Background: Patients with liver diseases are in a hypercoagulable state, as evidenced by enhanced in vitro thrombin generating capacity and elevated plasma levels of markers of in vivo thrombin generation. However, it is unknown by which mechanism in vivo activation of coagulation occurs.
Objectives: We aimed to clarify the mechanisms underlying enhanced in vivo thrombin generation to provide a rationale for targeted anticoagulant therapy.
Patients/methods: Overall, 191 patients diagnosed with stable or acutely decompensated cirrhosis, acute liver failure or injury, acute-on-chronic liver failure, or sepsis without underlying chronic liver disease were recruited from King's College Hospital, London, from 2017 to 2021 and compared with reference values of 41 healthy controls. We measured levels of markers of in vivo activation of coagulation and activation of the intrinsic and extrinsic pathways, their respective zymogens, and natural anticoagulants.
Results: Thrombin-antithrombin complexes, prothrombin fragment 1+2 (F1+2), and D-dimer levels were increased in acute and chronic liver disease, proportional to disease severity. Plasma levels of free activated factor XII (FXIIa), C1-esterase-inhibitor (C1inh)-FXIIa, C1inh-factor XI, C1inh-plasma kallikrein, factor-VIIa-antithrombin-complexes, and activated FVII were reduced in acute and chronic liver disease, even after adjusting for zymogen levels, which were also substantially reduced. Natural anticoagulants antithrombin and protein C were profoundly reduced in liver patients.
Conclusions: This study provides evidence of enhanced thrombin generation in liver disease without detectable activation of the intrinsic or extrinsic pathway. We propose that defective anticoagulant mechanisms highly amplify the low-grade activation of coagulation by either pathway.
Keywords: acute; blood coagulation; cirrhosis; hemostasis; liver failure; thrombosis.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.