Bleeding and Thrombotic Complications in Patients With Cirrhosis: A State-of-the-Art Appraisal

Abstract

Much has evolved over the past 25 years regarding our understanding of the coagulopathy of liver disease. Paradoxically, this form of coagulopathy is relatively hypercoagulability despite the common clinical impression of a hemorrhagic tendency. The latter is largely driven by portal-mesenteric venous pressure (ie, portal hypertension) and has little to do with hemostatic pathways. It cannot be emphasized enough that the INR does not offer a meaningful measure in this situation and may lead to interventions such as fresh frozen plasma that can actually worsen portal pressure and hence pressure-driven bleeding. With regard to procedure-related bleeding, we point out substantial differences in the definition of high-risk procedures and propose a new operational definition dependent on the applicability of local hemostatic measures, although this requires further investigation. The common occurrence of venous thrombosis in these patients requires careful consideration of hemostatic pathways and overall risk and benefit of intervention. The decision regarding anticoagulation therapy needs to be driven not only by a global assessment including history of non–portal hypertensive–related bleeding, but also by fall risk which can result in head trauma in patients prone to encephalopathy. This is probably best estimated by frailty but has yet to be adequately investigated. In the background of these concerns, several superimposed and complex conditions including infections and renal dysfunction should be taken into account. Inherited forms of thrombophilia in the setting of cirrhosis perhaps do not outweigh the thrombophilia inherent to liver disease but warrant further consideration. Much has evolved over the past 25 years regarding our understanding of the coagulopathy of liver disease. Paradoxically, this form of coagulopathy is relatively hypercoagulability despite the common clinical impression of a hemorrhagic tendency. The latter is largely driven by portal-mesenteric venous pressure (ie, portal hypertension) and has little to do with hemostatic pathways. It cannot be emphasized enough that the INR does not offer a meaningful measure in this situation and may lead to interventions such as fresh frozen plasma that can actually worsen portal pressure and hence pressure-driven bleeding. With regard to procedure-related bleeding, we point out substantial differences in the definition of high-risk procedures and propose a new operational definition dependent on the applicability of local hemostatic measures, although this requires further investigation. The common occurrence of venous thrombosis in these patients requires careful consideration of hemostatic pathways and overall risk and benefit of intervention. The decision regarding anticoagulation therapy needs to be driven not only by a global assessment including history of non–portal hypertensive–related bleeding, but also by fall risk which can result in head trauma in patients prone to encephalopathy. This is probably best estimated by frailty but has yet to be adequately investigated. In the background of these concerns, several superimposed and complex conditions including infections and renal dysfunction should be taken into account. Inherited forms of thrombophilia in the setting of cirrhosis perhaps do not outweigh the thrombophilia inherent to liver disease but warrant further consideration. Our understanding of coagulation disorders in liver disease patients has significantly evolved over the past 25 years. At the crux of these changes is our perception of the ubiquitous laboratory test called the international normalized ratio (INR). The test is derived from the prothrombin time (PT), which reflects the activity of liver-derived clotting factors I, II, V, VII, and X and the term normalization that refers to the results being adjusted among patients treated with vitamin K antagonists (VKAs) (such as warfarin) to account for variation in the activity of proprietary thromboplastins—a key reagent in measuring the PT. Bleeding in liver disease patients is a common problem, for example in variceal hemorrhage or possibly as a procedure-related complication. Because the liver synthesizes most of the key clotting factors, prolongation of the PT and hence the INR is common in patients with liver dysfunction. A relationship between a prolonged PT/INR and clinical bleeding in liver disease seemed obvious enough that for decades this was passed down through generations of trainees essentially as dogma through all fields of medicine. As a result, the emergence of data that convincingly refuted the apparent relationship has only slowly been taken up beyond the immediate fields of hepatology and hematology. It was a convergence of developments around the turn of the century that underpinned these changing concepts of cirrhotic coagulopathy. These developments included the emergence of a more global and practical view of the clotting cascade in the cell-based model of hemostasis and the subsequent development of recombinant activated factor VII.1Hedner U. Recombinant coagulation factor VIIa: from the concept to clinical application in hemophilia treatment in 2000.Semin Thromb Hemost. 2000; 26: 363-366Crossref PubMed Google Scholar Although the agent did not become a significantly useful tool for bleeding in cirrhosis, its development helped to shift emphasis away from the older notion of the intrinsic and extrinsic hemostatic pathways to newer and more global concepts of the clotting cascade in the cell-based model of hemostasis.1Hedner U. Recombinant coagulation factor VIIa: from the concept to clinical application in hemophilia treatment in 2000.Semin Thromb Hemost. 2000; 26: 363-366Crossref PubMed Google Scholar Seminal work from Armando Tripodi and his team, further described subsequently, also raised questions about the interpretation of a number of the conventional tests of hemostasis in cirrhosis patients. In addition, work from Ian Wanless and his team raised the question of an intrahepatic thrombotic process in the development of organ atrophy and resultant clinical deterioration.2Wanless I.R. Wong F. Blendis L.M. et al.Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension.Hepatology. 1995; 21: 1238-1247PubMed Google Scholar The first international meeting of the Coagulation in Liver Disease group in 2005 brought together many of these clinical investigators from diverse backgrounds to share data and experiences.3Caldwell S.H. Hoffman M. Lisman T. et al.Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.Hepatology. 2006; 44: 1039-1046Crossref PubMed Scopus (377) Google Scholar Tripodi and colleagues, demonstrated that the acquired deficiency of liver-synthesized protein C in cirrhosis combined with the preserved function of its co-factor, endothelial-derived thrombomodulin, results in a relatively hypercoagulable state measurable with the thrombin generation assay performed with and without thrombomodulin.4Tripodi A. Salerno F. Chantarangkul V. et al.Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests.Hepatology. 2005; 41: 553-558Crossref PubMed Scopus (538) Google Scholar,5Tripodi A. Primignani M. Chantarangkul V. et al.Thrombin generation in patients with cirrhosis: the role of platelets.Hepatology. 2006; 44: 440-445Crossref PubMed Scopus (299) Google Scholar This work also clearly demonstrated the deficiencies of the INR as a measure of hemostatic pathways in liver disease, as the PT/INR is dependent only on liver-derived procoagulant factors and does not take into account the significant deficiencies of liver-derived anticoagulant factors such as protein C. Around this time, Trotter and colleagues demonstrated remarkable interlaboratory variation in the PT/INR of patients with cirrhosis depending on use of various commercially available thromboplastins normalized to warfarin-treated patients, rather than liver disease patients.6Trotter J.F. Olson J. Lefkowitz J. et al.Changes in international normalized ratio (INR) and model for liver disease on of clinical PubMed Scopus Google Scholar This to further that demonstrated variation between clinical activity is normalized to a of cirrhosis patients as the rather than warfarin-treated A. Chantarangkul V. Primignani M. et international normalized ratio for cirrhosis prothrombin time results for model for liver disease PubMed Scopus Google V. et international normalized ratio as an of prothrombin time in PubMed Scopus Google Scholar the on as a practical clinical these also raised as yet about interlaboratory variation in the of Liver Disease which INR as a and is to assessment of disease and organ key development in this was the by Lisman and colleagues that the of in cirrhosis, to is significantly by the in derived factor which hemostatic activity the of T. J. et of in cirrhosis despite 2006; 44: PubMed Scopus Google Scholar factors that to to a state of hypercoagulability an acquired deficiency of liver-derived and endothelial-derived factor which to the state of A. T. T. et al.Thrombin generation and cirrhosis: state of the and Thromb Hemost. PubMed Scopus Google Scholar from these was the concept of a hemostatic in cirrhosis, which may actually be This is apparent in the common of cirrhotic portal vein thrombosis and in the occurrence of vein thrombosis in liver disease F. V. et and clotting a for portal vein thrombosis in Google et does not cirrhosis patients from venous 2006; PubMed Scopus Google S.H. Tripodi A. and treatment of portal vein thrombosis in patients with and without PubMed Google Scholar A has hypercoagulability as a of and can be as a of but we that the current of hypercoagulability as a significant factor in T. 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