Alterations in Fibrin Structure in Patients with Liver Diseases

Ton Lisman; Robert A. S. Ariëns

doi:10.1055/s-0036-1572327

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2016; 42(04): 389-396
DOI: 10.1055/s-0036-1572327

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Alterations in Fibrin Structure in Patients with Liver Diseases

Ton Lisman

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

,

Robert A. S. Ariëns

²Division of Cardiovascular and Diabetes Research, Thrombosis and Tissue Repair Group, Multidisciplinary Cardiovascular Research Centre and Leeds Institute for Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom

› Author Affiliations

Abstract

The hemostatic balance in patients with liver diseases is relatively well preserved due to concomitant alterations in pro- and antihemostatic pathways. Thrombin generation studies support the notion of hemostatic competence in liver diseases, but in such tests alterations in fibrinogen level and function are not taken into account. We have recently studied structural and functional properties of the fibrin clot in patients with liver diseases. Although we have confirmed previous findings that hypersialylation of the fibrinogen molecule in patients with liver diseases contributes to a defective fibrinogen-to-fibrin conversion, we have found that once the clot has been formed, it has a thrombogenic nature as assessed by permeability assays. These thrombogenic properties of the fibrin clot in cirrhosis relate to incompletely characterized intrinsic changes in the fibrinogen molecule, which may include oxidation and hypersialylation. In addition, in patients with nonalcoholic fatty liver disease thrombogenic properties of the fibrin clot are not only due to liver disease but also to obesity and the metabolic syndrome. During liver transplantation, the clot normalizes and becomes increasingly permeable, and the functional properties of the fibrin clot are markedly normalized by fibrinogen concentrate, when added to plasma samples in vitro. These new insights in the functional properties of the fibrin clot in patients with liver diseases facilitate a more rational approach to treatment and prevention of both bleeding and thrombotic complications.

Keywords

cirrhosis - nonalcoholic fatty liver disease - liver transplantation - fibrinogen - fibrin

Full Text

References

References
1 Lisman T, Leebeek FW, de Groot PG. Haemostatic abnormalities in patients with liver disease. J Hepatol 2002; 37 (2) 280-287
2 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (2) 147-156
3 Lisman T, Caldwell SH, Burroughs AK , et al; Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 2010; 53 (2) 362-371
4 Tripodi A, Salerno F, Chantarangkul V , et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41 (3) 553-558
5 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 (9) 1994-2000
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 (3) 753-756
7 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
8 Youngwon N, Kim JE, Lim HS, Han KS, Kim HK. Coagulation proteins influencing global coagulation assays in cirrhosis: hypercoagulability in cirrhosis assessed by thrombomodulin-induced thrombin generation assay. Biomed Res Int 2013; 2013: 856754
9 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 (1) 53-61
10 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
11 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
12 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
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 (3) 554-559
14 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
15 Potze W, Siddiqui MS, Boyett SL , et al. Preserved hemostatic status with pro-thrombotic features in patients with non-alcoholic fatty liver disease. Hepatology 2015; 62: 1302A-1303A
16 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (6) 878-885
17 Massicotte L, Denault AY, Beaulieu D , et al. Transfusion rate for 500 consecutive liver transplantations: experience of one liver transplantation center. Transplantation 2012; 93 (12) 1276-1281
18 Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010; 362 (9) 823-832
19 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 (7) 1524-1528 , quiz 1680
20 Søgaard KK, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol 2009; 104 (1) 96-101
21 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 (1) 1
22 Gulley D, Teal E, Suvannasankha A, Chalasani N, Liangpunsakul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci 2008; 53 (11) 3012-3017
23 Hugenholtz GC, Northup PG, Porte RJ, Lisman T. Is there a rationale for treatment of chronic liver disease with antithrombotic therapy?. Blood Rev 2015; 29 (2) 127-136
24 Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol 2013; 11 (9) 1064-1074
25 van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J Thromb Haemost 2003; 1 (12) 2677-2678
26 Danesh J, Lewington S, Thompson SG , et al; Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005; 294 (14) 1799-1809
27 de Moerloose P, Boehlen F, Neerman-Arbez M. Fibrinogen and the risk of thrombosis. Semin Thromb Hemost 2010; 36 (1) 7-17
28 Ni H, Denis CV, Subbarao S , et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 2000; 106 (3) 385-392
29 Collet JP, Allali Y, Lesty C , et al. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 2006; 26 (11) 2567-2573
30 Undas A, Podolec P, Zawilska K , et al. Altered fibrin clot structure/function in patients with cryptogenic ischemic stroke. Stroke 2009; 40 (4) 1499-1501
31 Undas A, Zawilska K, Ciesla-Dul M , et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114 (19) 4272-4278
32 Undas A, Nowakowski T, Cieśla-Dul M, Sadowski J. Abnormal plasma fibrin clot characteristics are associated with worse clinical outcome in patients with peripheral arterial disease and thromboangiitis obliterans. Atherosclerosis 2011; 215 (2) 481-486
33 Dunn EJ, Ariëns RA, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. Diabetologia 2005; 48 (6) 1198-1206
34 Sjøland JA, Sidelmann JJ, Brabrand M , et al. Fibrin clot structure in patients with end-stage renal disease. Thromb Haemost 2007; 98 (2) 339-345
35 Undas A, Ariëns RA. Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31 (12) e88-e99
36 Li R, Ren M, Luo M , et al. Monomeric C-reactive protein alters fibrin clot properties on endothelial cells. Thromb Res 2012; 129 (5) e251-e256
37 Hess K, Ajjan R, Phoenix F, Dobó J, Gál P, Schroeder V. Effects of MASP-1 of the complement system on activation of coagulation factors and plasma clot formation. PLoS ONE 2012; 7 (4) e35690
38 Hess K, Alzahrani SH, Price JF , et al. Hypofibrinolysis in type 2 diabetes: the role of the inflammatory pathway and complement C3. Diabetologia 2014; 57 (8) 1737-1741
39 Howes JM, Richardson VR, Smith KA , et al. Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. Diab Vasc Dis Res 2012; 9 (3) 216-225
40 Blombäck M, He S, Bark N, Wallen HN, Elg M. Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate. Br J Haematol 2011; 152 (6) 758-765
41 Undas A, Topór-Madry R, Tracz W, Pasowicz M. Effect of cigarette smoking on plasma fibrin clot permeability and susceptibility to lysis. Thromb Haemost 2009; 102 (6) 1289-1291
42 Jörneskog G, Hansson LO, Wallen NH, Yngen M, Blombäck M. Increased plasma fibrin gel porosity in patients with type I diabetes during continuous subcutaneous insulin infusion. J Thromb Haemost 2003; 1 (6) 1195-1201
43 Undas A, Brozek J, Jankowski M, Siudak Z, Szczeklik A, Jakubowski H. Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects. Arterioscler Thromb Vasc Biol 2006; 26 (6) 1397-1404
44 Undas A, Celinska-Löwenhoff M, Löwenhoff T, Szczeklik A. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost 2006; 4 (5) 1029-1036
45 Ajjan RA, Standeven KF, Khanbhai M , et al. Effects of aspirin on clot structure and fibrinolysis using a novel in vitro cellular system. Arterioscler Thromb Vasc Biol 2009; 29 (5) 712-717
46 Undas A, Brummel-Ziedins KE, Mann KG. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007; 109 (6) 2285-2292
47 de Maat MP, Nieuwenhuizen W, Knot EA, van Buuren HR, Swart GR. Measuring plasma fibrinogen levels in patients with liver cirrhosis. The occurrence of proteolytic fibrin(ogen) degradation products and their influence on several fibrinogen assays. Thromb Res 1995; 78 (4) 353-362
48 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 (1) 129-136
49 von Felten A, Straub PW, Frick PG. Dysfibrinogenemia in a patient with primary hepatoma. First observation of an acquired abnormality of fibrin monomer aggregation. N Engl J Med 1969; 280 (8) 405-409
50 Aiach M, Rogé J, Busy MF , et al. [Acquired dysfibrinogenemia and hepatic disorders. Apropos of 30 cases]. Sem Hop 1973; 49 (3) 183-197
51 Palascak JE, Martinez J. Dysfibrinogenemia associated with liver disease. J Clin Invest 1977; 60 (1) 89-95
52 Martinez J, Palascak JE, Kwasniak D. Abnormal sialic acid content of the dysfibrinogenemia associated with liver disease. J Clin Invest 1978; 61 (2) 535-538
53 Gralnick HR, Givelber H, Abrams E. Dysfibrinogenemia associated with hepatoma. Increased carbohydrate content of the fibrinogen molecule. N Engl J Med 1978; 299 (5) 221-226
54 Narvaiza MJ, Fernández J, Cuesta B, Páramo JA, Rocha E. Role of sialic acid in acquired dysfibrinogenemia associated with liver cirrhosis. Ric Clin Lab 1986; 16 (4) 563-568
55 Francis JL, Simmonds VJ, Ingram AJ. The effect of carbon tetrachloride-induced cirrhosis of the liver on fibrinogen-bound sialic acid and sialyltransferase activity in the rat. Med Lab Sci 1986; 43 (1) 38-43
56 Martinez J, Palascak J, Peters C. Functional and metabolic properties of human asialofibrinogen. J Lab Clin Med 1977; 89 (2) 367-377
57 Martinez J, MacDonald KA, Palascak JE. The role of sialic acid in the dysfibrinogenemia associated with liver disease: distribution of sialic acid on the constituent chains. Blood 1983; 61 (6) 1196-1202
58 Townsend RR, Hilliker E, Li YT, Laine RA, Bell WR, Lee YC. Carbohydrate structure of human fibrinogen. Use of 300-MHz 1H-NMR to characterize glycosidase-treated glycopeptides. J Biol Chem 1982; 257 (16) 9704-9710
59 Kononova O, Litvinov RI, Zhmurov A , et al. Molecular mechanisms, thermodynamics, and dissociation kinetics of knob-hole interactions in fibrin. J Biol Chem 2013; 288 (31) 22681-22692
60 Zauner G, Hoffmann M, Rapp E , et al. Glycoproteomic analysis of human fibrinogen reveals novel regions of O-glycosylation. J Proteome Res 2012; 11 (12) 5804-5814
61 Hugenholtz GC, Mccrae FL, 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; In press
62 Dang CV, Shin CK, Bell WR, Nagaswami C, Weisel JW. Fibrinogen sialic acid residues are low affinity calcium-binding sites that influence fibrin assembly. J Biol Chem 1989; 264 (25) 15104-15108
63 Marchi R, Arocha-Piñango CL, Nagy H, Matsuda M, Weisel JW. The effects of additional carbohydrate in the coiled-coil region of fibrinogen on polymerization and clot structure and properties: characterization of the homozygous and heterozygous forms of fibrinogen Lima (Aalpha Arg141—>Ser with extra glycosylation). J Thromb Haemost 2004; 2 (6) 940-948
64 Martinez M, Weisel JW, Ischiropoulos H. Functional impact of oxidative posttranslational modifications on fibrinogen and fibrin clots. Free Radic Biol Med 2013; 65: 411-418
65 Vairappan B. Endothelial dysfunction in cirrhosis: role of inflammation and oxidative stress. World J Hepatol 2015; 7 (3) 443-459
66 Becatti M, Marcucci R, Bruschi G , et al. Oxidative modification of fibrinogen is associated with altered function and structure in the subacute phase of myocardial infarction. Arterioscler Thromb Vasc Biol 2014; 34 (7) 1355-1361
67 Domingues MM, Macrae FL, Duval C , et al. Thrombin and fibrinogen γ' impact clot structure by marked effects on intrafibrillar structure and protofibril packing. Blood 2015;
68 Potze W, Siddiqui MS, Sanyal AJ. Vascular disease in patients with nonalcoholic fatty liver disease. Semin Thromb Hemost 2015; 41 (5) 488-493
69 Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome. Semin Thromb Hemost 2009; 35 (3) 277-287
70 Crook MA, Tutt P, Simpson H, Pickup JC. Serum sialic acid and acute phase proteins in type 1 and type 2 diabetes mellitus. Clin Chim Acta 1993; 219 (1–2) 131-138
71 He J, Mao W, Zhang J, Jin X. Association between serum sialic acid levels and nonalcoholic fatty liver disease: a cross-sectional study. Ann Nutr Metab 2015; 67 (2) 69-75
72 Dunn EJ, Philippou H, Ariëns RA, Grant PJ. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia 2006; 49 (5) 1071-1080
73 Clevenger B, Mallett SV. Transfusion and coagulation management in liver transplantation. World J Gastroenterol 2014; 20 (20) 6146-6158
74 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 (5) 538-546
75 Mallett SV. Clinical Utility of Viscoelastic Tests of Coagulation (TEG/ROTEM) in Patients with Liver Disease and during Liver Transplantation. Semin Thromb Hemost 2015; 41 (5) 527-537
76 Kirchner C, Dirkmann D, Treckmann JW , et al. Coagulation management with factor concentrates in liver transplantation: a single-center experience. Transfusion 2014; 54 (10 Pt 2) 2760-2768
77 Groeneveld DJ, Adelmeijer J, Hugenholtz GC, Ariëns RA, Porte RJ, Lisman T. Ex vivo addition of fibrinogen concentrate improves fibrin network structure in plasma samples taken during liver transplantation. J Thromb Haemost 2015; 13: 2192-2201
78 Porte RJ, Knot EA, Bontempo FA. Hemostasis in liver transplantation. Gastroenterology 1989; 97 (2) 488-501
79 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 (6) 978-984
80 Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 2010; 52 (3) 355-361
81 Arshad F, Ickx B, van Beem RT , et al. Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial. BMC Surg 2013; 13: 22