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Hemostasis in Liver Disease
CHAPTER 119
Hemostasis in Liver Disease Margarita Kushnir, MD and Henny H. Billett, MD Liver disease is associated with multiple hemostatic defects leading to both hemorrhagic and thrombotic manifestations. Its effect on coagulation factors, endogenous anticoagulants, and platelets results in rebalanced hemostasis and creates challenging clinical scenarios requiring careful management.
Decreased Synthesis of Pro- and Anticoagulant Factors: All coagulation factors (except FVIII and von Willebrand factor [VWF]) are synthesized in hepatocytes and can be deficient in chronic liver disease. FVIII and VWF are often elevated due to their increased production in endothelium. In the setting of acute liver failure, the rate of development of a coagulation factor deficiency is directly proportional to its half-life in plasma. Because FVII has the shortest half-life (approximately 4–5 hours) of all coagulation factors, patients with acute liver failure develop FVII deficiency before levels of other coagulation factors fall. Components of the common pathway of coagulation also have relatively short half-lives and become deficient next. Because of more pronounced deficiency of FVII and the factors involved in the common coagulation pathway, liver failure tends to have a greater effect on the prothrombin time (PT) compared with the partial thromboplastin time (PTT). FVIII, VWF, and fibrinogen are all acute phase reactants that are usually elevated early in liver failure, but as it progresses, fibrinogen falls due to decreased hepatic production while FVIII and VWF levels remain normal or high. The liver also synthesizes proteins that inhibit coagulation, such as protein C, protein S, and antithrombin. Deficiency of these proteins likely counteracts shortage of procoagulant factors. This helps maintain hemostasis but can also lead to inappropriate thrombosis.
Vitamin K Deficiency: In patients with cirrhosis and obstructive jaundice, decreased bile salt production and/or delivery can cause decreased absorption of fat-soluble vitamins in the small intestine, including vitamin K, an essential cofactor for the production of biologically active factors II, VII, IX, and X, as well as protein C and S. Prolonged antibiotic use, which inhibits the gut flora that produces Vitamin K, and severe dietary deficiency, as may occur in cases of starvation (usually medically induced) or alcoholic cirrhosis with continued alcohol abuse, may also contribute to a deficiency of vitamin K.
Thrombocytopenia: Thrombocytopenia in liver disease is also often multifactorial. Splenomegaly, caused by portal hypertension, results in sequestration of platelets and leads to their reduction in the circulation. Thrombocytopenia is further exacerbated by deficiency of thrombopoietin, a growth factor that stimulates the production and differentiation of megakaryocytes in the bone marrow, and is predominantly Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00119-7 Copyright © 2019 Elsevier Inc. All rights reserved.
723
724
Margarita Kushnir, MD and Henny H. Billett, MD
produced in the liver. Furthermore, underlying disease may shorten platelet survival due to hepatitis B and C viremia or antiplatelet antibodies, as can be seen in autoimmune hepatitis. Alcohol causes direct megakaryocyte toxicity and can also contribute to thrombocytopenia.
Fibrinogen: Fibrinogen levels tend to remain normal to only slightly depressed (usually >100 mg/dL) in chronic liver disease. However, the fibrinogen that is produced has increased amounts of sialic acid, which renders it less functional and prolongs the thrombin time. Despite this alteration, in most cases, the dysfibrinogen of liver disease does not contribute to a clinically meaningful coagulopathy.
Clinical Manifestations: Although bleeding has, for a long time, been considered a common manifestation of liver disease because of abnormal coagulations tests, it is increasingly recognized that cirrhosis is, to a greater extent, a prothrombotic condition. Many hemorrhagic complications of cirrhosis are caused by hemodynamic derangements of portal hypertension, such as gastropathy and esophageal varices, rather than an underlying hypocoagulable state. Because PT and PTT do not reflect levels of endogenous anticoagulant proteins (protein C, S, ATIII), standard coagulation tests are poorly predictive of bleeding in patients with liver disease. In fact, no association has been found between PT and bleeding in past studies. To account for the effect of reduced anticoagulant levels, assessments of global coagulation function using thrombin generation assays have been performed in several studies. There was no significant difference in endogenous thrombin potential when plasmas of patients with chronic cirrhosis and controls were compared. Despite significantly prolonged PT and PTT, patients with acute liver failure have also been found to have similar endogenous thrombin generation, in the presence of thrombomodulin, compared with healthy controls. Preserved thrombin generation is thought to be due to rebalanced coagulation attributed to reduction of protein C production and increase in factor VIII in liver disease. Patients with cirrhosis usually have mild–moderate thrombocytopenia until the later stages of the disease when it can worsen. Bleeding rarely occurs with platelet counts >50,000/μL. It is thought that an increase in VWF released from endothelial cells compensates for the thrombocytopenia to maintain normal platelet function until the platelet count is very severe. A 2006 study showed that thrombin generation in patients with cirrhosis correlates with platelet numbers and is diminished with severe thrombocytopenia. It was found that platelet count of 56,000 × 10/μL is required to generate thrombin amounts equivalent to lower limit of the normal range.
Monitoring Laboratory Parameters in Liver Disease: In patients with chronic liver disease, it is common to see prolonged PT and, to a lesser extent, PTT. Worsening in these parameters can indicate progressive impairment of synthetic liver function and is often accompanied by other lab abnormalities, such as hypoalbuminemia and hyperbilirubinemia. In an acutely ill patient with cirrhosis or new onset liver failure, it can be difficult to distinguish coagulopathy of advanced liver disease from disseminated intravascular coagulation (DIC) as both can cause hypofibrinogenemia, prolonged PT/PTT,
Hemostasis in Liver Disease
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and thrombocytopenia. D-dimer levels, like in DIC, are often elevated in liver disease, although elevations are generally more pronounced in DIC. Because FVIII, along with all other factors, is consumed in DIC, obtaining FVIII level may be helpful in differentiating between DIC and coagulopathy of liver disease, where it is normal or elevated. A helpful aide to distinguishing these is that in DIC, as the coagulopathy gets worse, the fibrinogen and VIII first increase and then decrease together whereas in liver disease, as the disease progresses and the fibrinogen decreases, the factor VIII will increase— an inverse relationship. However, coagulopathy and DIC may also coexist and clinical judgment is important in distinguishing these two entities. DIC is usually (but not always) acute and generally has an obvious underlying cause such as sepsis.
Management: As coagulation parameters do not reflect patient’s true hemostasis, it is not necessary to correct them in asymptomatic patients with cirrhosis. Before surgery, patients are often given products to lower their INR to less than 1.5 and increase fibrinogen to >100 mg/dL. Clinical outcome data do not support this approach as prophylactic transfusion of blood products has not been shown to reduce procedure-related bleeding in this population. There is also concern, particularly with administration of multiple units of fresh frozen plasma (FFP), for expansion of intravascular volume, which may actually increase the bleeding risk. A recent study used thromboelastography (TEG) to guide blood product transfusions before invasive procedures in patients with severe coagulopathy due to cirrhosis and showed that TEG significantly decreased the amount of blood products used compared with standard protocols, without an increase in bleeding complications. Patients are generally transfused with platelets to achieve platelet counts >50,000/μL before surgery (75,000/μL in ocular or neurosurgery). Response to platelet transfusions may be blunted due to splenomegaly, and this goal may be difficult to attain. Eltrombopag, a thrombopoietin-receptor agonist, has been used in patients with chronic liver disease before procedures; a significant decrease in platelet transfusion requirements among patients on eltrombopag was observed, but there was a higher rate of portal vein thrombosis. In acute bleeding, patients are usually treated with cryoprecipitate (for low fibrinogen levels) and platelets to keep platelet count above 50,000/μL. FFP is sometimes given, but volume is a concern, as volume overload can worsen portal hypertension and exacerbate bleeding. As there can be an element of vitamin K deficiency in any form of liver disease, vitamin K should be given. It is most reliably administered intravenously, given the edematous state and poor oral absorption in decompensated cirrhosis. In patients with concomitant renal failure, it is important to address uremia. Depending on the site of bleeding, local control is often the most important aspect of management as is the case with variceal bleeds, which can be treated endoscopically. If bleeding is difficult to control with these standard measures, other treatment modalities may be considered. Desmopressin (DDAVP) may transiently increase VWF to help maximize platelet efficiency, although high-quality data for this maneuver are lacking. The use of antifibrinolytics, such as aminocaproic acid or tranexamic acid, can also be tried as fibrinolysis is often abnormal in liver disease. Finally, prothrombin complex concentrates can be considered in life-threatening refractory bleeding, especially if FVII or other vitamin K–dependent factors are particularly low (e.g., FII and FX), and
726
Margarita Kushnir, MD and Henny H. Billett, MD
there is a dire concern about volume overload. However, the benefit of these products must be weighed against their relative contraindication in patients with liver failure because of their inherent thrombotic risk.
Anticoagulation in Liver Disease: Treatment of venous thromboembolism in patients with cirrhosis is complicated by concern for bleeding and baseline PT derangements. Anticoagulation may be precluded by large esophageal varices, which carry considerable bleeding risk. Extent of thrombosis is often an important determinant in assessing the risk: benefit ratio. Warfarin may be used in patients with normal PT. In patients with prolonged PT, low-molecular-weight heparin, which does not require INR monitoring, may be a better option. Direct oral anticoagulants have not been well studied in patients with chronic liver disease and are not commonly used. In the absence of active bleeding and high-risk varices, thromboprophylaxis is generally indicated in hospitalized patients with cirrhosis.
Further Reading Afdhal, N. H., Giannini, E. G., Tayyab, G., et al. (2012). Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med, 367(8), 716–724. Blonski, W., Siropaides, T., & Reddy, K. (2007). Coagulopathy in liver disease. Curr Treat Options Gastroenterol, 10(6), 464–473. Caldwell, S. H., Hoffman, M., Lisman, T., et al. (2006). Coagulation disorders and hemostasis in liver disease: Pathophysiology and critical assessment of current management. Hepatology, 44(4), 1039–1046. De Pietri, L., Bianchini, M., Montalti, R., et al. (2016). Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial. Hepatology, 63(2), 566–573. Gatt, A., Riddel, A., Calvaruso, V., et al. (2010). Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost, 8(9), 1994–2000. Habib, M., Roberts, L. N., Patel, R. K., et al. (2014). Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation. Liver Int, 34(5), 672–678. Kor, D. J., Stubbs, J. R., & Gajic, O. (2010). Perioperative coagulation management– fresh frozen plasma. Best Pract Res Clin Anaesthesiol, 24(1), 51–64. Kujovich, J. L. (2005). Hemostatic defects in end stage liver disease. Crit Care Clin, 21(3), 563–587. Northup, P. G., & Caldwell, S. H. (2013). Coagulation in liver disease: A guide for the clinician. Clin Gastroenterol Hepatol, 11(9), 1064–1074. Rai, R., Nagral, S., & Nagral, A. (2012). Surgery in a patient with liver disease. J Clin Exp Hepatol, 2(3), 238–246. Shah, N. L., Intagliata, N. M., & Northup, P. G. (2014). Procoagulant therapeutics in liver disease: A critique and clinical rationale. Nat Rev Gastroenterol Hepatol, 11(11), 675–682. Stellingwerff, M., Brandsma, A., Lisman, T., et al. (2012). Prohemostatic interventions in liver surgery. Semin Thromb Hemost, 38(3), 244–249. Tripodi, A., Chantarangkul, V., Primignani, M., et al. (2012). Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: Considerations on the efficacy of treatment with fresh-frozen plasma. Intern Emerg Med, 7(2), 139–144.
Hemostasis in Liver Disease
727
Tripodi, A., Primignani, M., Chantarangkul, V., et al. (2006). Thrombin generation in patients with cirrhosis: The role of platelets. Hepatology, 44(2), 440–445. Tripodi, A., & Manucci, P. (July 14, 2011). The coagulopathy of chronic liver disease. N Engl J Med, 365(2), 147–156. Trotter, J. (2006). Coagulation abnormalities in patients who have liver disease. Clin Liver Dis, 10(3), 665–678.
Hemostasis in Liver Disease Margarita Kushnir, MD and Henny H. Billett, MD Liver disease is associated with multiple hemostatic defects leading to both hemorrhagic and thrombotic manifestations. Its effect on coagulation factors, endogenous anticoagulants, and platelets results in rebalanced hemostasis and creates challenging clinical scenarios requiring careful management.
Decreased Synthesis of Pro- and Anticoagulant Factors: All coagulation factors (except FVIII and von Willebrand factor [VWF]) are synthesized in hepatocytes and can be deficient in chronic liver disease. FVIII and VWF are often elevated due to their increased production in endothelium. In the setting of acute liver failure, the rate of development of a coagulation factor deficiency is directly proportional to its half-life in plasma. Because FVII has the shortest half-life (approximately 4–5 hours) of all coagulation factors, patients with acute liver failure develop FVII deficiency before levels of other coagulation factors fall. Components of the common pathway of coagulation also have relatively short half-lives and become deficient next. Because of more pronounced deficiency of FVII and the factors involved in the common coagulation pathway, liver failure tends to have a greater effect on the prothrombin time (PT) compared with the partial thromboplastin time (PTT). FVIII, VWF, and fibrinogen are all acute phase reactants that are usually elevated early in liver failure, but as it progresses, fibrinogen falls due to decreased hepatic production while FVIII and VWF levels remain normal or high. The liver also synthesizes proteins that inhibit coagulation, such as protein C, protein S, and antithrombin. Deficiency of these proteins likely counteracts shortage of procoagulant factors. This helps maintain hemostasis but can also lead to inappropriate thrombosis.
Vitamin K Deficiency: In patients with cirrhosis and obstructive jaundice, decreased bile salt production and/or delivery can cause decreased absorption of fat-soluble vitamins in the small intestine, including vitamin K, an essential cofactor for the production of biologically active factors II, VII, IX, and X, as well as protein C and S. Prolonged antibiotic use, which inhibits the gut flora that produces Vitamin K, and severe dietary deficiency, as may occur in cases of starvation (usually medically induced) or alcoholic cirrhosis with continued alcohol abuse, may also contribute to a deficiency of vitamin K.
Thrombocytopenia: Thrombocytopenia in liver disease is also often multifactorial. Splenomegaly, caused by portal hypertension, results in sequestration of platelets and leads to their reduction in the circulation. Thrombocytopenia is further exacerbated by deficiency of thrombopoietin, a growth factor that stimulates the production and differentiation of megakaryocytes in the bone marrow, and is predominantly Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00119-7 Copyright © 2019 Elsevier Inc. All rights reserved.
723
724
Margarita Kushnir, MD and Henny H. Billett, MD
produced in the liver. Furthermore, underlying disease may shorten platelet survival due to hepatitis B and C viremia or antiplatelet antibodies, as can be seen in autoimmune hepatitis. Alcohol causes direct megakaryocyte toxicity and can also contribute to thrombocytopenia.
Fibrinogen: Fibrinogen levels tend to remain normal to only slightly depressed (usually >100 mg/dL) in chronic liver disease. However, the fibrinogen that is produced has increased amounts of sialic acid, which renders it less functional and prolongs the thrombin time. Despite this alteration, in most cases, the dysfibrinogen of liver disease does not contribute to a clinically meaningful coagulopathy.
Clinical Manifestations: Although bleeding has, for a long time, been considered a common manifestation of liver disease because of abnormal coagulations tests, it is increasingly recognized that cirrhosis is, to a greater extent, a prothrombotic condition. Many hemorrhagic complications of cirrhosis are caused by hemodynamic derangements of portal hypertension, such as gastropathy and esophageal varices, rather than an underlying hypocoagulable state. Because PT and PTT do not reflect levels of endogenous anticoagulant proteins (protein C, S, ATIII), standard coagulation tests are poorly predictive of bleeding in patients with liver disease. In fact, no association has been found between PT and bleeding in past studies. To account for the effect of reduced anticoagulant levels, assessments of global coagulation function using thrombin generation assays have been performed in several studies. There was no significant difference in endogenous thrombin potential when plasmas of patients with chronic cirrhosis and controls were compared. Despite significantly prolonged PT and PTT, patients with acute liver failure have also been found to have similar endogenous thrombin generation, in the presence of thrombomodulin, compared with healthy controls. Preserved thrombin generation is thought to be due to rebalanced coagulation attributed to reduction of protein C production and increase in factor VIII in liver disease. Patients with cirrhosis usually have mild–moderate thrombocytopenia until the later stages of the disease when it can worsen. Bleeding rarely occurs with platelet counts >50,000/μL. It is thought that an increase in VWF released from endothelial cells compensates for the thrombocytopenia to maintain normal platelet function until the platelet count is very severe. A 2006 study showed that thrombin generation in patients with cirrhosis correlates with platelet numbers and is diminished with severe thrombocytopenia. It was found that platelet count of 56,000 × 10/μL is required to generate thrombin amounts equivalent to lower limit of the normal range.
Monitoring Laboratory Parameters in Liver Disease: In patients with chronic liver disease, it is common to see prolonged PT and, to a lesser extent, PTT. Worsening in these parameters can indicate progressive impairment of synthetic liver function and is often accompanied by other lab abnormalities, such as hypoalbuminemia and hyperbilirubinemia. In an acutely ill patient with cirrhosis or new onset liver failure, it can be difficult to distinguish coagulopathy of advanced liver disease from disseminated intravascular coagulation (DIC) as both can cause hypofibrinogenemia, prolonged PT/PTT,
Hemostasis in Liver Disease
725
and thrombocytopenia. D-dimer levels, like in DIC, are often elevated in liver disease, although elevations are generally more pronounced in DIC. Because FVIII, along with all other factors, is consumed in DIC, obtaining FVIII level may be helpful in differentiating between DIC and coagulopathy of liver disease, where it is normal or elevated. A helpful aide to distinguishing these is that in DIC, as the coagulopathy gets worse, the fibrinogen and VIII first increase and then decrease together whereas in liver disease, as the disease progresses and the fibrinogen decreases, the factor VIII will increase— an inverse relationship. However, coagulopathy and DIC may also coexist and clinical judgment is important in distinguishing these two entities. DIC is usually (but not always) acute and generally has an obvious underlying cause such as sepsis.
Management: As coagulation parameters do not reflect patient’s true hemostasis, it is not necessary to correct them in asymptomatic patients with cirrhosis. Before surgery, patients are often given products to lower their INR to less than 1.5 and increase fibrinogen to >100 mg/dL. Clinical outcome data do not support this approach as prophylactic transfusion of blood products has not been shown to reduce procedure-related bleeding in this population. There is also concern, particularly with administration of multiple units of fresh frozen plasma (FFP), for expansion of intravascular volume, which may actually increase the bleeding risk. A recent study used thromboelastography (TEG) to guide blood product transfusions before invasive procedures in patients with severe coagulopathy due to cirrhosis and showed that TEG significantly decreased the amount of blood products used compared with standard protocols, without an increase in bleeding complications. Patients are generally transfused with platelets to achieve platelet counts >50,000/μL before surgery (75,000/μL in ocular or neurosurgery). Response to platelet transfusions may be blunted due to splenomegaly, and this goal may be difficult to attain. Eltrombopag, a thrombopoietin-receptor agonist, has been used in patients with chronic liver disease before procedures; a significant decrease in platelet transfusion requirements among patients on eltrombopag was observed, but there was a higher rate of portal vein thrombosis. In acute bleeding, patients are usually treated with cryoprecipitate (for low fibrinogen levels) and platelets to keep platelet count above 50,000/μL. FFP is sometimes given, but volume is a concern, as volume overload can worsen portal hypertension and exacerbate bleeding. As there can be an element of vitamin K deficiency in any form of liver disease, vitamin K should be given. It is most reliably administered intravenously, given the edematous state and poor oral absorption in decompensated cirrhosis. In patients with concomitant renal failure, it is important to address uremia. Depending on the site of bleeding, local control is often the most important aspect of management as is the case with variceal bleeds, which can be treated endoscopically. If bleeding is difficult to control with these standard measures, other treatment modalities may be considered. Desmopressin (DDAVP) may transiently increase VWF to help maximize platelet efficiency, although high-quality data for this maneuver are lacking. The use of antifibrinolytics, such as aminocaproic acid or tranexamic acid, can also be tried as fibrinolysis is often abnormal in liver disease. Finally, prothrombin complex concentrates can be considered in life-threatening refractory bleeding, especially if FVII or other vitamin K–dependent factors are particularly low (e.g., FII and FX), and
726
Margarita Kushnir, MD and Henny H. Billett, MD
there is a dire concern about volume overload. However, the benefit of these products must be weighed against their relative contraindication in patients with liver failure because of their inherent thrombotic risk.
Anticoagulation in Liver Disease: Treatment of venous thromboembolism in patients with cirrhosis is complicated by concern for bleeding and baseline PT derangements. Anticoagulation may be precluded by large esophageal varices, which carry considerable bleeding risk. Extent of thrombosis is often an important determinant in assessing the risk: benefit ratio. Warfarin may be used in patients with normal PT. In patients with prolonged PT, low-molecular-weight heparin, which does not require INR monitoring, may be a better option. Direct oral anticoagulants have not been well studied in patients with chronic liver disease and are not commonly used. In the absence of active bleeding and high-risk varices, thromboprophylaxis is generally indicated in hospitalized patients with cirrhosis.
Further Reading Afdhal, N. H., Giannini, E. G., Tayyab, G., et al. (2012). Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med, 367(8), 716–724. Blonski, W., Siropaides, T., & Reddy, K. (2007). Coagulopathy in liver disease. Curr Treat Options Gastroenterol, 10(6), 464–473. Caldwell, S. H., Hoffman, M., Lisman, T., et al. (2006). Coagulation disorders and hemostasis in liver disease: Pathophysiology and critical assessment of current management. Hepatology, 44(4), 1039–1046. De Pietri, L., Bianchini, M., Montalti, R., et al. (2016). Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial. Hepatology, 63(2), 566–573. Gatt, A., Riddel, A., Calvaruso, V., et al. (2010). Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost, 8(9), 1994–2000. Habib, M., Roberts, L. N., Patel, R. K., et al. (2014). Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation. Liver Int, 34(5), 672–678. Kor, D. J., Stubbs, J. R., & Gajic, O. (2010). Perioperative coagulation management– fresh frozen plasma. Best Pract Res Clin Anaesthesiol, 24(1), 51–64. Kujovich, J. L. (2005). Hemostatic defects in end stage liver disease. Crit Care Clin, 21(3), 563–587. Northup, P. G., & Caldwell, S. H. (2013). Coagulation in liver disease: A guide for the clinician. Clin Gastroenterol Hepatol, 11(9), 1064–1074. Rai, R., Nagral, S., & Nagral, A. (2012). Surgery in a patient with liver disease. J Clin Exp Hepatol, 2(3), 238–246. Shah, N. L., Intagliata, N. M., & Northup, P. G. (2014). Procoagulant therapeutics in liver disease: A critique and clinical rationale. Nat Rev Gastroenterol Hepatol, 11(11), 675–682. Stellingwerff, M., Brandsma, A., Lisman, T., et al. (2012). Prohemostatic interventions in liver surgery. Semin Thromb Hemost, 38(3), 244–249. Tripodi, A., Chantarangkul, V., Primignani, M., et al. (2012). Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: Considerations on the efficacy of treatment with fresh-frozen plasma. Intern Emerg Med, 7(2), 139–144.
Hemostasis in Liver Disease
727
Tripodi, A., Primignani, M., Chantarangkul, V., et al. (2006). Thrombin generation in patients with cirrhosis: The role of platelets. Hepatology, 44(2), 440–445. Tripodi, A., & Manucci, P. (July 14, 2011). The coagulopathy of chronic liver disease. N Engl J Med, 365(2), 147–156. Trotter, J. (2006). Coagulation abnormalities in patients who have liver disease. Clin Liver Dis, 10(3), 665–678.