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Coagulation Disorders and Bleeding in Liver Disease: Future Directions
Coag ulation Disorders a nd Ble eding in Liver Dis eas e : Future Direc tions Stephen H. Caldwell, MDa,*, Arun J. Sanyal, MDb KEYWORDS Coagulation Bleeding Cirrhosis Liver disease Hyperfibrinolysis Dysfibrinogen Heparinoids
From the foregoing articles, it is evident that several long-held tenets regarding the pathophysiology and assessment of coagulopathy in liver disease are undergoing scrutiny and revision. Among the most important concepts to emerge over the past few years is that the typical cirrhotic patient has multiple and frequently opposing factors that influence hemostasis and clot formation and, perhaps most importantly, that the conventional international normalized ratio (INR) is a limited measure of this disturbance, especially in terms of predicting adequate, excessive, or inadequate clot formation. Coupled with the limitations and risks associated with blood product infusion, this situation calls into question many common clinical practices and increases the need for clinical and laboratory-based investigation. BLEEDING RISK ASSESSMENT
Bleeding risk assessment affects many day-to-day aspects of the clinical practice of hepatology, from the mundane rescheduling of a procedure because of a prolonged INR to life-threatening anasarca or transfusion-associated lung injury, with the excessive and often counterproductive administration of plasma. The use of plasma to correct INR preprocedure to some arbitrary number, however, completely misses the pathways measured by this test and the pathophysiology leading to its prolongation. One example is its use in a patient in liver failure from initially unrecognized Budd-Chiari syndrome whose INR was prolonged to 9 seconds but whose research thromboelastogram clearly identified a hypercoagulable state.
a
GI/Hepatology Division, Digestive Health Center of Excellence, University of Virginia Medical Center, Box 800708, Charlottesville, VA 22908 0708, USA b Division of GI/Hepatology and Nutrition, Department of Internal Medicine, VCU School of Medicine, MCV Box 980341, Richmond, VA 23298 0341, USA * Corresponding author. E-mail address: [email protected] (S.H. Caldwell). Clin Liver Dis 13 (2009) 155–157 doi:10.1016/j.cld.2008.09.011 1089-3261/08/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
liver.theclinics.com
156
Caldwell & Sanyal
Clearly, patients who have liver failure, whether acute or acute-on-chronic failure, may have serious bleeding problems. A pressing need exists to develop, validate, and disseminate a global measure of coagulation that is clinically meaningful. Some candidate tests that are under evaluation include thromboelastography, endogenous thrombin generation, and platelet function. In other words, translational research is essential to apply the recent laboratory advances, to define more precisely where a given patient is in terms of coagulation and hemostasis and thus how to apply the most appropriate management strategy. Indeed, inappropriate reliance on the INR and failure to risk stratify bleeding risk effectively in cirrhosis may explain, in part, the variable results seen in many of the recombinant factor VIIa trials over the past 10 years (see the article by Shah and colleagues elsewhere in this issue). BLOOD PRODUCT AND PROCOAGULANT USE IN CIRRHOSIS
It is increasingly recognized that changes in conventional patterns of blood product use in clinical practice are warranted. However, to define such an undertaking better, it is helpful to understand how these products are being used in current practice. To this end, efforts are underway to measure total blood product use in patients who have liver disease at multiple centers around the world, to assess common practices and to determine variation in practice and assess indications and outcomes of their use. It is hoped that such a ‘‘snapshot’’ of current practice will provide some guidance in the development of clinical investigation to ‘‘translate’’ recent laboratory advances into improved clinical care. IMPLEMENTATION OF THE INTERNATIONAL NORMALIZED RATIOLIVER?
Two studies from centers in Italy and France (see article by Tripodi and colleagues in this issue) have independently demonstrated the usefulness of a new version of the INR that is free of the coumadin-based reference range.1,2 It takes into account many of the unique aspects of the coagulopathy of liver disease and it results in remarkable reproducibility. Thus, the prospect seems feasible of eradicating the significant interlaboratory variation in INR and, hence, in the Model for End-Stage Liver Disease (MELD) score that Trotter and colleagues have demonstrated in the United States (see article by Arjal and Trotter in this issue) and which has been more recently demonstrated in Europe by Lisman and colleagues.3,4 However, proponents of the MELD score, although acknowledging the potential usefulness of the INRliver, note the excellent performance of the MELD score using the conventional INR and the difficulty in implementing a new standard. Nonetheless, the prospect of significant variation of the MELD (up to 20%) using the conventional INR, and the implications of this situation for organ allocation, warrant efforts to develop the INRliver as the new standard by which MELD is measured, which clearly presents a challenge in implementing a broad change in laboratory practice. However, the growing impact on health care of chronic liver disease due to viral hepatitis, nonalcoholic steatohepatitis, and alcohol-related liver disease support the need to address this problem effectively. PROGRESSION OF CIRRHOSIS DUE TO PARENCHYMAL EXTINCTION
Cirrhosis, which is commonly tagged with the adjective ‘‘end-stage,’’ is often a stable condition, potentially for many years. Several developments can underlie deterioration of stable cirrhosis to the state commonly referred to as ‘‘decompensated cirrhosis.’’ Liver atrophy is often an associated finding in this state, which usually does represent an ‘‘end-stage’’ condition. Wanless and colleagues were the first to demonstrate the
Coagulation Disorders and Bleeding in Liver Disease
role of prothrombotic conditions in causing diffuse atrophy through a process they called ‘‘parenchymal extinction’’ (see the articles by Anstee and colleagues and Northup in this issue).5 The mechanisms involved appear to be more complex than simple stasis and clot formation, although these may certainly contribute. Rather, the process may also involve thrombin-related signaling pathways and possibly platelet activation. Recognition of this process as a common means by which cirrhosis progresses raises the prospect of some form of anticoagulation as a means of preventing organ atrophy. Further studies of this provocative strategy are clearly warranted. SUMMARY
Much has changed since the seminal paper of Boks and colleagues, which demonstrated the wide spectrum of abnormalities in the coagulation system in patients who have acute and chronic liver disease and the possible role of hyperfibrinolysis in bleeding in many of these patients.6 With a growing number of therapeutic options and increasing recognition of the inherent limitations of conventional laboratory measures of coagulation in the patient who has liver disease, it is now incumbent on us to explore how best to apply (or withhold) specific agents in specific situations. This exploration will clearly require well-focused translational research to understand and bring into sharp focus the various problems present, from dysfibrinogen to endogenous heparinoids, to uremia, to hypercoagulable conditions. The challenge lies ahead. REFERENCES
1. Tripodi A. How to implement the modified international normalized ratio for cirrhosis (INR(liver)) for model for end-stage liver disease calculation. Hepatology 2008; 47:1423–4. 2. Bellest L, Eschwege V, Poupon R, et al. A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology. Hepatology 2007;46:528–34. 3. Trotter JF, Olson J, Lefkowitz J, et al. Changes in international normalized ratio (INR) and Model for End-Stage Liver Disease (MELD) based on selection of clinical laboratory. Am J Transpl 2007;7:1624–8. 4. Lisman T, van Leeuwen Y, Adelmeijer J, et al. Interlaboratory variability in assessment of the model of end-stage liver disease score. Liver International 2008;28: 1344–51. 5. Wanless IR, Wong F, Blendis LM, et al. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995;21:1238–47. 6. Boks AL, Brommer EJ, Schalm SW, et al. Hemostasis and fibrinolysis in severe liver failure and their relation to hemorrhage. Hepatology 1986;6:79–86.
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From the foregoing articles, it is evident that several long-held tenets regarding the pathophysiology and assessment of coagulopathy in liver disease are undergoing scrutiny and revision. Among the most important concepts to emerge over the past few years is that the typical cirrhotic patient has multiple and frequently opposing factors that influence hemostasis and clot formation and, perhaps most importantly, that the conventional international normalized ratio (INR) is a limited measure of this disturbance, especially in terms of predicting adequate, excessive, or inadequate clot formation. Coupled with the limitations and risks associated with blood product infusion, this situation calls into question many common clinical practices and increases the need for clinical and laboratory-based investigation. BLEEDING RISK ASSESSMENT
Bleeding risk assessment affects many day-to-day aspects of the clinical practice of hepatology, from the mundane rescheduling of a procedure because of a prolonged INR to life-threatening anasarca or transfusion-associated lung injury, with the excessive and often counterproductive administration of plasma. The use of plasma to correct INR preprocedure to some arbitrary number, however, completely misses the pathways measured by this test and the pathophysiology leading to its prolongation. One example is its use in a patient in liver failure from initially unrecognized Budd-Chiari syndrome whose INR was prolonged to 9 seconds but whose research thromboelastogram clearly identified a hypercoagulable state.
a
GI/Hepatology Division, Digestive Health Center of Excellence, University of Virginia Medical Center, Box 800708, Charlottesville, VA 22908 0708, USA b Division of GI/Hepatology and Nutrition, Department of Internal Medicine, VCU School of Medicine, MCV Box 980341, Richmond, VA 23298 0341, USA * Corresponding author. E-mail address: [email protected] (S.H. Caldwell). Clin Liver Dis 13 (2009) 155–157 doi:10.1016/j.cld.2008.09.011 1089-3261/08/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
liver.theclinics.com
156
Caldwell & Sanyal
Clearly, patients who have liver failure, whether acute or acute-on-chronic failure, may have serious bleeding problems. A pressing need exists to develop, validate, and disseminate a global measure of coagulation that is clinically meaningful. Some candidate tests that are under evaluation include thromboelastography, endogenous thrombin generation, and platelet function. In other words, translational research is essential to apply the recent laboratory advances, to define more precisely where a given patient is in terms of coagulation and hemostasis and thus how to apply the most appropriate management strategy. Indeed, inappropriate reliance on the INR and failure to risk stratify bleeding risk effectively in cirrhosis may explain, in part, the variable results seen in many of the recombinant factor VIIa trials over the past 10 years (see the article by Shah and colleagues elsewhere in this issue). BLOOD PRODUCT AND PROCOAGULANT USE IN CIRRHOSIS
It is increasingly recognized that changes in conventional patterns of blood product use in clinical practice are warranted. However, to define such an undertaking better, it is helpful to understand how these products are being used in current practice. To this end, efforts are underway to measure total blood product use in patients who have liver disease at multiple centers around the world, to assess common practices and to determine variation in practice and assess indications and outcomes of their use. It is hoped that such a ‘‘snapshot’’ of current practice will provide some guidance in the development of clinical investigation to ‘‘translate’’ recent laboratory advances into improved clinical care. IMPLEMENTATION OF THE INTERNATIONAL NORMALIZED RATIOLIVER?
Two studies from centers in Italy and France (see article by Tripodi and colleagues in this issue) have independently demonstrated the usefulness of a new version of the INR that is free of the coumadin-based reference range.1,2 It takes into account many of the unique aspects of the coagulopathy of liver disease and it results in remarkable reproducibility. Thus, the prospect seems feasible of eradicating the significant interlaboratory variation in INR and, hence, in the Model for End-Stage Liver Disease (MELD) score that Trotter and colleagues have demonstrated in the United States (see article by Arjal and Trotter in this issue) and which has been more recently demonstrated in Europe by Lisman and colleagues.3,4 However, proponents of the MELD score, although acknowledging the potential usefulness of the INRliver, note the excellent performance of the MELD score using the conventional INR and the difficulty in implementing a new standard. Nonetheless, the prospect of significant variation of the MELD (up to 20%) using the conventional INR, and the implications of this situation for organ allocation, warrant efforts to develop the INRliver as the new standard by which MELD is measured, which clearly presents a challenge in implementing a broad change in laboratory practice. However, the growing impact on health care of chronic liver disease due to viral hepatitis, nonalcoholic steatohepatitis, and alcohol-related liver disease support the need to address this problem effectively. PROGRESSION OF CIRRHOSIS DUE TO PARENCHYMAL EXTINCTION
Cirrhosis, which is commonly tagged with the adjective ‘‘end-stage,’’ is often a stable condition, potentially for many years. Several developments can underlie deterioration of stable cirrhosis to the state commonly referred to as ‘‘decompensated cirrhosis.’’ Liver atrophy is often an associated finding in this state, which usually does represent an ‘‘end-stage’’ condition. Wanless and colleagues were the first to demonstrate the
Coagulation Disorders and Bleeding in Liver Disease
role of prothrombotic conditions in causing diffuse atrophy through a process they called ‘‘parenchymal extinction’’ (see the articles by Anstee and colleagues and Northup in this issue).5 The mechanisms involved appear to be more complex than simple stasis and clot formation, although these may certainly contribute. Rather, the process may also involve thrombin-related signaling pathways and possibly platelet activation. Recognition of this process as a common means by which cirrhosis progresses raises the prospect of some form of anticoagulation as a means of preventing organ atrophy. Further studies of this provocative strategy are clearly warranted. SUMMARY
Much has changed since the seminal paper of Boks and colleagues, which demonstrated the wide spectrum of abnormalities in the coagulation system in patients who have acute and chronic liver disease and the possible role of hyperfibrinolysis in bleeding in many of these patients.6 With a growing number of therapeutic options and increasing recognition of the inherent limitations of conventional laboratory measures of coagulation in the patient who has liver disease, it is now incumbent on us to explore how best to apply (or withhold) specific agents in specific situations. This exploration will clearly require well-focused translational research to understand and bring into sharp focus the various problems present, from dysfibrinogen to endogenous heparinoids, to uremia, to hypercoagulable conditions. The challenge lies ahead. REFERENCES
1. Tripodi A. How to implement the modified international normalized ratio for cirrhosis (INR(liver)) for model for end-stage liver disease calculation. Hepatology 2008; 47:1423–4. 2. Bellest L, Eschwege V, Poupon R, et al. A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology. Hepatology 2007;46:528–34. 3. Trotter JF, Olson J, Lefkowitz J, et al. Changes in international normalized ratio (INR) and Model for End-Stage Liver Disease (MELD) based on selection of clinical laboratory. Am J Transpl 2007;7:1624–8. 4. Lisman T, van Leeuwen Y, Adelmeijer J, et al. Interlaboratory variability in assessment of the model of end-stage liver disease score. Liver International 2008;28: 1344–51. 5. Wanless IR, Wong F, Blendis LM, et al. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995;21:1238–47. 6. Boks AL, Brommer EJ, Schalm SW, et al. Hemostasis and fibrinolysis in severe liver failure and their relation to hemorrhage. Hepatology 1986;6:79–86.
157