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Coagulopathy and bleeding in liver disease
MANAGEMENT PROBLEMS IN LIVER DISEASE
bleeding.6 In a large UK national audit, 76% of cirrhotics with AVB were given red blood cells (RBCs), 35% fresh frozen plasma and 16% platelets.7,8 In a UK audit of blood component use in cirrhosis, 30% of all hospitalized patients with cirrhosis were given a blood component, either for treatment of bleeding or to address a perceived risk of bleeding.8 The evidence base to guide the use of blood components and haemostatic agents in cirrhosis is weak, and excessive RBC transfusion following gastrointestinal bleeding is not without risk.9 Liberal blood transfusion in patients with cirrhosis can lead to hypervolaemia, which increases bleeding severity and rebleeding, probably due to a direct effect on portal pressure.9
Coagulopathy and bleeding in liver disease Vipul Jairath
Abstract One of the many complications of cirrhosis is the development of a complex disorder of haemostasis with abnormal coagulation indices such as prolonged prothrombin time and low platelet count. Greater understanding of the thrombotic complications of cirrhosis has altered our traditional perception of liver disease as a pro-haemorrhagic disorder. Coagulation status in cirrhosis is now thought to be re-balanced in the stable state, but easily tipped towards a bleeding or thrombotic event in the setting of an appropriate trigger, such as hospitalization or infection.
Factors contributing to bleeding Infection is a well-known precipitant of bleeding in cirrhosis. This may result from the direct influence of portal haemodynamics or an effect on coagulation itself. For example, infection in cirrhosis has been associated with an increased concentration of circulating heparinoids, which may indirectly promote bleeding.10 In addition, uraemia, due to concomitant renal impairment in patients with cirrhosis, can also contribute to a bleeding tendency because of abnormal platelet-vessel wall interactions and platelet dysfunction.11,12 Platelets play an essential role in triggering of the coagulation cascade and in maintaining stable clots after episodes of bleeding. A low platelet count is seen in liver cirrhosis due to reduced production, sequestration in the spleen and increased turnover. As well as the reduction in platelet count, platelets may also be dysfunctional, although there is some evidence that an elevated level of von Willebrand factor in patients with liver cirrhosis partially compensates for defects in platelet number and function.13
Keywords cirrhosis; coagulation; thrombosis; variceal bleeding
Introduction Normal coagulation is dependent upon an interplay between opposing pro- and anticoagulant drivers to maintain physiological haemostasis and prevent unwanted episodes of bleeding or thrombosis. The end product of the coagulation cascade is the generation of thrombin, which cleaves soluble fibrinogen into fibrin to form a blood clot.1 Since the liver is the site of synthesis of almost all coagulation factors, patients with cirrhosis can develop a complex disorder of haemostasis, characterized by deficiencies in pro- and anticoagulant factors, anaemia, low platelet count, low fibrinogen concentration and evidence of excessive fibrinolysis. These derangements have led us to perceive cirrhosis as a prohaemorrhagic disorder. However, increasing evidence of the thrombotic complications associated with cirrhosis2,3 has challenged this assumption.4 We now consider coagulation in liver cirrhosis to be rebalanced, leading to a pro-coagulant phenotype with an increased propensity towards developing thrombosis.5
Liver disease and thrombosis What is less well appreciated is the thrombotic phenotype of patients with cirrhosis. Thromboses in the portal vasculature occur in 10e15% of patients with cirrhosis,14 probably because of sluggish blood flow through the liver due to intrahepatic portal hypertension. Moreover, several large population-based studies, in hospitalized patients as well as ambulant outpatients, have shown an increased incidence of peripheral venous thrombotic events such as deep vein thrombosis and pulmonary embolism.2,3,15 Aside from derangements in the coagulation cascade, other factors that may contribute to the risk of thrombo-embolism include immobility, hospitalization and increasing age. Venous thrombosis in patients with cirrhosis is clinically challenging due to the perceived risk of anticoagulation in patients at high risk of bleeding from varices or other sites, as well as the potential difficulty in monitoring anticoagulation. Furthermore, an increased risk of large vessel thrombotic complications in cirrhosis is counterintuitive, in the presence of conventional coagulation indices suggesting hypocoagulation and the frequent haemorrhagic complications observed in clinical practice. As well as large vessel thromboses, small vessel thromboses within the liver parenchyma also occur, and typically display a more indolent course. Histological examination of explanted human livers has shown that occlusion of intra-hepatic vasculature can lead to localized ischaemia and infarction, a process termed
Liver disease and bleeding The traditional dogma in undergraduate medical education was that patients with cirrhosis are auto-anticoagulated due to a prolonged prothrombin time (or an increased international normalized ratio) and a low platelet count. Bleeding episodes complicating cirrhosis range from the relatively trivial (e.g. purpura, gingival bleeding) through to life-threatening haemorrhage following acute variceal bleeding (AVB). Cirrhosis is also a major indication for the transfusion of blood components, not only to treat but also to prevent
Vipul Jairath BSc MBChB (hons) DPhil (Oxon) MRCP is a Locum Consultant Gastroenterologist at the John Radcliffe Hospital in Oxford and an NIHR Clinical Trials Fellow at the Oxford Clinical Trials Unit, UK. His research interests include clinical trials, outcomes research in gastrointestinal bleeding and coagulation abnormalities in liver and inflammatory bowel diseases. Competing interests: none declared.
MEDICINE 43:11
664
Ó 2015 Elsevier Ltd. All rights reserved.
MANAGEMENT PROBLEMS IN LIVER DISEASE
3 Sogaard KK, Horvath-Puho E, Gronbaek H, Jepsen P, Vilstrup H, Sorensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol 2009; 104: 96e101. 4 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365: 147e56. 5 Jairath V, Burroughs AK. Anticoagulation in patients with liver cirrhosis: complication or therapeutic opportunity? Gut 2013 Apr; 62: 479e82. 6 Wallis JP, Wells AW, Chapman CE. Changing indications for red cell transfusion from 2000 to 2004 in the North of England. Transfus Med 2006; 16: 411e7. 7 Hearnshaw SA. Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut 2011; 10: 1327e35. 8 Jairath V, Rehal S, Logan R, et al. Acute variceal haemorrhage in the United Kingdom: patient characteristics, management and outcomes in a nationwide audit. Dig Liver Dis 2014; 46: 419e26. 9 Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368: 11e21. 10 Senzolo M, Coppell J, Cholongitas E, et al. The effects of glycosaminoglycans on coagulation: a thromboelastographic study. Blood Coagul Fibrinolysis 2007; 18: 227e36. 11 Benigni A, Boccardo P, Galbusera M, et al. Reversible activation defect of the platelet glycoprotein IIbeIIIa complex in patients with uremia. Am J Kidney Dis 1993; 22: 668e76. 12 Escolar G, Cases A, Bastida E, et al. Uremic platelets have a functional defect affecting the interaction of von Willebrand factor with glycoprotein IIbeIIIa. Blood 1990; 76: 1336e40. 13 Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatol 2006; 44: 53e61. 14 Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010; 31: 366e74. 15 Ali M, Ananthakrishnan AN, McGinley EL, Saeian K. Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. Dig Dis Sci 2011; 56: 2152e9. 16 Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatol 1995; 21: 1238e47. 17 Villa E, Camma C, Marietta M, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterol 2012; 143. 1253e1260 e4. 18 Tripodi A, Mannucci PM. Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research. J Hepatol 2007; 46: 727e33. 19 Tripodi A, Primignani M, Chantarangkul V, et al. An imbalance of provs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterol 2009; 137: 2105e11. 20 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: 1994e2000. 21 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116: 878e85.
Factors associated with bleeding and thrombosis in liver cirrhosis17 Promoters of bleeding
Promoters of thrombosis
Thrombocytopenia
Deficiency in anticoagulant factors Elevated factor VIII Increased von Willebrand factor
Thrombocytopathy Deficiency in pro-coagulant factors Low fibrinogen Anaemia Hyperfibrinolysis
Deficiency of ADAMTS-13 gene Elevated circulating microvesicles
Table 1
‘parenchymal extinction’.16 Thus, a pro-thrombotic propensity may contribute to disease progression. A pilot trial of anticoagulation in patients with advanced cirrhosis at risk of portal vein thrombosis showed that the anticoagulated group had significantly better outcomes, a lower incidence of portal vein thrombosis and decompensation at 2 years, and improved survival.17
Measuring the coagulation profile in liver disease The apparent paradox between bleeding and thrombosis is easier to understand if one considers the tests used conventionally to measure coagulation. Assessment of coagulation status in daily clinical practice involves measurement of the prothrombin time (PT) and activated partial thromboplastin time (APTT), which are somewhat crude and static measures of coagulation. PT is sensitive only to thrombin generation, the endpoint of the clotting cascade, as a function of procoagulant factors and is insensitive to the inhibition of thrombin by anticoagulant factors.18 It does not provide an accurate assessment of bleeding risk in patients with cirrhosis, nor prognosis after invasive procedures or acute bleeding, but is nonetheless used routinely to guide transfusion for both the prevention and treatment of bleeding. Global tests of clotting such as thromboelastography or thrombin generation may be more accurate reflections of overall coagulation status. For example, thrombin generation assays using the plasma of patients with cirrhosis indicate a normal to hypercoagulable profile in comparison to healthy controls in the resting state.19,20 This is explained by a concomitant decrease in anticoagulant factors as well as the presence of procoagulant factors in cirrhosis. In stable cirrhosis, prolongation of PT is rarely associated with abnormal global assays of coagulation such as thrombin generation (TG) or thromboelastometry (ROTEM).4,21 Overall this has lead to the concept of ‘re-balanced haemostasis’,21 However, this new balance is precarious and may be tipped towards bleeding, thrombosis or even both, in the setting of an appropriate precipitant such as infection (Table 1). A REFERENCES 1 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258e64. 2 Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol 2010; 8: 800e5.
MEDICINE 43:11
665
Ó 2015 Elsevier Ltd. All rights reserved.
bleeding.6 In a large UK national audit, 76% of cirrhotics with AVB were given red blood cells (RBCs), 35% fresh frozen plasma and 16% platelets.7,8 In a UK audit of blood component use in cirrhosis, 30% of all hospitalized patients with cirrhosis were given a blood component, either for treatment of bleeding or to address a perceived risk of bleeding.8 The evidence base to guide the use of blood components and haemostatic agents in cirrhosis is weak, and excessive RBC transfusion following gastrointestinal bleeding is not without risk.9 Liberal blood transfusion in patients with cirrhosis can lead to hypervolaemia, which increases bleeding severity and rebleeding, probably due to a direct effect on portal pressure.9
Coagulopathy and bleeding in liver disease Vipul Jairath
Abstract One of the many complications of cirrhosis is the development of a complex disorder of haemostasis with abnormal coagulation indices such as prolonged prothrombin time and low platelet count. Greater understanding of the thrombotic complications of cirrhosis has altered our traditional perception of liver disease as a pro-haemorrhagic disorder. Coagulation status in cirrhosis is now thought to be re-balanced in the stable state, but easily tipped towards a bleeding or thrombotic event in the setting of an appropriate trigger, such as hospitalization or infection.
Factors contributing to bleeding Infection is a well-known precipitant of bleeding in cirrhosis. This may result from the direct influence of portal haemodynamics or an effect on coagulation itself. For example, infection in cirrhosis has been associated with an increased concentration of circulating heparinoids, which may indirectly promote bleeding.10 In addition, uraemia, due to concomitant renal impairment in patients with cirrhosis, can also contribute to a bleeding tendency because of abnormal platelet-vessel wall interactions and platelet dysfunction.11,12 Platelets play an essential role in triggering of the coagulation cascade and in maintaining stable clots after episodes of bleeding. A low platelet count is seen in liver cirrhosis due to reduced production, sequestration in the spleen and increased turnover. As well as the reduction in platelet count, platelets may also be dysfunctional, although there is some evidence that an elevated level of von Willebrand factor in patients with liver cirrhosis partially compensates for defects in platelet number and function.13
Keywords cirrhosis; coagulation; thrombosis; variceal bleeding
Introduction Normal coagulation is dependent upon an interplay between opposing pro- and anticoagulant drivers to maintain physiological haemostasis and prevent unwanted episodes of bleeding or thrombosis. The end product of the coagulation cascade is the generation of thrombin, which cleaves soluble fibrinogen into fibrin to form a blood clot.1 Since the liver is the site of synthesis of almost all coagulation factors, patients with cirrhosis can develop a complex disorder of haemostasis, characterized by deficiencies in pro- and anticoagulant factors, anaemia, low platelet count, low fibrinogen concentration and evidence of excessive fibrinolysis. These derangements have led us to perceive cirrhosis as a prohaemorrhagic disorder. However, increasing evidence of the thrombotic complications associated with cirrhosis2,3 has challenged this assumption.4 We now consider coagulation in liver cirrhosis to be rebalanced, leading to a pro-coagulant phenotype with an increased propensity towards developing thrombosis.5
Liver disease and thrombosis What is less well appreciated is the thrombotic phenotype of patients with cirrhosis. Thromboses in the portal vasculature occur in 10e15% of patients with cirrhosis,14 probably because of sluggish blood flow through the liver due to intrahepatic portal hypertension. Moreover, several large population-based studies, in hospitalized patients as well as ambulant outpatients, have shown an increased incidence of peripheral venous thrombotic events such as deep vein thrombosis and pulmonary embolism.2,3,15 Aside from derangements in the coagulation cascade, other factors that may contribute to the risk of thrombo-embolism include immobility, hospitalization and increasing age. Venous thrombosis in patients with cirrhosis is clinically challenging due to the perceived risk of anticoagulation in patients at high risk of bleeding from varices or other sites, as well as the potential difficulty in monitoring anticoagulation. Furthermore, an increased risk of large vessel thrombotic complications in cirrhosis is counterintuitive, in the presence of conventional coagulation indices suggesting hypocoagulation and the frequent haemorrhagic complications observed in clinical practice. As well as large vessel thromboses, small vessel thromboses within the liver parenchyma also occur, and typically display a more indolent course. Histological examination of explanted human livers has shown that occlusion of intra-hepatic vasculature can lead to localized ischaemia and infarction, a process termed
Liver disease and bleeding The traditional dogma in undergraduate medical education was that patients with cirrhosis are auto-anticoagulated due to a prolonged prothrombin time (or an increased international normalized ratio) and a low platelet count. Bleeding episodes complicating cirrhosis range from the relatively trivial (e.g. purpura, gingival bleeding) through to life-threatening haemorrhage following acute variceal bleeding (AVB). Cirrhosis is also a major indication for the transfusion of blood components, not only to treat but also to prevent
Vipul Jairath BSc MBChB (hons) DPhil (Oxon) MRCP is a Locum Consultant Gastroenterologist at the John Radcliffe Hospital in Oxford and an NIHR Clinical Trials Fellow at the Oxford Clinical Trials Unit, UK. His research interests include clinical trials, outcomes research in gastrointestinal bleeding and coagulation abnormalities in liver and inflammatory bowel diseases. Competing interests: none declared.
MEDICINE 43:11
664
Ó 2015 Elsevier Ltd. All rights reserved.
MANAGEMENT PROBLEMS IN LIVER DISEASE
3 Sogaard KK, Horvath-Puho E, Gronbaek H, Jepsen P, Vilstrup H, Sorensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol 2009; 104: 96e101. 4 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365: 147e56. 5 Jairath V, Burroughs AK. Anticoagulation in patients with liver cirrhosis: complication or therapeutic opportunity? Gut 2013 Apr; 62: 479e82. 6 Wallis JP, Wells AW, Chapman CE. Changing indications for red cell transfusion from 2000 to 2004 in the North of England. Transfus Med 2006; 16: 411e7. 7 Hearnshaw SA. Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut 2011; 10: 1327e35. 8 Jairath V, Rehal S, Logan R, et al. Acute variceal haemorrhage in the United Kingdom: patient characteristics, management and outcomes in a nationwide audit. Dig Liver Dis 2014; 46: 419e26. 9 Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368: 11e21. 10 Senzolo M, Coppell J, Cholongitas E, et al. The effects of glycosaminoglycans on coagulation: a thromboelastographic study. Blood Coagul Fibrinolysis 2007; 18: 227e36. 11 Benigni A, Boccardo P, Galbusera M, et al. Reversible activation defect of the platelet glycoprotein IIbeIIIa complex in patients with uremia. Am J Kidney Dis 1993; 22: 668e76. 12 Escolar G, Cases A, Bastida E, et al. Uremic platelets have a functional defect affecting the interaction of von Willebrand factor with glycoprotein IIbeIIIa. Blood 1990; 76: 1336e40. 13 Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatol 2006; 44: 53e61. 14 Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010; 31: 366e74. 15 Ali M, Ananthakrishnan AN, McGinley EL, Saeian K. Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. Dig Dis Sci 2011; 56: 2152e9. 16 Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatol 1995; 21: 1238e47. 17 Villa E, Camma C, Marietta M, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterol 2012; 143. 1253e1260 e4. 18 Tripodi A, Mannucci PM. Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research. J Hepatol 2007; 46: 727e33. 19 Tripodi A, Primignani M, Chantarangkul V, et al. An imbalance of provs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterol 2009; 137: 2105e11. 20 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: 1994e2000. 21 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116: 878e85.
Factors associated with bleeding and thrombosis in liver cirrhosis17 Promoters of bleeding
Promoters of thrombosis
Thrombocytopenia
Deficiency in anticoagulant factors Elevated factor VIII Increased von Willebrand factor
Thrombocytopathy Deficiency in pro-coagulant factors Low fibrinogen Anaemia Hyperfibrinolysis
Deficiency of ADAMTS-13 gene Elevated circulating microvesicles
Table 1
‘parenchymal extinction’.16 Thus, a pro-thrombotic propensity may contribute to disease progression. A pilot trial of anticoagulation in patients with advanced cirrhosis at risk of portal vein thrombosis showed that the anticoagulated group had significantly better outcomes, a lower incidence of portal vein thrombosis and decompensation at 2 years, and improved survival.17
Measuring the coagulation profile in liver disease The apparent paradox between bleeding and thrombosis is easier to understand if one considers the tests used conventionally to measure coagulation. Assessment of coagulation status in daily clinical practice involves measurement of the prothrombin time (PT) and activated partial thromboplastin time (APTT), which are somewhat crude and static measures of coagulation. PT is sensitive only to thrombin generation, the endpoint of the clotting cascade, as a function of procoagulant factors and is insensitive to the inhibition of thrombin by anticoagulant factors.18 It does not provide an accurate assessment of bleeding risk in patients with cirrhosis, nor prognosis after invasive procedures or acute bleeding, but is nonetheless used routinely to guide transfusion for both the prevention and treatment of bleeding. Global tests of clotting such as thromboelastography or thrombin generation may be more accurate reflections of overall coagulation status. For example, thrombin generation assays using the plasma of patients with cirrhosis indicate a normal to hypercoagulable profile in comparison to healthy controls in the resting state.19,20 This is explained by a concomitant decrease in anticoagulant factors as well as the presence of procoagulant factors in cirrhosis. In stable cirrhosis, prolongation of PT is rarely associated with abnormal global assays of coagulation such as thrombin generation (TG) or thromboelastometry (ROTEM).4,21 Overall this has lead to the concept of ‘re-balanced haemostasis’,21 However, this new balance is precarious and may be tipped towards bleeding, thrombosis or even both, in the setting of an appropriate precipitant such as infection (Table 1). A REFERENCES 1 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258e64. 2 Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol 2010; 8: 800e5.
MEDICINE 43:11
665
Ó 2015 Elsevier Ltd. All rights reserved.