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

Lee, K C L; Baker, L; Mallett, S; Riddell, A; Chowdary, P; Alibhai, H I K; Chang, Y M; Priestnall, S L; Stanzani, G; Davies, N; Mookerjee, R; Jalan, R; Agarwal, B

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.

Citation

Lee, K. C. L., Baker, L., Mallett, S., Riddell, A., Chowdary, P., Alibhai, H. I. K., Chang, Y. M., Priestnall, S. L., Stanzani, G., Davies, N., Mookerjee, R., Jalan, R., & Agarwal, B. (2017). Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs. https://doi.org/10.1038/s41598-017-09508-3

• Journal Article Type: Article
• Acceptance Date: Jul 26, 2017
• Publication Date: Aug 24, 2017
• Deposit Date: May 15, 2018
• Publicly Available Date: May 15, 2018
• Journal: Scientific Reports (Nature)
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 1
• Pages: 9347
• DOI: https://doi.org/10.1038/s41598-017-09508-3
• Public URL: https://rvc-repository.worktribe.com/output/1390734