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31.07.2018 | Review Article | Ausgabe 5/2018

Hepatology International 5/2018

Algorithms for managing coagulation disorders in liver disease

Hepatology International > Ausgabe 5/2018
R. Todd Stravitz
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Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s12072-018-9886-6) contains supplementary material, which is available to authorized users.


Patients with advanced liver disease have traditionally been considered at risk for bleeding complications. However, although bleeding in patients with cirrhosis frequently occurs due to complications of portal hypertension, research performed within the last 15 years has increasingly shown that hemostasis in patients with liver failure generally achieves a state of “rebalance”, whereby compensatory systems restore a relatively neutral or even slightly pro-thrombotic state. Much recent clinical and in vitro research has, in fact, shown over-compensation, such that patients with acute and stable chronic liver failure may have a thrombotic tendency, which may participate in the progression of liver disease and cause systemic and portal thrombosis. Investigators have started to identify differences in hemostasis in patients with unstable cirrhosis, the newly defined syndrome of acute-on-chronic liver failure (ACLF), compared to those with stable cirrhosis. The following discussion will summarize much of the background of rebalanced hemostasis in patients with cirrhosis and acute liver failure (ALF), and suggest management algorithms for coagulation abnormalities before invasive procedures, during active bleeding, and for prophylaxis and treatment of thrombotic complications.

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Supplementary material 1 (PPTX 39 kb) Suppl Table 1. Hemostasis in patients with stable and unstable cirrhosis (acute decompensation and ACLF). (Adapted from Fisher, et al. J Crit Care. 2018; 43: 54) (33). Suppl Table 2. Predictors of major bleeding events in critically ill patients admitted to the ICU. 211 patients with cirrhosis, 87% of whom had ACLF, were followed prospectively for major bleeding events. Area-under-the-ROC curve analysis identified fibrinogen concentration, platelet count, and aPTT as predictors of major bleeding, but not the INR (left table). Multivariate analysis (right table) shows that a plasma fibrinogen concentration of < 60 mg/dl was most highly predictive of major bleeding. (Adapted from Drolz, et al. Hepatology. 2016; 64: 556) (35)
Supplementary material 2 (PPTX 705 kb) Suppl Fig. 1. Thrombin generation in patients with cirrhosis and normal healthy controls. The two bars on the left depict thrombin generation in patients with cirrhosis and healthy controls, and show that cirrhotics generate less thrombin than controls due to decreased synthesis of pro-hemostatic coagulation factors (most importantly, factors V and VII) in the former. The experiments depicted in the two bars on the right include thrombomodulin (TM) in the reaction mixture, an endogenous endothelial activator of the anticoagulant, protein C. Thus, since protein C and pro-hemostatic factors are liver-derived and are proportionally decreased in patients with liver failure, thrombin generation remains “rebalanced”, as long as TM is added to the reaction mixture to activate protein C. (Adapted from Tripodi, et al. Hepatology. 2005; 41: 553) (9). Suppl Fig. 2. VonWillebrand factor levels in plasma from patients with cirrhosis and acute liver failure. In patients with cirrhosis and ALF, endothelial secretion of vonWillebrand factor (vWF) increases as a function of the severity of liver failure (left panel). In the middle and right panels, the same number of platelets is incubated in chambers with either plasma from normal healthy controls (middle panel) or plasma from patients with ALF (right panel). The increased platelet aggregation in the right compared to the middle panel demonstrates the functional significance of increased vWF in the former. (Adapted from Lisman, et al., Hepatology. 2006; 44: 53 and Hugenholtz, et al, Hepatology. 2013; 58: 752) (12, 43). Suppl Fig. 3. Risk of venous thromboembolism (VTE), deep venous thrombosis (DVT), and pulmonary embolism (PE) in patients with cirrhosis: Meta-analysis of 15 controlled studies. (Data adapted from Ambrosino, et al. Thrombosis Haemost. 2017; 117: 139) (19). Suppl Fig. 4. Patients with cirrhosis are hypercoagulable as assessed by the factor VIII/protein C ratio, in proportion to the severity of liver failure (adapted from Tripodi, et al. Gastroenterology. 2009; 137: 2105) (5). Suppl Fig. 5. Hypercoagulability in patients with cirrhosis as assessed by the FVIII/Protein C ratio predicts decompensation. The clinical course of patients with stable cirrhosis was followed over time with routine assessment for new-onset ascites and variceal bleeding. Those patients with a more hypercoagulable profile of the FVIII/Protein C ratio were more likely to decompensate than those with a lower ratio (adapted from Kalambokis, et al. J Hepatol. 2016; 65: 921) (21). Suppl Fig. 6. Anticoagulation may delay hepatic decompensation in patients with cirrhosis by slowing parenchymal extinction. The left panel describes the incidence of decompensation of stable cirrhosis in patients randomized to receive either enoxaparin or placebo, and shows a markedly delayed decompensation in the former group. A possible explanation for this observation is presented by the diagram on the right, in which the progression of parenchymal collapse of the cirrhotic liver spatially parallels thrombotic occlusion of the hepatic microvasculature within the same vascular distribution (adapted from Villa, et al. Gastroenterology. 2012; 143: 1253 (left panel) (27) and Wanless, et al. Hepatology. 1995; 21: 1238 (right panel)) (14). Suppl Fig. 7. Precipitating events and organ system failure in patients with acute-on-chronic liver failure. Based upon 303 patients with ACLF from the CLIF Consortium. (Adapted from Moreau, et al. Gastroenterology. 2013; 144: 1426) (2). Suppl Fig. 8. Blood product transfusion and bleeding complications in 1770 patients with ALF over 18 years of the ALF Study Group Registry. (Adapted from Stravitz, et al. Hepatology. 2018, in press) (37). Suppl Fig. 9. Concentration of microparticles in plasma of patients with acute liver failure. Left panel: Microparticle (MP) concentration in patients with ALI/ALF compared to normal healthy controls. Right panel: microparticle tissue factor (MPTF) activity in patients with ALI/ALF compared to normal healthy controls. MPTF activity is a measure of pro-coagulant activity, as it reflects the synergistic effect of phosphatidylserine (on the everted surface of MPs) and tissue factor on the production of factor Xa (adapted from: Stravitz, et al. Hepatology. 2013; 58: 304) (41). Suppl Fig. 10. Safety and efficacy of anticoagulation in patients with cirrhosis and portal vein thrombosis: Meta-analysis of six controlled studies (adapted from Loffredo, et al. Gastroenterology. 2017; 153: 480) (62)
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