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

Potze, Wilma; Adelmeijer, Jelle; Lisman, Ton

doi:10.1002/hep.27350

Cited by 52 publications

(43 citation statements)

References 6 publications

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“…The incidence of complications, also including bleeding episodes, related to anticoagulation in this study was similar in patients with or without cirrhosis. Recurrence of thrombosis of the portal vein under treatment with rivaroxaban may indicate insufficient dosing or, as suggested by in vitro results, that the potency of this drug might be reduced in cirrhotic patients. Further studies, preferably randomized clinical trials including a large number of patients are needed to address this issue.…”

Section: Discussionsupporting

confidence: 54%

“…In this context, patients with advanced liver disease raise a double challenge primarily due to the known derangements of the coagulation system, and secondarily due to the potential impact of the impairment of the liver function on the efficacy and safety of DOACs. This is especially relevant because of the nowadays confirmed high prevalence of thrombotic events in patients with cirrhosis with the ensuing increase in the use of anticoagulants …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antithrombotic treatment with direct‐acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis

Gottardi

Trebicka

Klinger

et al. 2016

Liver International

187

141

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Antithrombotic treatment with direct‐acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis

Gottardi

Trebicka

Klinger

et al. 2016

Liver International

187

141

View full text Add to dashboard Cite

show abstract

“…The second caveat of using antihemostatic drugs in patients with liver disease is altered drug potency. The complex hemostatic changes of liver disease were recently shown to impact drug potency (at least in vitro) . Using in vitro thrombin generation tests it has been demonstrated that the extent by which thrombin generation is inhibited by various anticoagulant drugs may differ tremendously between patients and controls.…”

Section: Prevention and Management Of Thrombosis In Liver Diseasesmentioning

confidence: 99%

Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases

Lisman

Porte

2017

Research and Practice in Thrombosis and Haemostasis

Self Cite

107

129

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Essentials Patients with liver diseases may acquire substantial changes in all components of hemostasis.Hemostasis is in unstable balance due to simultaneous changes in pro‐ and antihemostatic systems.Intrahepatic activation of hemostasis may contribute to disease progression.Optimal strategies for prevention and treatment of bleeding and thrombosis are currently unknown. Patients with liver diseases may develop alterations in all components of the hemostatic system. Thrombocytopenia, low levels of coagulation factors and inhibitors, low levels of fibrinolytic proteins, and increased levels of endothelial‐derived proteins such as von Willebrand factor are all part of the coagulopathy of liver disease. Due to concomitant changes in pro‐ and antihemostatic drivers, the net effects of these complex hemostatic changes have long been unclear. According to current concepts, the hemostatic system of patients with liver disease is in an unstable balance, which explains the occurrence of both bleeding and thrombotic complications. This review will discuss etiology and management of bleeding and thrombosis in liver disease and will outline unsolved clinical questions. In addition, we will discuss the role of intrahepatic activation of coagulation for progression of liver disease, a novel paradigm with potential consequences for the general management of patients with liver disease.

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“…Given the major alterations in the haemostatic system of patients with cirrhosis, the efficacy of pro‐ and antihaemostatic strategies may be unpredictable. We have previously demonstrated that in patients with compensated cirrhosis the in vitro anticoagulant effects of some of the commonly used drugs was decreased, whereas the anticoagulant effects of others were increased as compared to anticoagulant effects in healthy individuals . Another study has shown a lack of prohaemostatic effect of in vitro addition of fresh frozen plasma to plasma from patients with compensated cirrhosis, despite improvements in plasma levels of coagulation factors .…”

Section: Introductionmentioning

confidence: 99%

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

Lisman

Kleiss

Patel

et al. 2018

Liver International

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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.

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

Cited by 52 publications

References 6 publications

Antithrombotic treatment with direct‐acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis

Antithrombotic treatment with direct‐acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis

Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases

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

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