Differential In Vitro Inhibition of Thrombin Generation by Anticoagulant Drugs in Plasma from Patients with Cirrhosis

Abstract

BackgroundTreatment and prevention of thrombotic complications is frequently required in patients with cirrhosis. However anticoagulant therapy is often withheld from these patients, because of the perceived bleeding diathesis. As a result of the limited clinical experience, the anticoagulant of choice for the various indications is still not known.ObjectivesWe evaluated the in vitro effect of clinically approved anticoagulant drugs in plasma from patients with cirrhosis.Patients/MethodsThirty patients with cirrhosis and thirty healthy controls were studied. Thrombin generation assays were performed before and after addition of unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and rivaroxaban, to estimate anticoagulant potencies of these drugs.ResultsAddition of dabigatran led to a much more pronounced reduction in endogenous thrombin potential in patients compared to controls (72.6% reduction in patients vs. 12.8% reduction in controls, P<0.0001). The enhanced effect of dabigatran was proportional to the severity of disease. In contrast, only a slightly increased anticoagulant response to heparin and low molecular weight heparin and even a reduced response to fondaparinux and rivaroxaban was observed in plasma from cirrhotic patients as compared to control plasma.ConclusionsThe anticoagulant potency of clinically approved drugs differs substantially between patients with cirrhosis and healthy individuals. Whereas dabigatran and, to a lesser extent, heparin and low molecular weight heparin are more potent in plasma from patients with cirrhosis, fondaparinux and rivaroxaban showed a decreased anticoagulant effect. These results may imply that in addition to dose adjustments based on altered pharmacokinetics, drug-specific dose adjustments based on altered anticoagulant potency may be required in patients with cirrhosis.

Anticoagulation in chronic liver disease

“…Dabigatran is an oral direct thrombin inhibitor; no differences in coagulation markers were observed after its administration between healthy controls and patients with Child-Pugh B cirrhosis (Stangier et al, 2008), but its in vitro anticoagulant effect has been demonstrated to increase with increasing severity of liver disease (Potze et al, 2014). No clinical trials to date have used it in chronic liver disease patients.…”

“…• In vitro data suggest that cirrhotics may have much increased sensitivity to the anticoagulant effect of dabigatran (Potze et al, 2014) Idarucizumab (Pollack et al, 2015).…”

Decreased in vitro anticoagulant potency of Rivaroxaban and Apixaban in plasma from patients with cirrhosis

“…4 We recently showed altered in vitro potency of different anticoagulant drugs in patients with cirrhosis, compared to patients with intact liver function. 5 A theoretical risk for excessive anticoagulation when using these drugs in patients with cirrhosis and concomitant alterations in their hemostatic system exists.…”

Treating thrombosis in cirrhosis patients with new oral agents: Ready or not?

“…However, we would like to emphasize recent reports advancing a more cautionary tone concerning in vitro efficacy and safety of these medications. 3,4 Cirrhosis patients are typically excluded from clinical trials assessing anticoagulants and clinicians are often left to extrapolate when developing treatment plans in this challenging population. While our series is small and no significant bleeding occurred, there is certainly risk when using these new agents, as the ability to monitor and rescue from bleeding is currently limited.…”