Intern Emerg Med DOI 10.1007/s11739-015-1215-7
CE - COMMENTARY
Venous thromboembolism in patients with liver diseases Valerio De Stefano • Elena Rossi
Received: 4 February 2015 / Accepted: 12 February 2015 Ó SIMI 2015
Chronic liver diseases (CLD) are characterized by decreased levels of most procoagulant factors and thrombocytopenia, leading to the assumption that they are a prototype of an acquired bleeding disorder. Indeed, decreased levels of procoagulant proteins are accompanied by impaired hepatic synthesis of the main natural anticoagulant proteins (antithrombin and protein C); in contrast, factor VIII levels are significantly increased. Finally, reduced levels of inhibitors of fibrinolysis are, at least in part, balanced by reduced levels of profibrinolytic factors, in particular plasminogen [1–5] (Table 1). Low levels of antithrombin and protein C and high levels of factor VIII are both pro-haemostatic drivers leading to an increased risk of venous thromboembolism (VTE) [6]. Thus, in patients with CLD the net effect of all haemostatic changes is often a rebalanced functional system. An intact thrombin generating capacity has been described in patients with cirrhosis [7]; in particular, patients with liver disease are resistant to the action of thrombomodulin, the physiological activator of the anticoagulant protein C [1]. This rebalanced system is far more precarious and potentially unstable compared to the physiological haemostatic balance, so that CLD patients are prone to both bleeding and thrombotic complications. Liver fibrosis following chronic injury is influenced by a procoagulant imbalance in CLD; in fact, several studies show an association between hypercoagulability and accelerated fibrosis progression, and among patients with chronic viral hepatitis or non-alcoholic fatty liver disease, advanced fibrosis is significantly more likely in those with inherited thrombophilia (factor V Leiden) or in those with protein C deficiency, high factor VIII levels, or V. De Stefano (&) E. Rossi Institute of Hematology, Catholic University, Rome, Italy e-mail: [email protected]
hyperhomocysteinemia (reviewed in ref. [8]). Liver injury triggers a process of cellular transdifferentiation through which the quiescent perisinusoidal hepatic stellate cell is converted into a myofibroblast with pro-inflammatory and pro-fibrogenic activity. Stellate cell activation is mediated by protease-activated receptor (PAR)-1 and PAR-2 liver injury-driven hepatic upregulation, and the subsequent profibrogenic response via PAR-1 thrombin-mediated activation and PAR-2 factor Xa-mediated activation [8]. Fibrosis is a main determinant of the association between cirrhosis and portal vein thrombosis, the prevalence of portal vein thrombosis being dependent upon the severity of the disease, which is less than 1 % in patients with compensated disease and up to 25 % among those who are candidates for liver transplantation [8]. All in all, advanced liver disease by causing blood stasis and venous wall changes secondary to portal hypertension may induce portal venous thrombosis, which in turn can aggravate liver disease. The role of hypercoagulability due to inherited thrombophilia [9], antiphospholipid antibodies [10], and JAK2 V617F-positive myeloproliferative neoplasms [11, 12] as concurrent causes of portal vein thrombosis in cirrhotic patients is definitely weaker than that observed in patients with non-cirrhotic non-malignant portal vein thrombosis [13]. However, the thrombotic potential in CLD patients is systemic, as demonstrated by the risk of VTE, which is not limited to the portal venous axis. Several studies show a rate of VTE in patients with CLD between 0.5 and 6.3 %, in most cases not exceeding 2 %, as systematically reviewed [8, 14–16]. In the present issue of Intern Emerg Med, Qi et al. [17] conducted a systematic review and meta-analysis of all relevant studies published on the epidemiology of VTE in patients with CLD. Notably, they carried out an exhaustive search for relevant papers and they were able to include 20
123
Intern Emerg Med Table 1 Pro-haemorrhagic and pro-thrombotic alterations in chronic liver diseases (modified from references [4, 5]) Pro-haemorrhagic drivers Hemodynamics
High portal pressure
Pro-thrombotic drivers Low portal venous blood flow Fibrosis-related venous wall changes
Primary haemostasis
Low platelet counts
Coagulation
Decreased fibrinogen, factor II, V, VII, IX, and X levels
Decreased antithrombin, protein C and S levels
Increased TPA levels
Decreased plasminogen, factor XIII, alpha-2-antiplasmin and TAFI levels
Fibrinolysis
Increased VWF levels Increased high molecular weight VWF levels (decreased ADAMTS13 levels) Increased factor VIII levels
Increased PAI-1 levels VWF von Willebrand factor, TPA tissue plasminogen activator, TAFI thrombin activatable fibrinolysis inhibitor, PAI plasminogen activator inhibitor
papers, whereas the aforementioned reviews analyzed 6–12 studies [8, 14–16]; more importantly, the studies added by Qi et al. [17] to their review cover over 600,000 patients with CLD, significantly increasing the sample size and the depth of analysis. However, five of the overall included studies were published in abstract or letter forms, so that information was limited. An additional strength of the review of Qi et al. [17] is the employment of a meta-analytical procedure to evaluate the available data. In all, the pooled rate of VTE in patients with CLD is 1 %, with about one-third of the cases complicated by pulmonary embolism. The pooled proportion is unaffected by diagnosis (liver cirrhosis or unclassified liver diseases), whereas studies involving fewer than 1000 patients show a slightly higher incidence and prevalence compared to those involving more than 1000 patients, likely due to an enhanced possibility of selection bias [17]. Additional data analyzed by Qi et al. [17] present evidence that in the majority of studies, the risk of VTE is increased in CLD patients by approximately 1.7- to 2-fold with respect to the controls, as previously reported [8]. The 1.7-fold increase in risk of VTE in cirrhotic patients has been recently confirmed in a nationwide study [18]. Qi et al. [17] acknowledge the limitations of their study, including the significant heterogeneity found in nearly all meta-analyses. However, they confirm that a non-trivial proportion of CLD patients are prone to an increased thrombotic risk; this calls for studies aimed at the investigation of the risk stratification of patients according to the presence of patient- or disease-linked factors, and the opportunity of thromboprophylaxis in this setting. As in the general population, cancer, trauma or surgery during hospitalization and a previous history of VTE are strong predictors of VTE in CLD patients [19]; other factors associated with a higher risk of VTE in cirrhosis include black race, co-morbidities, malnutrition, central venous line placement, and diabetes [15, 20]. Coagulopathy might
123
protect patients from VTE [20]; yet, the INR measurement is not associated with the risk of VTE, and the risk does not decrease with worsening INR [14–16]. Unlike INR, hypoalbuminemia seems a more accurate surrogate for the risk of VTE, possibly mirroring an overall decrease of liver synthetic function including an impaired production of natural anticoagulants [14–16]. As already mentioned, the role of inherited or acquired thrombophilia as determinants of portal vein thrombosis has been investigated in cirrhotic patients [9, 10], but it is quite unexplored in CLD patients with VTE. The growing evidence that CLD patients carry a significant risk of VTE calls for antithrombotic prophylaxis, at least during high-risk circumstances. Instead, current guidelines generally recommend the avoidance of pharmacological prophylaxis with heparin in patients at high risk of bleeding, such as those with a platelet count \50 9 109/L (odds ratio for bleeding in hospitalized patients 3.3) or those with multiple risk factors including hepatic failure (INR [1.5) (odds ratio for bleeding in hospitalized patients 2.2) [21, 22]. However, a recent metaanalysis aimed at investigating the efficacy and safety of the use of heparin in patients with liver cirrhosis finds that its use is not related to higher rates of bleeding in cirrhotic patients (pooled odds ratio 0.87, 95 % CI 0.34–2.18) and does not decrease the risk of VTE (pooled odds ratio 1.65, 95 % CI 0.36–7.54) [23]. Unfortunately, the available evidence is flawed by heterogeneous heparin schedules and the selection criteria of patients across the studies. Conflict of interest
None.
Statement of human and animal rights This article does not contain any studies with human participants or animals performed by any of the authors, being a review commentary on the scientific literature. Informed consent
No informed consent is required.
Intern Emerg Med
References 1. Tripodi A, Primignani M, Chantarangkul V, Dell’Era A, Clerici M, de Franchis R, Colombo M, Mannucci PM (2009) An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 137:2105–2111 2. Lisman T, Caldwell SH, Burroughs AK, Northup PG, Senzolo M, Stravitz RT, Tripodi A, Trotter JF, Valla DC, Porte RJ, Coagulation in Liver Disease Study Group (2010) Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 53:362–371 3. Tripodi A, Primignani M, Mannucci PM (2010) Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged. Intern Emerg Med 5:7–12 4. Tripodi A, Mannucci PM (2011) The coagulopathy of chronic liver disease. N Engl J Med 365:147–156 5. Valla DC, Rautou PE (2015) The coagulation system in patients with end-stage liver disease. Liver Int 35(1):139–144 6. Martinelli I, De Stefano V, Mannucci PM (2014) Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 11:140–156 7. Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannucci PM (2005) Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 41:553–558 8. Tripodi A, Anstee QM, Sogaard KK, Primignani M, Valla DC (2011) Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 9:1713–1723 9. Qi X, Ren W, De Stefano V, Fan D (2014) Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 12:1801–1812 10. Qi X, De Stefano V, Su C, Bai M, Guo X, Fan D (2015) Associations of antiphospholipid antibodies with splanchnic vein thrombosis. A systematic review with meta-analysis. Medicine 94:e496 11. Qi X, Zhang C, Han G, Zhang W, He C, Yin Z, Liu Z, Bai W, Li R, Bai M, Yang Z, Wu K, Fan D (2012) Prevalence of the JAK2V617F mutation in Chinese patients with Budd-Chiari syndrome and portal vein thrombosis: a prospective study. J Gastroenterol Hepatol 27:1036–1043 12. Saugel B, Lee M, Feichtinger S, Hapfelmeier A, Schmid RM, Siveke JT (2015) Thrombophilic factor analysis in cirrhotic patients with portal vein thrombosis. J Thromb Thrombolysis. doi:10.1007/s11239-014-1124-z
13. De Stefano V, Martinelli I (2010) Splanchnic vein thrombosis: clinical presentation, risk factors and treatment. Intern Emerg Med 5:487–494 14. Buresi M, Hull R, Coffin CS (2012) Venous thromboembolism in cirrhosis: a review of the literature. Can J Gastroenterol 26:905–908 15. Aggarwal A, Puri K, Liangpunsakul S (2014) Deep vein thrombosis and pulmonary embolism in cirrhotic patients: systematic review. World J Gastroenterol 20:5737–5745 16. Yang ZJ, Costa KA, Novelli EM, Smith RE (2014) Venous thromboembolism in cirrhosis. Clin Appl Thromb Hemost 20:169–178 17. Qi X, Ren W, Guo X, Fan D (2014) Epidemiology of venous thromboembolism in patients with liver diseases: a systematic review and meta-analysis. Intern Emerg Med. doi:10.1007/ s11739-014-1163-7 18. Ng KJ, Lee YK, Huang MY, Hsu CY, Su YC (2015) Risks of venous thromboembolism in patients with liver cirrhosis: a nationwide cohort study in Taiwan. J Thromb Haemost 13:206–213 19. Barclay SM, Jeffres MN, Nguyen K, Nguyen T (2013) Evaluation of pharmacologic prophylaxis for venous thromboembolism in patients with chronic liver disease. Pharmacotherapy 33:375–382 20. Ali M, Ananthakrishnan AN, McGinley EL, Saeian K (2011) Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. Dig Dis Sci 56:2152–2159 21. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S, Murad MH, American College of Chest Physicians (2012) Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e195S–e226S 22. Decousus H, Tapson VF, Bergmann JF, Chong BH, Froehlich JB, Kakkar AK, Merli GJ, Monreal M, Nakamura M, Pavanello R, Pini M, Piovella F, Spencer FA, Spyropoulos AC, Turpie AG, Zotz RB, Fitzgerald G, Anderson FA, IMPROVE Investigators (2011) Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 139:69–79 23. Go´mezCuervo C, BisbalPardo O, Pe´rez-JacoisteAsı´n MA (2013) Efficacy and safety of the use of heparin as thromboprophylaxis in patients with liver cirrhosis: a systematic review and metaanalysis. Thromb Res 132:414–419
123
CE - COMMENTARY
Venous thromboembolism in patients with liver diseases Valerio De Stefano • Elena Rossi
Received: 4 February 2015 / Accepted: 12 February 2015 Ó SIMI 2015
Chronic liver diseases (CLD) are characterized by decreased levels of most procoagulant factors and thrombocytopenia, leading to the assumption that they are a prototype of an acquired bleeding disorder. Indeed, decreased levels of procoagulant proteins are accompanied by impaired hepatic synthesis of the main natural anticoagulant proteins (antithrombin and protein C); in contrast, factor VIII levels are significantly increased. Finally, reduced levels of inhibitors of fibrinolysis are, at least in part, balanced by reduced levels of profibrinolytic factors, in particular plasminogen [1–5] (Table 1). Low levels of antithrombin and protein C and high levels of factor VIII are both pro-haemostatic drivers leading to an increased risk of venous thromboembolism (VTE) [6]. Thus, in patients with CLD the net effect of all haemostatic changes is often a rebalanced functional system. An intact thrombin generating capacity has been described in patients with cirrhosis [7]; in particular, patients with liver disease are resistant to the action of thrombomodulin, the physiological activator of the anticoagulant protein C [1]. This rebalanced system is far more precarious and potentially unstable compared to the physiological haemostatic balance, so that CLD patients are prone to both bleeding and thrombotic complications. Liver fibrosis following chronic injury is influenced by a procoagulant imbalance in CLD; in fact, several studies show an association between hypercoagulability and accelerated fibrosis progression, and among patients with chronic viral hepatitis or non-alcoholic fatty liver disease, advanced fibrosis is significantly more likely in those with inherited thrombophilia (factor V Leiden) or in those with protein C deficiency, high factor VIII levels, or V. De Stefano (&) E. Rossi Institute of Hematology, Catholic University, Rome, Italy e-mail: [email protected]
hyperhomocysteinemia (reviewed in ref. [8]). Liver injury triggers a process of cellular transdifferentiation through which the quiescent perisinusoidal hepatic stellate cell is converted into a myofibroblast with pro-inflammatory and pro-fibrogenic activity. Stellate cell activation is mediated by protease-activated receptor (PAR)-1 and PAR-2 liver injury-driven hepatic upregulation, and the subsequent profibrogenic response via PAR-1 thrombin-mediated activation and PAR-2 factor Xa-mediated activation [8]. Fibrosis is a main determinant of the association between cirrhosis and portal vein thrombosis, the prevalence of portal vein thrombosis being dependent upon the severity of the disease, which is less than 1 % in patients with compensated disease and up to 25 % among those who are candidates for liver transplantation [8]. All in all, advanced liver disease by causing blood stasis and venous wall changes secondary to portal hypertension may induce portal venous thrombosis, which in turn can aggravate liver disease. The role of hypercoagulability due to inherited thrombophilia [9], antiphospholipid antibodies [10], and JAK2 V617F-positive myeloproliferative neoplasms [11, 12] as concurrent causes of portal vein thrombosis in cirrhotic patients is definitely weaker than that observed in patients with non-cirrhotic non-malignant portal vein thrombosis [13]. However, the thrombotic potential in CLD patients is systemic, as demonstrated by the risk of VTE, which is not limited to the portal venous axis. Several studies show a rate of VTE in patients with CLD between 0.5 and 6.3 %, in most cases not exceeding 2 %, as systematically reviewed [8, 14–16]. In the present issue of Intern Emerg Med, Qi et al. [17] conducted a systematic review and meta-analysis of all relevant studies published on the epidemiology of VTE in patients with CLD. Notably, they carried out an exhaustive search for relevant papers and they were able to include 20
123
Intern Emerg Med Table 1 Pro-haemorrhagic and pro-thrombotic alterations in chronic liver diseases (modified from references [4, 5]) Pro-haemorrhagic drivers Hemodynamics
High portal pressure
Pro-thrombotic drivers Low portal venous blood flow Fibrosis-related venous wall changes
Primary haemostasis
Low platelet counts
Coagulation
Decreased fibrinogen, factor II, V, VII, IX, and X levels
Decreased antithrombin, protein C and S levels
Increased TPA levels
Decreased plasminogen, factor XIII, alpha-2-antiplasmin and TAFI levels
Fibrinolysis
Increased VWF levels Increased high molecular weight VWF levels (decreased ADAMTS13 levels) Increased factor VIII levels
Increased PAI-1 levels VWF von Willebrand factor, TPA tissue plasminogen activator, TAFI thrombin activatable fibrinolysis inhibitor, PAI plasminogen activator inhibitor
papers, whereas the aforementioned reviews analyzed 6–12 studies [8, 14–16]; more importantly, the studies added by Qi et al. [17] to their review cover over 600,000 patients with CLD, significantly increasing the sample size and the depth of analysis. However, five of the overall included studies were published in abstract or letter forms, so that information was limited. An additional strength of the review of Qi et al. [17] is the employment of a meta-analytical procedure to evaluate the available data. In all, the pooled rate of VTE in patients with CLD is 1 %, with about one-third of the cases complicated by pulmonary embolism. The pooled proportion is unaffected by diagnosis (liver cirrhosis or unclassified liver diseases), whereas studies involving fewer than 1000 patients show a slightly higher incidence and prevalence compared to those involving more than 1000 patients, likely due to an enhanced possibility of selection bias [17]. Additional data analyzed by Qi et al. [17] present evidence that in the majority of studies, the risk of VTE is increased in CLD patients by approximately 1.7- to 2-fold with respect to the controls, as previously reported [8]. The 1.7-fold increase in risk of VTE in cirrhotic patients has been recently confirmed in a nationwide study [18]. Qi et al. [17] acknowledge the limitations of their study, including the significant heterogeneity found in nearly all meta-analyses. However, they confirm that a non-trivial proportion of CLD patients are prone to an increased thrombotic risk; this calls for studies aimed at the investigation of the risk stratification of patients according to the presence of patient- or disease-linked factors, and the opportunity of thromboprophylaxis in this setting. As in the general population, cancer, trauma or surgery during hospitalization and a previous history of VTE are strong predictors of VTE in CLD patients [19]; other factors associated with a higher risk of VTE in cirrhosis include black race, co-morbidities, malnutrition, central venous line placement, and diabetes [15, 20]. Coagulopathy might
123
protect patients from VTE [20]; yet, the INR measurement is not associated with the risk of VTE, and the risk does not decrease with worsening INR [14–16]. Unlike INR, hypoalbuminemia seems a more accurate surrogate for the risk of VTE, possibly mirroring an overall decrease of liver synthetic function including an impaired production of natural anticoagulants [14–16]. As already mentioned, the role of inherited or acquired thrombophilia as determinants of portal vein thrombosis has been investigated in cirrhotic patients [9, 10], but it is quite unexplored in CLD patients with VTE. The growing evidence that CLD patients carry a significant risk of VTE calls for antithrombotic prophylaxis, at least during high-risk circumstances. Instead, current guidelines generally recommend the avoidance of pharmacological prophylaxis with heparin in patients at high risk of bleeding, such as those with a platelet count \50 9 109/L (odds ratio for bleeding in hospitalized patients 3.3) or those with multiple risk factors including hepatic failure (INR [1.5) (odds ratio for bleeding in hospitalized patients 2.2) [21, 22]. However, a recent metaanalysis aimed at investigating the efficacy and safety of the use of heparin in patients with liver cirrhosis finds that its use is not related to higher rates of bleeding in cirrhotic patients (pooled odds ratio 0.87, 95 % CI 0.34–2.18) and does not decrease the risk of VTE (pooled odds ratio 1.65, 95 % CI 0.36–7.54) [23]. Unfortunately, the available evidence is flawed by heterogeneous heparin schedules and the selection criteria of patients across the studies. Conflict of interest
None.
Statement of human and animal rights This article does not contain any studies with human participants or animals performed by any of the authors, being a review commentary on the scientific literature. Informed consent
No informed consent is required.
Intern Emerg Med
References 1. Tripodi A, Primignani M, Chantarangkul V, Dell’Era A, Clerici M, de Franchis R, Colombo M, Mannucci PM (2009) An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 137:2105–2111 2. Lisman T, Caldwell SH, Burroughs AK, Northup PG, Senzolo M, Stravitz RT, Tripodi A, Trotter JF, Valla DC, Porte RJ, Coagulation in Liver Disease Study Group (2010) Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 53:362–371 3. Tripodi A, Primignani M, Mannucci PM (2010) Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged. Intern Emerg Med 5:7–12 4. Tripodi A, Mannucci PM (2011) The coagulopathy of chronic liver disease. N Engl J Med 365:147–156 5. Valla DC, Rautou PE (2015) The coagulation system in patients with end-stage liver disease. Liver Int 35(1):139–144 6. Martinelli I, De Stefano V, Mannucci PM (2014) Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 11:140–156 7. Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannucci PM (2005) Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 41:553–558 8. Tripodi A, Anstee QM, Sogaard KK, Primignani M, Valla DC (2011) Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 9:1713–1723 9. Qi X, Ren W, De Stefano V, Fan D (2014) Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 12:1801–1812 10. Qi X, De Stefano V, Su C, Bai M, Guo X, Fan D (2015) Associations of antiphospholipid antibodies with splanchnic vein thrombosis. A systematic review with meta-analysis. Medicine 94:e496 11. Qi X, Zhang C, Han G, Zhang W, He C, Yin Z, Liu Z, Bai W, Li R, Bai M, Yang Z, Wu K, Fan D (2012) Prevalence of the JAK2V617F mutation in Chinese patients with Budd-Chiari syndrome and portal vein thrombosis: a prospective study. J Gastroenterol Hepatol 27:1036–1043 12. Saugel B, Lee M, Feichtinger S, Hapfelmeier A, Schmid RM, Siveke JT (2015) Thrombophilic factor analysis in cirrhotic patients with portal vein thrombosis. J Thromb Thrombolysis. doi:10.1007/s11239-014-1124-z
13. De Stefano V, Martinelli I (2010) Splanchnic vein thrombosis: clinical presentation, risk factors and treatment. Intern Emerg Med 5:487–494 14. Buresi M, Hull R, Coffin CS (2012) Venous thromboembolism in cirrhosis: a review of the literature. Can J Gastroenterol 26:905–908 15. Aggarwal A, Puri K, Liangpunsakul S (2014) Deep vein thrombosis and pulmonary embolism in cirrhotic patients: systematic review. World J Gastroenterol 20:5737–5745 16. Yang ZJ, Costa KA, Novelli EM, Smith RE (2014) Venous thromboembolism in cirrhosis. Clin Appl Thromb Hemost 20:169–178 17. Qi X, Ren W, Guo X, Fan D (2014) Epidemiology of venous thromboembolism in patients with liver diseases: a systematic review and meta-analysis. Intern Emerg Med. doi:10.1007/ s11739-014-1163-7 18. Ng KJ, Lee YK, Huang MY, Hsu CY, Su YC (2015) Risks of venous thromboembolism in patients with liver cirrhosis: a nationwide cohort study in Taiwan. J Thromb Haemost 13:206–213 19. Barclay SM, Jeffres MN, Nguyen K, Nguyen T (2013) Evaluation of pharmacologic prophylaxis for venous thromboembolism in patients with chronic liver disease. Pharmacotherapy 33:375–382 20. Ali M, Ananthakrishnan AN, McGinley EL, Saeian K (2011) Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. Dig Dis Sci 56:2152–2159 21. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S, Murad MH, American College of Chest Physicians (2012) Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e195S–e226S 22. Decousus H, Tapson VF, Bergmann JF, Chong BH, Froehlich JB, Kakkar AK, Merli GJ, Monreal M, Nakamura M, Pavanello R, Pini M, Piovella F, Spencer FA, Spyropoulos AC, Turpie AG, Zotz RB, Fitzgerald G, Anderson FA, IMPROVE Investigators (2011) Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 139:69–79 23. Go´mezCuervo C, BisbalPardo O, Pe´rez-JacoisteAsı´n MA (2013) Efficacy and safety of the use of heparin as thromboprophylaxis in patients with liver cirrhosis: a systematic review and metaanalysis. Thromb Res 132:414–419
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