Global hemostatic profiling in patients with decompensated cirrhosis and bacterial infections

Abstract

Background & aims: Bacterial infections in cirrhosis are associated with increased bleeding risk. To assess the factors responsible for bleeding tendency in patients with bacterial infections, we conducted a prospective study comparing all 3 aspects of hemostasis (platelets, coagulation, and fibrinolysis) in hospitalized patients with decompensated cirrhosis with vs. without bacterial infections.

Methods: Primary hemostasis assessment included whole blood platelet aggregation and von Willebrand factor (VWF). Coagulation assessment included procoagulant factors (fibrinogen, factor II, V, VII, VIII, IX, X, XI, XII, XIII), natural anticoagulants (protein C, protein S, antithrombin) and thrombomodulin-modified thrombin generation test. Fibrinolysis assessment included fibrinolytic factors (plasminogen, t-PA, PAI-1, α2-AP, TAFIa/ai) and plasmin-antiplasmin complex (PAP).

Results: Eighty patients with decompensated cirrhosis were included (40 with and 40 without bacterial infections). Severity of cirrhosis and platelet count were comparable between groups. At baseline, patients with cirrhosis and bacterial infections had significantly lower whole blood platelet aggregation, without significant differences in VWF. Regarding coagulation, bacterial infections were associated with reduced procoagulant factors VII and XII, and a significant reduction of all natural anticoagulants. However, thrombomodulin-modified thrombin generation was comparable between the study groups. Finally, although mixed potentially hypo-fibrinolytic (lower plasminogen) and hyper-fibrinolytic (higher t-PA) changes were present in bacterial infections, a comparable level of PAP was detected in both groups. Upon resolution of infection (n = 29/40), platelet aggregation further deteriorated whereas coagulation and fibrinolysis factors returned to levels observed in patients without bacterial infections.

Conclusion: In hospitalized patients with decompensated cirrhosis, bacterial infections are associated with reduced whole blood platelet aggregation and a significant decrease of all natural anticoagulants, which may unbalance hemostasis and potentially increase the risk of both bleeding and thrombosis.

Lay summary: Bacterial infections are a common issue in hospitalized patients with decompensated cirrhosis (i.e. patients hospitalized due to severe complications of advanced chronic liver disease). Patients with decompensated cirrhosis who acquire infections may be at increased risk of bleeding complications following invasive procedures (that is a procedure in which the body is penetrated or entered, for instance by a needle or a tube). As bleeding complications in decompensated cirrhosis are associated with a high risk of further decompensation and death, there is an urgent need to understand the factors responsible for such increased bleeding tendency. Herein, we investigated the alterations of hemostasis (that is the physiological process responsible for clot formation and stability) in patients with decompensated cirrhosis and bacterial infections. We found that development of bacterial infections in these patients is associated with alterations of hemostasis (particularly of platelets and clotting cascade) that may increase the risk of both bleeding and thrombotic complications.

Keywords: ACLF, acute-on-chronic liver failure; AKI, acute kidney injury; AT, antithrombin; ETP, endogenous thrombin potential; F, factor; FXIII, fibrin-stabilizing factor XIII; MELD, model for end-stage liver disease; PAI-1, plasminogen activator inhibitor-1; PAP, plasmin-antiplasmin complex; PC, protein C; PS, protein S; TAFIa/ai, activated and inactivated thrombin-activatable fibrinolytic inhibitor; TM, thrombomodulin; VWF, von Willebrand factor; cirrhosis; coagulation; fibrinolysis; infections; platelets; t-PA, tissue-type plasminogen activator; α2-AP, α2-antiplasmin.

Graphical abstract

Fig. 1

Flow chart of the study. ACLF, acute-on-chronic liver failure; CKD, chronic kidney disease; HCC, hepatocellular carcinoma; ICU, intensive care unit; PVT, portal vein thrombosis; VH, variceal hemorrhage; VTE, venous thromboembolism.

Fig. 2

Whole blood platelet aggregation in patients with cirrhosis. In patients with platelet count <100x10⁹/L, ADP-induced platelet aggregation was more altered in patients with vs. without bacterial infections. Mann-Whitney U test. For numerical values, refer to Table S1.

Fig. 3

Evolution of platelet aggregation after resolution of infection. Resolution of infection is associated with a significant reduction of whole blood platelet aggregation, independent of baseline platelet count and agonist used. Wilcoxon matched-pairs signed rank test. ASPI, arachidonic acid; TRAP, thrombin receptor activating peptide.

Fig. 4

Levels of procoagulant factors and natural anticoagulants in cirrhosis patients with vs. without bacterial infections. The grey area refers to the reference range in healthy individuals. Mann-Whitney U test. BI, bacterial infection.

Fig. 5

Thrombin generation results in patients with and without bacterial infections. Mann-Whitney U test (solid line); Kruskal-Wallis test (dotted line). BI, bacterial infection; ETP, endogenous thrombin potential; TM, thrombomodulin.

Fig. 6

Evolution of coagulation and fibrinolysis at resolution of infection. Resolution of bacterial infection was not associated with significant changes in activation of coagulation and fibrinolysis, as evidenced by the unchanged levels of thrombin-antithrombin complex (top) and plasmin-antiplasmin complex (bottom). Wilcoxon matched-pairs signed rank test.