Intraperitoneal activation of the coagulation system via tissue factor-exposing extracellular vesicles and enhanced fibrinolysis in patients with advanced chronic liver disease and ascites

Background and aims:

The development of ascites is the most common first hepatic decompensation. Ascitic fluid (AF) is a dynamic medium that enters and leaves the peritoneal cavity at high rates. The presence of AF may affect the haemostatic balance of patients with advanced chronic liver disease (ACLD).

We aimed to investigate bi-directional interactions between AF and the coagulation system in patients with ACLD.

Methods:

We included patients with ACLD with (n = 25) and without ascites (n = 25), matched for severity of portal hypertension (i.e. hepatic venous pressure gradient). We determined routine and experimental coagulation parameters and performed clotting experiments in AF and plasma.

Fig. 1

Results:

In AF, extracellular vesicle (EV)-associated tissue factor (TF)-activity was high (A), while activities of other coagulation factors were low, as compared to plasma of the same patients (B). Strong correlations between albumin levels and coagulation factor activities in AF suggested that coagulation factors diffuse from plasma into AF (C/D). In vitro, AF was clearly procoagulant. The procoagulant potential of AF was abolished by (i) depletion of EV from AF, (ii) filtration of AF through a 0.1 µm membrane, or (iii) by addition of a TF-neutralizing antibody to AF (E). The EV-depleted fraction of AF (supernatant) induced fibrinolysis, which was prevented by aprotinin, indicating the presence of plasminogen activators in AF (F). In plasma, EV-associated TF-activity was low and did not differ between patients with or without ascites. Parameters reflecting fibrinolysis were highly elevated in plasma of patients with ascites compared to patients without ascites (G/H).

Conclusions:

Coagulation and fibrinolysis become activated intraperitoneally in patients with ACLD and ascites. While TF-exposing EV in AF seem unable to pass the peritoneal barrier, fibrinolytic enzymes appear to get activated in AF, re-enter the circulation, and induce systemic fibrinolysis. This interaction might explain elevated D-dimer levels in patients with ascites.