Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis

Abstract

In the setting of liver cirrhosis (LC), profound hemostatic changes occur, which affect primary hemostasis, coagulation, and fibrinolysis. They involve prohemorrhagic and prothrombotic alterations at each of these steps. Patients with cirrhosis exhibit multifactorial thrombocytopenia and in vitro thrombocytopathy, counterbalanced by increased von Willebrand factor. The resultant shift is difficult to assess, but overall these changes probably result in a rebalanced primary hemostasis. Concerning coagulation, the reduced activity of coagulation factors is counterbalanced by an increase in factor VIII (produced by liver sinusoidal endothelial cells), a decrease of the natural anticoagulants, and complex changes, including changes in circulating microparticles, cell-free DNA, and neutrophil extracellular traps. Overall, these alterations result in a procoagulant state. As for fibrinolysis, increased tissue-type and urokinase-type plasminogen activators, a relatively decreased plasminogen activator inhibitor 1, and decreased levels of thrombin-activatable fibrinolysis inhibitor and α2-antiplasmin are counterbalanced by decreased plasminogen and a decreased fibrin clot permeability. Whether and how these changes shift fibrinolysis remains to be determined. Overall, the current consensus is that in patients with cirrhosis, the hemostasis is shifted toward a procoagulant state. We review the published evidence for the concept of LC as a prothrombotic state, discuss discordant data, and highlight the impact of the underlying cause of LC on the resultant imbalance. (Hepatology 2020;71:2135-2148). Primary HemostasisChanges of primary hemostasis in patients with LC are shown in Table 1.Abbreviations: ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 repeats 13;Hepatology, June 2020 ZERMATTEN ET AL. 2136pRoHeMoRRHagIC CHaNgeS thrombocytopenia Thrombocytopenia (platelets <150 × 10 9 /L) occurs in up to 78% (1) of patients with LC, moderate thrombocytopenia (platelets 50-75 × 10 9 /L) occurs in approximately 13%, (2) and severe thrombocytopenia (platelets <50 × 10 9 /L) occurs in 1% to 2%. (3) Decreased production and increased clearance of platelets are both involved in LC-associated thrombocytopenia ( Fig. 1). Indeed, reticulated/immature platelets and glycocalicin (proteolytic extracellular fragment of glycoprotein 1b), which are markers of platelet production, are decreased in LC. (4) However, reticulated/ immature platelet fraction and glycocalicin index, which are markers of platelet turnover, are increased in patients with LC versus healthy donors (4,5) and in thrombocytopenic versus non-thrombocytopenic patients with LC. (4,6) Moreover, the mean platelet survival is decreased in LC, (7) indicating an increased platelet turnover. Differences across LC causes are possible. Indeed, reticulated platelets are increased in hepatitis C virus (HCV)-induced LC and decreased in alcohol-induced LC and hepatitis B virus (HBV)induced LC. (5) DeCReaSeD pRoDUCtIoN oF plateletSDecreased production is due to decre...

Biomarkers of liver dysfunction correlate with a prothrombotic and not with a prohaemorrhagic profile in patients with cirrhosis

“…37 An anti-oxidative effect could also influence coagulation and the prothrombotic haemostatic profile. 8 Therefore, the relation between albumin levels and procoagulant state in patients with liver cirrhosis could be based not only on its relation to cirrhosis severity but also to a direct pathophysiologic role of albumin in haemostasis.…”

“…Of note, the platelet count seems not to be predictive for either spontaneous or post-procedural bleeding complications in patients with liver cirrhosis. [38][39][40] This is likely due to the 'rebalanced' primary haemostasis by hyperactive platelets 8,40 and increased von Willebrand factor levels. 8 Moreover, there is no generally accepted gold standard for the analysis of primary haemostasis and fibrinolysis in patients with liver cirrhosis.…”

“…Indeed, haemostatic differences were described across the different cirrhosis aetiologies. 8 The relation between liver dysfunction biomarkers and the prothrombotic state could be different according to cirrhosis aetiology. Therefore, larger studies are required in order to identify potential differences in the relation between liver dysfunction biomarkers and thrombin generation for diverse cirrhosis aetiologies.…”

“…proteins C/S and antithrombin. 8 Routine coagulation assays, such as PT or aPTT, are not sensitive to the changes occurring in natural anticoagulants and they only assess the reduced levels of coagulation factors. In contrast, thrombin generation assays without and with thrombomodulin (TM) or Protac ® , as protein C activators, can evaluate both prohaemorrhagic and prothrombotic changes.…”

Reduced Clot Stability by Thromboelastography as a Potential Indicator of Procedure‐Related Bleeding in Decompensated Cirrhosis

“…(20) It provides real-time data on clot strength and stability as a result of the interplay between soluble clotting factors and inhibitors and platelets. In the setting of cirrhosis, where a multitude of known and unknown hemostatic alterations exist, (12) this functional test appears to be more informative than the quantitative determination of one or more components of the hemostatic cascade. (18) In our study, TEG was significantly more altered in patients who had a procedure-related bleeding versus those who did not, indicative of a relatively more severe hypocoagulable state.…”