Title: Thrombomodulin-modified thrombin generation testing detects a hypercoagulable state in patients with cirrhosis regardless of the exact experimental conditions
Abstract: Patients with cirrhosis have substantial alterations in their hemostatic system due to impaired synthesis and/or catabolism of hemostatic proteins [ [1] Lisman T. Leebeek F.W. de Groot P.G. Haemostatic abnormalities in patients with liver disease. J Hepatol. 2002; 37: 280-287 Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar ]. Despite this, coagulation potential appears intact due to a concomitant decline of pro- and anticoagulant proteins [ [2] Lisman T. Porte R.J. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood. 2010; 116: 878-885 Crossref PubMed Scopus (414) Google Scholar ]. Evidence for a rebalanced status has been provided by several studies in which thrombin generation (TG) tests were performed in presence of thrombomodulin (TM) or Protac®, a thrombin-dependent or direct activator of the anticoagulant protein C system, respectively. Initially it was reported that thrombin generation with such a modified thrombin generation test was equal to that of healthy volunteers [ [3] Tripodi A. Salerno F. Chantarangkul V. Clerici M. Cazzaniga M. Primignani M. et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005; 41: 553-558 Crossref PubMed Scopus (512) Google Scholar ]. However, subsequent studies reported enhanced thrombin generation in patients [ 4 Gatt A. Riddell A. Calvaruso V. Tuddenham E.G. Makris M. Burroughs A.K. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost. 2010; 8: 1994-2000 Crossref PubMed Scopus (153) Google Scholar , 5 Lisman T. Bakhtiari K. Pereboom I.T.A. Hendriks H.G.D. Meijers J.C.M. Porte R.J. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol. 2010; 52: 355-361 Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar , 6 Kleinegris M.C. Habets C. van de Sande D. Henskens Y. ten Cate-Hoek A. van Deursen C. et al. Liver cirrhosis is associated with hypercoagulability, decreased clot strength and normal fibrinolysis. J Thromb Haemost. 2013; 11: 49-50 Google Scholar , 7 Chaireti R. Rajani R. Berqquist A. Melin T. Friis-Liby I.L. Kapraali M. et al. Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event. Thromb Res. 2014; 134: 455-461 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar ]. Better insight in whether patients with cirrhosis are normo- or hypercoagulable is essential in the discussions on prophylactic antithrombotic therapy for these patients [ 8 Lisman T. Kamphuisen P.W. Northup P.G. Porte R.J. Established and new-generation antithrombotic drugs in patients with cirrhosis - possibilities and caveats. J Hepatol. 2013; 59: 358-366 Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar , 9 Northup P.G. Intagliata N.M. Anticoagulation in cirrhosis patients: what don't we know?. Liver Int. 2011; 31: 4-6 Crossref PubMed Scopus (14) Google Scholar ]. The discrepancies between the studies might reflect differences in patient selection or differences in test conditions. Different concentrations and sources of TM have been used in TM-modified TG assays. For example Potze et al. [ [10] Potze W. Arshad F. Adelmeijer J. Blokzijl H. van den Berg A.P. Meijer J.C. et al. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PLoS One. 2014; 9 ([in press])https://doi.org/10.1371/journal.pone.0088390 Crossref PubMed Scopus (66) Google Scholar ] used a commercially available reagent with an unknown concentration of TM, Youngwon et al. [ [11] Youngwon N. Kim J.E. Lim H.S. Han K.S. Kim H.K. Coagulation proteins influencing global coagulation assays in cirrhosis: hypercoagulability in cirrhosis assessed by thrombomodulin-induced thrombin generation assay. Biomed Res Int. 2013; ([in press])https://doi.org/10.1155/2013/856754 Crossref PubMed Scopus (22) Google Scholar ] used both 5nM and 2,5nM of TM, while Tripodi et al. [ [3] Tripodi A. Salerno F. Chantarangkul V. Clerici M. Cazzaniga M. Primignani M. et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005; 41: 553-558 Crossref PubMed Scopus (512) Google Scholar ] and Chaireti et al. [ [7] Chaireti R. Rajani R. Berqquist A. Melin T. Friis-Liby I.L. Kapraali M. et al. Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event. Thromb Res. 2014; 134: 455-461 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar ] used 4nM TM. Tripodi et al. [ [3] Tripodi A. Salerno F. Chantarangkul V. Clerici M. Cazzaniga M. Primignani M. et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005; 41: 553-558 Crossref PubMed Scopus (512) Google Scholar ] and Potze et al. [ [10] Potze W. Arshad F. Adelmeijer J. Blokzijl H. van den Berg A.P. Meijer J.C. et al. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PLoS One. 2014; 9 ([in press])https://doi.org/10.1371/journal.pone.0088390 Crossref PubMed Scopus (66) Google Scholar ] triggered the coagulation with 1pM of tissue factor (TF). In the study of Youngwon et al. [ [11] Youngwon N. Kim J.E. Lim H.S. Han K.S. Kim H.K. Coagulation proteins influencing global coagulation assays in cirrhosis: hypercoagulability in cirrhosis assessed by thrombomodulin-induced thrombin generation assay. Biomed Res Int. 2013; ([in press])https://doi.org/10.1155/2013/856754 Crossref PubMed Scopus (22) Google Scholar ] both 1pM and 5pM of TF were used to trigger coagulation. We measured thrombin generation at varying concentrations of thrombomodulin and TF, to investigate whether the normal- or hypercoagulable state observed in liver disease patients is dependent on the test conditions used in the TG assay.
Publication Year: 2014
Publication Date: 2014-07-17
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 43
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