Evaluation of coagulation abnormalities in acute liver failure

Background & Aims

In acute liver failure (ALF), prothrombin time (PT) and its derivative prothrombin time ratio (PTR) are elevated, and are considered predictors of increased bleeding risk. We aimed at determining whether increased PT/PTR reflects the haemostatic potential and bleeding risk in ALF patients.

Methods

Twenty consecutive ALF patients were recruited. Samples were analysed on admission for standard laboratory clotting tests (e.g. PT), thromboelastography (TEG), individual pro and anticoagulant factors and thrombin generation (TG) kinetics with and without Protac®, a snake venom protein C activator, and microparticle assay. TG was also measured in 20 age and sex matched healthy volunteers.

Results

PT was significantly raised (50.7 s ± 7.2, p = 0.0001) but did not correlate with TEG parameters. TEG tracings were consistent with a hypocoagulable state in 20%, normal in 45%, and hypercoagulable in 35% of the patients. There was a concomitant and proportional reduction in plasma levels of both procoagulants and natural anticoagulant proteins, in conjunction with a significant elevation in plasma levels of factors-VIII (FVIII) and Von Willebrand factor, and microparticles, culminating in an overall efficient, albeit reduced, thrombin generation capacity in comparison with healthy individuals. A heparin-like effect (HLE) was also noted in most patients. No significant clinical bleeding complications occurred and no blood transfusions were required.

Conclusions

In ALF, despite grossly deranged PT in all patients, estimation of bleeding risk suggests that the coagulation disturbance in ALF patients is complex and heterogeneous for which an individualised approach is required.

Introduction

Coagulopathy and hepatic encephalopathy (HE) are cardinal features of acute liver failure (ALF). The prothrombin time (PT) and its derivation, the PTR, and the commonly used ‘International normalised ratio’ (INR) have become the standard tests to assess coagulopathy in liver disorders, as not only do they serve as good prognostic indicators, but are broadly considered to correlate with bleeding risk and thus guide blood product replacement for invasive procedures. However, there is increasing evidence that in liver disease, the PT/INR as an indicator of coagulopathy may be misleading, as bleeding is rare unless when it occurs as a complication of co-existent portal hypertension and/or sepsis and renal failure. The overall haemostatic potential and the clinical consequences thereof, in liver disease, seem to represent the sum total of the modulating effect of a multitude of pro and antihaemostatic drivers activated simultaneously and in varying degrees. The important players are clotting factors, both pro and anticoagulants (most of which are synthesized solely by the liver), platelets, and the endothelium. Correcting coagulopathy delays intervention, introduces transfusion-related complications, and eliminates relevance of PT as an indicator of prognosis and need for liver transplantation. In patients with stable non-infected compensated and decompensated cirrhosis and, during liver transplantation, an increasing body of evidence not only shows a state of ‘balanced’ haemostasis in chronic liver disease [1], [2], [3], but even hypercoagulability with thrombotic complications [4], [5]. Our group have already documented increased clotting of continuous renal replacement therapy (CRRT) circuits in those liver failure patients requiring renal support [6]. It is not clear whether a similar discrepancy exists between the clotting parameters in ALF when patients typically present with much higher PT/INRs and derangement of other measures of coagulation than patients with cirrhosis.

The aims of this study were to determine whether increased PT/PTR reflects the haemostatic potential and bleeding risk in ALF patients. A comprehensive assessment of plasma levels of pro and anticoagulants factors, the relative contribution of platelets and fibrinogen towards clot strength, the role of endogenous heparinoids and the resultant heparin-like effect (HLE, plasma microparticle activity), and the role of procoagulant phospholipids on clotting time were undertaken in order to understand coagulation findings and their relationship with clinical outcomes (bleeding/thrombosis) in patients presenting with ALF.