In vitro efficacy of pro‐ and anticoagulant strategies in compensated and acutely ill patients with cirrhosis

Abstract

Background & AimsA simultaneous decline in pro‐ and anticoagulant drivers in patients with liver diseases results in a “rebalanced” haemostatic system, even in acutely ill patients. Nevertheless, both bleeding and thrombotic events are common. Here, we explored efficacy of pro‐ and antihaemostatic strategies in compensated and acutely ill cirrhotics which may be unpredictable given the profound haemostatic changes.MethodsWe tested the effects in vitro of the addition of clinically relevant doses of commonly used pro‐ and antihaemostatic strategies in plasma from healthy individuals (n = 30) and patients with compensated (n = 18) and acutely decompensated cirrhosis (n = 18), and acute‐on‐chronic liver failure (n = 10). We used thrombin generation tests and fibrin clot permeability assays to assess potency of various approaches.ResultsFresh frozen plasma and recombinant factor VIIa modestly increased thrombin generation (10%‐20%). Prothrombin complex concentrate increased thrombin generation two‐fold in controls and 2‐4‐fold in patients. Clot permeability decreased after addition of fibrinogen concentrate by 51% in controls and by 50%‐60% in patients. Low molecular weight heparin decreased thrombin generation by 18% in controls and by 23%‐54% in patients. Similarly, dabigatran decreased thrombin generation by 33% in controls and by 47%‐100% in patients. In contrast, rivaroxaban decreased thrombin generation by 55% in controls, but only by 11%‐38% in patients.ConclusionsThese in vitro data suggest little prohaemostatic effect of fresh frozen plasma and recombinant factor VIIa in acutely ill cirrhotics, whereas prothrombin complex concentrate and fibrinogen concentrate clearly improved haemostasis. Furthermore, our data suggest the requirement for dose adjustments of commonly used anticoagulants in these patients.

Prothrombin Complex Concentrates for Coagulopathy in Liver Disease: Single‐Center, Clinical Experience in 105 Patients

“…An ex vivo study of PCC conducted using blood samples from liver transplant recipients showed that PCC was more effective than FFP in increasing thrombin generation . Similarly, in a study testing the effects of in vitro addition of hemostatic agents using thrombin generation tests, FFP and rFVIIa only modestly increased thrombin generation in patients with compensated and acutely decompensated cirrhosis, whereas PCC increased thrombin generation 2‐fold to 4‐fold in these patients and approximately 2‐fold in healthy individuals . In a clinical study conducted across a range of settings, which included a small cohort of patients with liver disease, PCC therapy was associated with a trend toward a reduction in INR .…”

Nails in the coffin of fresh frozen plasma to prevent or treat bleeding in cirrhosis?

“…4 In vitro experiments have indicated that FFP does not increase coagulation potential in patients with cirrhosis as it supplies both pro-and anticoagulant proteins in equal amounts. 5 As a result, although plasma levels of individual coagulation factors increase and as a consequence the prothrombin time and INR may decrease, actual thrombin generating capacity does not change or may even decrease. Further, in many procedures undertaken in patients with CLD, procedural risk appears lower than generally appreciated.…”

Thrombin Generation and Cirrhosis: State of the Art and Perspectives

“…61 Indeed, in vitro studies suggest major differences in the anticoagulant potency of commonly used anticoagulant drugs. 35,62 In addition, the pharmacokinetics of anticoagulant agents may be different in patients with cirrhosis. This might be particularly relevant for direct oral anticoagulants that are partially cleared by liver, and dose adjustments may be required in patients with cirrhosis.…”

“…For example, Lisman et al have demonstrated enhanced in vitro potency of prothrombin complex concentrates in patients with cirrhosis, suggesting dose-reductions may be required for these types of agents. 62 Moreover, it would be important to pay attention to a potential tilt of the fragile balance toward (more) hypercoagulability, if no AT is administered (PCC), or if AT is in insufficient amounts in FFP.…”