, Vella K, Zammit D. et al. Fibrinogen measurement in liver disease: validation of the functional fibrinogen thromboelastography assay and a novel mathematical predictive model. Blood Transfus 2019; 17 (03) 237-246
    PubMedGoogle Scholar
  • 75 Kopec AK, Luyendyk JP. Role of Fibrin(ogen) in progression of liver disease: guilt by association?. Semin Thromb Hemost 2016; 42 (04) 397-407
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Budnick IM, Davis JPE, Sundararaghavan A. et al. Transfusion with cryoprecipitate for very low fibrinogen levels does not affect bleeding or survival in critically ill cirrhosis patients. Thromb Haemost 2021; 121 (10) 1317-1325
    Article in Thieme ConnectPubMedGoogle Scholar
  • 77 Lisman T, Ariëns RAS. Alterations in fibrin structure in patients with liver diseases. Semin Thromb Hemost 2016; 42 (04) 389-396
    Article in Thieme ConnectPubMedGoogle Scholar
  • 78 de Vries JJ, Snoek CJM, Rijken DC, de Maat MPM. Effects of post-translational modifications of fibrinogen on clot formation, clot structure, and fibrinolysis: a systematic review. Arterioscler Thromb Vasc Biol 2020; 40 (03) 554-569
    CrossrefPubMedGoogle Scholar
  • 79 Francis JL, Armstrong DJ. Fibrinogen-bound sialic acid levels in the dysfibrinogenaemia of liver disease. Haemostasis 1982; 11 (04) 215-222
    PubMedGoogle Scholar
  • 80 Poole LG, Kopec AK, Groeneveld DJ. et al. Factor XIII cross-links fibrin(ogen) independent of fibrin polymerization in experimental acute liver injury. Blood 2021; 137 (18) 2520-2531
    CrossrefPubMedGoogle Scholar
  • 81 Hugenholtz GCG, Macrae F, Adelmeijer J. et al. Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen. J Thromb Haemost 2016; 14 (05) 1054-1066
    CrossrefPubMedGoogle Scholar
  • 82 Undas A, Kaczmarek P, Sladek K. et al. Fibrin clot properties are altered in patients with chronic obstructive pulmonary disease. Beneficial effects of simvastatin treatment. Thromb Haemost 2009; 102 (06) 1176-1182
    PubMedGoogle Scholar
  • 83 Kwasny-Krochin B, Gluszko P, Undas A. Unfavorably altered fibrin clot properties in patients with active rheumatoid arthritis. Thromb Res 2010; 126 (01) e11-e16
    CrossrefPubMedGoogle Scholar
  • 84 Undas A, Plicner D, Stepień E, Drwiła R, Sadowski J. Altered fibrin clot structure in patients with advanced coronary artery disease: a role of C-reactive protein, lipoprotein(a) and homocysteine. J Thromb Haemost 2007; 5 (09) 1988-1990
    CrossrefPubMedGoogle Scholar
  • 85 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
    CrossrefPubMedGoogle Scholar
  • 86 von Meijenfeldt FA, Lisman T. Fibrinolysis in patients with liver disease. Semin Thromb Hemost 2021; 47 (05) 601-609
    Article in Thieme ConnectPubMedGoogle Scholar
  • 87 Levi M, van der Poll T. Coagulation and sepsis. Thromb Res 2017; 149: 38-44
    CrossrefPubMedGoogle Scholar
  • 88 Gando S, Levi M, Toh C-H. Disseminated intravascular coagulation. Nat Rev Dis Primers 2016; 2: 16037
    CrossrefPubMedGoogle Scholar
  • 89 Bernal W, Williams R. Beyond KCH selection and options in acute liver failure. Hepatol Int 2018; 12 (03) 204-213
    CrossrefPubMedGoogle Scholar
  • 90 Fisher NC, Mutimer DJ. Central venous cannulation in patients with liver disease and coagulopathy–a prospective audit. Intensive Care Med 1999; 25 (05) 481-485
    CrossrefPubMedGoogle Scholar
  • 91 Roberts LN, Bernal W. Management of bleeding and thrombosis in critically ill patients with liver disease. Semin Thromb Hemost 2015; 41 (05) 520-526
    Article in Thieme ConnectPubMedGoogle Scholar
  • 92 Ow T-W, Fatourou E, Rabinowich L. et al. Prevalence of bleeding and thrombosis in critically ill patients with chronic liver disease. Thromb Haemost 2021; (e-Pub ahead of print) DOI: 10.1055/a-1667-7293.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 93 Giannini EG, Greco A, Marenco S, Andorno E, Valente U, Savarino V. Incidence of bleeding following invasive procedures in patients with thrombocytopenia and advanced liver disease. Clin Gastroenterol Hepatol 2010; 8 (10) 899-902 , quiz e109
    CrossrefPubMedGoogle Scholar
  • 94 Northup PG, Garcia-Pagan JC, Garcia-Tsao G. et al. Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2021; 73 (01) 366-413
    CrossrefPubMedGoogle Scholar
  • 95 O'Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA clinical practice update: coagulation in cirrhosis. Gastroenterology 2019; 157 (01) 34-43.e1
    CrossrefPubMedGoogle Scholar
  • 96 O'Shaughnessy DF, Atterbury C, Bolton Maggs P. et al; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126 (01) 11-28
    CrossrefPubMedGoogle Scholar
  • 97 Lisman T, Bernal W. Management of hemostatic disorders in patients with advanced liver disease admitted to an intensive care unit. Transfus Med Rev 2017; 31 (04) 245-251
    CrossrefPubMedGoogle Scholar
  • 98 Swan D, Carrier M, Lisman T, Thachil J. Heparin - Messias or Verschlimmbesserung?. J Thromb Haemost 2021; 19 (10) 2373-2382
    CrossrefPubMedGoogle Scholar
  • 99 van den Boom BP, von Meijenfeldt FA, Adelmeijer J, Roberts LN, Bernal W, Lisman T. Heparins have adequate ex vivo anticoagulant effects in hospitalized patients with cirrhosis. J Thromb Haemost 2021; 19 (06) 1472-1482
    CrossrefPubMedGoogle Scholar
  • 100 Kopec AK, Joshi N, Luyendyk JP. Role of hemostatic factors in hepatic injury and disease: animal models de-liver. J Thromb Haemost 2016; 14 (07) 1337-1349
    CrossrefPubMedGoogle Scholar
  • 101 Meijenfeldt FAV, Jenne CN. Netting liver disease: neutrophil extracellular traps in the initiation and exacerbation of liver pathology. Semin Thromb Hemost 2020; 46 (06) 724-734
    Article in Thieme ConnectPubMedGoogle Scholar