Abstract
Hepatic cirrhosis is characterized by complex abnormalities of the fibrinolytic system. Little is known about the possible association between these alterations and thrombosis. The aim of this study was to evaluate the fibrinolytic profile in cirrhotic individuals with and without portal vein thrombosis (PVT). We measured thrombin activatable fibrinolysis inhibitor (TAFI), total amount of activated TAFI (TAFIa/ai), plasminogen activator inhibitor (PAI-1), plasminogen and fibrinogen plasma levels in 66 cirrhotic patients (33 with and 33 without PVT) and in 66 healthy volunteers. TAFI plasma levels (median [range]) were significantly lower in cirrhotic individuals (5.6 μg/ml [1.7–11.7]) than in controls (10.1 μg/ml [6.6–14.2], p < 0.0001), while TAFIa/ai levels were significantly higher in cases (18.3 ng/ml [0.3–35.4]) than in controls (15.9 ng/ml [7.4–41], p = 0.02). Cirrhotic patients with PVT had higher TAFI (6.6 μg/ml [2.9–10.1]), TAFIa/ai (19.2 ng/ml [11.6–35.4]) and PAI-1 (33.1 ng/ml [27.6–56.3]) plasma levels than those without PVT (3.9 μg/ml [1.7–11.7], p = 0.001; 15.6 ng/ml [10.3–33.9], p = 0.037; 15.9 ng/ml [2.5–29.1], p = 0.004. The fibrinolytic profile in cirrhotic individuals with PVT is characterized by higher levels of TAFI, TAFIa/ai and PAI-1 than in those without PVT. These alterations identify a hypofibrinolytic condition that may increase the risk of developing a thrombotic event.
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References
Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy KR, Tripodi A, Sanyal AJ (2006) Coagulation in Liver Disease Group. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology 44:1039–1046
Tripodi A, Primignani M, Chantarangkul V, Dell’Era A, Clerici M, de Franchis R, Colombo M, Mannucci PM (2009) An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 137:2105–2111
Tripodi A, Legnani C, Chantarangkul V, Cosmi B, Palareti G, Mannucci PM (2008) High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism. J Thromb Haemost 6:1327–1333
Martinelli I, Primignani M, Aghemo A, Reati R, Bucciarelli P, Fabris F, Battaglioli T, Dell’Era A, Mannucci PM (2009) High levels of factor VIII and risk of extra-hepatic portal vein obstruction. J Hepatol 50:916–922
Søgaard KK, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen HT (2009) Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case–control study. Am J Gastroenterol 104:96–101
Amitrano L, Brancaccio V, Guardascione MA, Margaglione M, Sacco M, Martino R, De Nucci C, Mosca S, Iannaccone L, Ames PR, Romano L, Balzano A (2002) Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia. Endoscopy 34:535–538
Mangia A, Villani MR, Cappucci G, Santoro R, Ricciardi R, Facciorusso D, Leandro G, Caruso N, Andriulli A (2005) Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors. Eur J Gastroenterol Hepatol 17:745–751
Denninger MH, Chaït Y, Casadevall N, Hillaire S, Guillin MC, Bezeaud A, Erlinger S, Briere J, Valla D (2000) Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology 31:587–591
Amitrano L, Guardascione MA, Brancaccio V, Margaglione M, Manguso F, Iannaccone L, Grandone E, Balzano A (2004) Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 40:736–741
Ogston D, Bennett B, Ogston CM (1971) The fibrinolytic enzyme system in hepatic cirrhosis and malignant metastases. J Clin Pathol 24:822–826
Huber K, Kirchheimer JC, Korninger C, Binder BR (1991) Hepatic synthesis and clearance of components of the fibrinolytic system in healthy volunteers and in patients with different stages of liver cirrhosis. Thromb Res 62:491–500
Simpson AJ, Booth NA, Moore N, Bennett B (1990) The platelet and plasma pools of plasminogen activator inhibitor (PAI-1) vary independently in disease. Br J Haematol 75:54354–54358
Folsom AR, Cushman M, Heckbert SR, Rosamond WD, Aleksic N (2003) Prospective study of fibrinolytic markers and venous thromboembolism. J Clin Epidemiol 56:598–603
Prins MH, Hirsh J (1991) A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 151:1721–1731
Meltzer ME, Lisman T, de Groot PG, Meijers JC, le Cessie S, Doggen CJ, Rosendaal FR (2010) Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 116:113–121
Hoekstra J, Guimarães AH, Leebeek FW, DarwishMurad S, Malfliet JJ, Plessier A et al (2010) European Network for Vascular Disorders of the Liver (EN-Vie). Impaired fibrinolysis as a risk factor for Budd–Chiari syndrome. Blood 115:388–395
Balta G, Altay C, Gurgey A (2002) PAI-1 gene 4G/5G genotype: a risk factor for thrombosis in vessels of internal organs. Am J Hematol 71:89–93
Ben-Ari Z, Osman E, Hutton RA, Burroughs AK (1999) Disseminated intravascular coagulation in liver cirrhosis: fact or fiction? Am J Gastroenterol 94:2977–2982
Paramo JA, Rocha E (1993) Hemostasis in advanced liver disease. Semin Thromb Hemost 19:184–190
Wilde JT, Kitchen S, Kinsey S, Greaves M, Preston FE (1989) Plasma-D-dimer levels and their relationship to serum fibrinogen/fibrin degradation products in hypercoagulable states. Br J Haematol 71:65–70
Vukovich T, Teufelsbauer H, Fritzer M, Kreuzer S, Knoflach P (1995) Hemostasis activation in patients with liver cirrhosis. Thromb Res 77:271–278
Colucci M, Binetti BM, Branca MG, Clerici C, Morelli A, Semeraro N, Gresele P (2003) Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 38:230–237
Lisman T, Leebeek FW, Mosnier LO, Bouma BN, Meijers JC, Janssen HL, Nieuwenhuis HK, De Groot PG (2001) Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 121:131–139
Tripodi A, Primignani M, Mannucci PM (2010) Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged. Intern Emerg Med 5:7–12
Bouma BN, Mosnier LO (2003) Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis. Pathophysiol Haemost Thromb 33:375–381
Bajzar L (2000) Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol 20:2511–2518
Bajzar L, Morser J, Nesheim M (1996) TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombinthrombomodulin complex. J Biol Chem 271:603–608
Nesheim M, Wang W, Boffa M, Nagashima M, Morser J, Bajzar L (1997) Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 78:386–391
Van Tilburg NH, Rosendaal FR, Bertina RM (2000) Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 95:2855–2859
Colucci M, Binetti BM, Tripodi A, Chantarangkul V, Semeraro N (2004) Hyperthrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism. Blood 103:2157–2161
Rossetto V, Spiezia L, Senzolo M, Rodriguez K, Gavasso S, Woodhams B, Simioni P (2012) Factor VIIa-antithrombin complexes in patients with non-neoplastic portal vein thrombosis with and without cirrhosis. Int J Lab Hematol 35:101–105
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646–649
Haddad MC, Clark DC, Sharif HS, al Shahed M, Aideyan O, Sammak BM (1992) MR, CT, and ultrasonography of splanchnic venous thrombosis. GastrointestRadiol 17:34–40
Spiezia L, Rossetto V, Campello E, Gavasso S, Woodhams B, Tormene D, Simioni P (2010) Factor VIIa-antithrombin complexes in patients with arterial and venous thrombosis. Thromb Haemost 03:1188–1192
Tregouet DA, Schnabel R, Alessi MC, Godefroy T, Declerck PJ, Nicaud V, Munzel T, Bickel C, Rupprecht HJ, Lubos E, Zeller T, Juhan-Vague I, Blankenberg S, Tiret L, Morange PE (2009) Activated thrombin activatable fibrinolysis inhibitor levels are associated with the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 1:49–57
Verdú J, Pascual M, Benlloch S, Snachez J, Lucas J (2006) Thrombin activatable fibrinolysis inhibitor (TAFI) polymorphisms and plasma TAFI levels measured with an ELISA insensitive to isoforms in patients with venous thromboembolic disease (VTD). Thromb Haemost 95:585–586
Declerck PJ, Alessi MC, Verstreken M, Kruithof EK, Juhan-Vague I, Collen D (1988) Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 71:220–225
Declerck PJ, Collen D (1990) Measurement of plasminogen activator inhibitor (PAI-1) in plasma with various monoclonal antibody-based enzyme-linked immunosorbent assays. Thromb Res Suppl X:3–9
Leiper K, Croll A, Booth NA, Moore NR, Sinclair T, Bennett B (1994) Tissue plasminogen activator, plasminogen activator inhibitors, and activator-inhibitor complex in liver disease. J Clin Pathol 47:214–217
Ferguson JW, Helmy A, Ludlam C, Webb DJ, Hayes PC, Newby DC (2008) Hyperfibrinolysis in alcoholic cirrhosis: relative plasminogen activator inhibitor type 1 deficiency. Thromb Res 121:675–680
Zhang D, Hao J, Yang N (2010) Protein C and D-dimer are related to portal vein thrombosis in patients with liver cirrhosis. J Gastroenterol Hepatol l25:116–121
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None except Barry Woodhams, ex Scientific Director at DiagnosticaStago, who now works as a consultant (HaemaCon Ltd, Bromley, UK).
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Rossetto, V., Spiezia, L., Senzolo, M. et al. Does decreased fibrinolysis have a role to play in the development of non-neoplastic portal vein thrombosis in patients with hepatic cirrhosis?. Intern Emerg Med 9, 397–403 (2014). https://doi.org/10.1007/s11739-013-0929-7
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DOI: https://doi.org/10.1007/s11739-013-0929-7