Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs

Karla Chui Luan Lee,Hatim Alibhai,Rajiv Jalan,Pratima Chowdary,Giacomo Stanzani,Anne Riddell,Nathan Davies,Yu-Mei Chang,Rajeshwar Mookerjee,Luisa Baker,Simon Priestnall,Banwari Agarwal,Susan Mallett

doi:10.1038/s41598-017-09508-3

Abstract

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to ‘ALF’, defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats–13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability.

Highlights

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists
Acetaminophen (APAP) treatment leads to acute liver injury (ALI) and failure (ALF) associated with elevation in International Normalised Ratio (INR)
We describe for the first time the evolution of coagulation disturbance from health through ALI to established acute liver failure (ALF), prior to the onset of multi-organ failure, in a pig model of APAP-induced ALF

Summary

Introduction

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. It is possible that the large heterogeneity in coagulation disturbances observed in ALI/ALF patients is due in part to the cross-sectional nature of study designs, resulting in inclusion of patients at the time of admission to the Intensive Care Unit, rather than at specific stages of liver failure or at the onset of specific complications of liver failure. Complications such as superimposed infection; endothelial dysfunction; and renal failure requiring extracorporeal therapies and use of inotropes may all independently contribute to coagulation disturbances. Coagulopathy and underlying mechanisms for coagulation disturbance were assessed longitudinally in systemic and portal blood from the time of induction of liver injury up to the development of full-blown liver failure

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