Clin Mol Hepatol > Volume 27(4); 2021 > Article
Chun, Choe, Lee, Cho, Kim, Yoo, and Kim: Treatment of direct oral anticoagulants in patients with liver cirrhosis and portal vein thrombosis

Abstract

Although patients with cirrhosis are known to be in a state of “rebalance” in that pro- and anticoagulant factors increase the risk for both bleeding and thrombosis, the prevalence of portal vein thrombosis (PVT) in patients with cirrhosis can be up to 26%. Therefore, physicians should consider anticoagulation for the prevention and management of PVT in patients with cirrhosis who are at high risk of PVT. Vitamin K antagonist or low molecular weight heparin is suggested as the standard treatment for PVT in cirrhosis. With the advent of new direct-acting oral anticoagulants (DOACs), there is a paradigm shift of switching to DOACs for the treatment of PVT in patients with cirrhosis. However, the safety and efficacy of DOACs in the treatment of PVT was not well-known in patients with cirrhosis. Therefore, this review focused on the current knowledge about the efficacy, safety concerns, and hepatic metabolism of DOACs in patients with cirrhosis and PVT.

INTRODUCTION

Liver cirrhosis is associated with a high risk of bleeding secondary to coagulopathy, and is characterized by prolonged bleeding time, thrombocytopenia, increased prothrombin time (PT), and a hypofibrinolytic state [1]. A simultaneous decrease in protein C and S levels, endothelial activation, and reduced antithrombin synthesis contribute to a prothrombotic state in these patients [2]. Reportedly, the von Willebrand factor level (an antihemostasis driver for low platelet counts observed in patients with cirrhosis) was significantly elevated in relation to the platelet-vascular wall interaction [3]. Concomitant alterations in pro- and antihemostatic processes lead to rebalanced hemostasis, although routine laboratory tests for hemostasis that focus on platelet count estimation or the international normalized ratio (INR) for PT suggest a hypocoagulable state (Fig. 1). A meta-analysis of 29 studies (n=13,276 patients with cirrhosis) reported that INR did not serve as a significant correlate for periprocedural bleeding; no significant association was observed between periprocedural bleeding and pre-procedural INR [4].
However, this hemostatic rebalance in patients with cirrhosis is not a fixed phenomenon compared with healthy individuals, and is affected by factors such as infection, renal failure, and surgery. Previous studies have reported new-onset major bleeding in 17–20% of patients with cirrhosis admitted to the intensive care unit [5,6]. A recent meta-analysis of 27 studies (n=93,191) reported that the incidence of intracranial hemorrhage was 2.0% in patients with cirrhosis, who showed a significantly increased risk of subarachnoid hemorrhage (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.80–3.09; P<0.001) and intracranial hemorrhage (HR, 1.48; 95% CI, 1.06–2.05; P<0.05) [7]. In contrast, the incidence of venous thromboembolism (VTE), including deep vein thrombosis or pulmonary embolism, was 0.5–6.3% in hospitalized patients with cirrhosis [8,9]. A recent study showed that hemostatic balance may fluctuate between a hypo- and hypercoagulable state in cases of decompensated cirrhosis with acute kidney injury (AKI) [10]. Among 80 patients with decompensated cirrhosis (40 patients each with and without AKI), those with cirrhosis and AKI had lower platelet aggregation and secretion (indicative of impaired platelet function) and lower protein C, protein S, and antithrombin levels together with increased thrombin formation, which indicate hypercoagulability [10]. Platelet function and coagulopathy improved in patients with decompensated cirrhosis after AKI resolution [10].
Patients with cirrhosis have shown varying hypo- or hypercoagulability tendencies; a recent study using a thromboelastography test (RoTEM®, which is a more accurate indicator of coagulation status than PT or platelet counts in patients with cirrhosis) showed that patients with cirrhosis were more likely to be predisposed to a hypocoagulable (bleeding risk) than a hypercoagulable state (thrombosis risk). Thromboelastography is a point-of-care viscoelastic test of hemostasis in whole blood for accurate measurement of real-time global clot formation and dissolution [11].
Despite a predominant bleeding tendency, portal vein thrombosis (PVT) is more common in patients with cirrhosis owing to PV flow impairment and vascular endothelial cell injury [12]. Serag et al. [13] reported that portal flow velocity was significantly lower in patients with cirrhosis who developed PVT compared to those without PVT (14.2±2.3 cm/s vs. 17.8±2.6 cm/s, P<0.001). These changes concomitant with endothelial injury contribute to PVT in patients with cirrhosis [12]. Studies have shown that PVT is significantly associated with progressive hepatic decompensation and a high mortality risk in patients with cirrhosis [14].
Several direct-acting oral anticoagulants (DOACs) developed in recent years are useful to overcome the limitations of previously popular anticoagulants, such as vitamin K antagonists (VKAs) and heparin [15]. The oral direct thrombin inhibitor, dabigatran etexilate (Pradaxa®), and oral direct activated factor Xa inhibitors, such as rivaroxaban (Xarelto®), apixaban (Eliquis®), and edoxaban (Lixiana®), are currently licensed for use in patients with indications for anticoagulation, including VTE prophylaxis, as well as for the treatment and prevention of stroke and systemic embolic events in cases of non-valvular atrial fibrillation [15]. Although betrixaban (Bevyxxa®) has also been recently licensed for VTE prevention, few reports have established the efficacy and safety of betrixaban in patients with cirrhosis [16]. We investigated the efficacy and safety, as well as the potential role of DOACs (dabigatran etexilate, rivaroxaban, apixaban, and edoxaban) in patients with cirrhosis with a focus on their role in PVT.

DEFINITION OF PVT

No standardized definition is available for PVT owing to its heterogeneous etiology, manifestations, natural history, and therapeutic options. Although the terminology and classification systems for PVT vary extensively in the literature, PVT is usually defined as thrombosis of the PV and/or its right or left branches with extension of the thrombus into the mesenteric or splenic veins, associated with complete or partial occlusion. PVT may also be classified into acute or chronic types. The European Association for the Study of the Liver (EASL) guidelines published in 2016 do not define the exact periods that correspond to acute and chronic PVT, but define acute PVT as PVT in patients “without malignancy and cirrhosis” and “cirrhotic PVT.” Acute PVT is defined as “recent” thrombosis of the PV and/or its right or left branches [17].
According to the American Association for the Study of Liver Diseases (AASLD) guidelines published in 2020, acute PVT is defined as “the sudden formation of a thrombus within the portal vein.” The thrombus can variably involve portions of the mesenteric and/or splenic vein [18,19]. The term “recent (present for <6 months)” is preferred over “acute,” as the latter implies both clinical symptoms and recent-onset thrombosis, considering that patients with acute PVT do not always develop clinical symptoms. According to the AASLD guidelines (2020), chronic PVT (duration ≥6 months) [19], also referred to as portal cavernoma, is attributable to replacement of the obstructed PV by a network of hepatopetal collateral veins that bypass the thrombosed vein segment [18]. Portoportal collaterals or periportal varices, which develop over 1–3 months, represent a typical manifestation of chronic PVT [20] which is associated with an increased risk of portal cholangiopathy, acute decompensation, and mortality [21].
With regard to the treatment of “recent PVT,” the AASLD guideline recommends initial medical anticoagulation and local or systemic thrombolytics in selected patients in whom intestinal ischemia persists despite anticoagulation [19]. Observation alone with serial 3-month imaging without therapy is considered in patients with cirrhosis who show “recent” thrombosis of small intrahepatic sub-branches of the PV or minimally occlusive main PV thrombosis (<50% luminal obstruction). However, anticoagulation should be considered to prevent progressive thrombosis and portal hypertension in patients with cirrhosis who have “recent” occlusive or partially occlusive thrombosis of the main PV (>50% luminal obstruction) or mesenteric veins [19]. With regard to treatment of “chronic PVT,” the AASLD guideline indicates no confirmed benefit of anticoagulant or interventional therapy in patients with chronic complete occlusion of the main PV or cavernous transformation of the PV with established collaterals, and recommends that treatment should focus on the management of portal hypertension-induced complications [19]. PV recanalization (PVR) followed by transjugular intrahepatic portosystemic shunt (TIPS) should be considered in liver transplantation candidates with chronic PVT to create a physiological anastomosis between the graft and recipient PV. PVR followed by TIPS should also be considered in patients with chronic PVT and recurrent bleeding and/or ascites refractory to medical therapy. The AASLD guidelines do not explicitly define the treatment period between recent and chronic PVT; this period depends on clinical situations for the treatment of acute or chronic PVT [21,19].
The EASL guidelines recommend at least 6-month maintenance anticoagulation therapy for cirrhotic PVT, which should be initiated after ensuring adequate prophylaxis for gastrointestinal (GI) bleeding. The EASL guidelines do not provide detailed recommendations for acute PVT in patients with cirrhosis. Furthermore, TIPS was indicated in most cases for portal hypertension-induced complications, such as recurrent bleeding and/or refractory ascites, and not for PVT; therefore, the applicability of TIPS for PVT treatment is not discussed by the EASL guidelines.
The classification of PVT differs between the two aforementioned guidelines; therefore, treatment duration for PVT and the type of anticoagulation therapy (with or without DOACs) also differ between these guidelines. The AASLD guidelines highlight the role of medical anticoagulation to treat acute PVT in patients with cirrhosis, although medical anticoagulation is not clearly indicated in patients with chronic partial occlusion. The EASL guidelines emphasize the role of medical anticoagulation for cirrhotic PVT. Table 1 summarizes the EASL and AASLD clinical guidelines for the definition and management of PVT in patients with cirrhosis [17,19].

PATHOPHYSIOLOGY OF PVT

The pathophysiology of PVT in cirrhosis is multifactorial and results mainly from alterations in the different components of Virchow’s triad: reduced portal blood flow, a hypercoagulable state, or vascular endothelial injury (Fig. 2) [22]. Recent studies have reported that cirrhosis patients with portal blood flow less than 15 cm/s were at increased risk of developing PVT [23,24]. In addition, an increase in portal blood inflow through portosystemic collaterals also seems to influence PVT development [25,26].
Second, hypercoagulability can contribute to pathologic thrombus formation in the PV in cirrhosis patients. Previous studies suggested that the low protein C levels directly impact thrombosis in patients with cirrhosis [27], and an increased ratio between factor VIII and protein C in cirrhosis appears to be responsible for the intrinsic resistance to the anti-coagulant activity of thrombomodulin, a key endothelial receptor in the inhibitory process of thrombin generation in the macro- and micro-circulation [3,28].
Lastly, vascular endothelial damage can lead to thrombosis with the exposure of tissue factor, subsequent stimulation of thrombin production, and promotion of platelet aggregation [29], and the presence of endotoxin increases tissue factor expression on the endothelial surface while simultaneously decreasing thrombomodulin expression [30].

GRADES OF PVT

PVT is historically classified into the following types: cirrhotic or noncirrhotic, acute or chronic, occlusive or non-occlusive, and malignant or nonmalignant [31,32]. However, the most widely used classification, which is of prognostic value in patients awaiting liver transplantation, is that proposed by Yerdel et al. [33] as follows: grade I, <50% luminal thrombosis of the main PV with or without minimal extension into the superior mesenteric vein (SMV); grade II, >50% luminal thrombosis of the PV, including complete thrombosis, with or without minimal extension into the SMV; grade III, complete PVT thrombosis with thrombus extension into the proximal SMV with patent distal SMV; and grade IV, complete PVT and SMV thrombosis (Table 2).

EPIDEMIOLOGY OF PVT IN PATIENTS WITH CIRRHOSIS

The relative risk of PVT is 7-fold higher in patients with cirrhosis than in the general population, which is estimated to be<1.0% [34]. The prevalence of PVT in patients with cirrhosis is 1–26%, with an annual incidence of 3–17%, depending on the severity of cirrhosis (PVT prevalence increases with cirrhosis progression) [35]. A recent national multicenter study including 753 patients with cirrhosis reported that the incidence rate of PVT was 6.1 per 100 patient-years [36]. A prospective cohort study that included a majority of patients with compensated cirrhosis (Child-Pugh class A) reported a 1-year cumulative incidence of PVT of 3.7–4.6% [37,38]. Other cohort studies that included a majority of patients with decompensated cirrhosis (Child-Pugh B or C) reported a 1-year cumulative incidence of PVT of 16.4–17.9% [23,39]. A recent large-scale multicenter retrospective study in China which investigated 2,826 patients with cirrhosis reported that the prevalence of PVT in patients with cirrhosis and acute decompensation was 9.36%, which was significantly higher than the 5.2% observed in those with cirrhosis without acute decompensation (P=0.04) [40].

CURRENT GUIDELINES FOR THE TREATMENT FOR PVT IN PATIENTS WITH CIRRHOSIS

Conventional treatments using low-molecular-weight heparin (LMWH) and VKAs

The AASLD guidelines recommend medical anticoagulation to treat recent PVT in patients with cirrhosis and recent occlusive or partially occlusive main PV thrombosis (>50% luminal obstruction) [19]. Additionally, local or systemic thrombolytic therapy can be considered in selected patients with recent PVT in whom intestinal ischemia persists despite medical anticoagulation [19].
The EASL guidelines recommend at least 6-month administration of anticoagulants, such as LMWH or VKAs, at therapeutic doses for chronic PVT [17]. The AASLD guidelines recommend TIPS concomitant with medical anticoagulation in patients with recurrent bleeding and/or refractory ascites. DOAC therapy is suggested for treatment “in part” as a recommendation based on small cohort studies [19]. Both guidelines suggest sustained anticoagulation in patients with PVT awaiting liver transplantation until completion of the procedure [17,19]. TIPS or PVR followed by TIPS should be considered in patients with progressive PVT unresponsive to anticoagulation, who await liver transplantation [17,19].

Mechanism underlying the action of LMWH, VKAs, and direct anticoagulants

LMWH inhibits the final common pathway of the coagulation cascade, which is the conversion of fibrinogen into fibrin by the activity of thrombin, and blocks the coagulation pathway by activating antithrombin III that binds to and inhibits factor Xa [41]. VKAs block the function of the vitamin K epoxide reductase complex in the liver, leading to depletion of the reduced form of vitamin K that serves as a cofactor for gamma carboxylation of vitamin K-dependent coagulation factors [42]. Without gamma carboxylation, the vitamin K-dependent factors, such as factors II, VII, IX, and X, cannot function, as they cannot adequately bind calcium and phospholipid membranes needed for their hemostatic function [43]. The mechanisms of the DOAC (dabigatran, rivaroxaban, apixaban, and edoxaban) are as follows. Dabigatran is a reversible, potent, competitive direct thrombin inhibitor [44]. Unlike heparin, which can only bind free thrombin, dabigatran is capable of binding and inhibiting both free and clot-bound thrombin [45]. Rivaroxaban, apixaban, and edoxaban inhibit both free and clot-bound factor Xa, as well as prothrombinase activity, and do not require cofactors (such as antithrombin) to exert their anticoagulant effect [46]. Unlike indirect factor Xa inhibitors, they inhibit both free and clot-bound factor Xa, as well as prothrombinase activity. By inhibiting factor Xa, the three DOACs decrease thrombin generation and thrombus development.

Efficacy and safety of low-molecular-weight heparin and vitamin K antagonist treatments

LMWH is the preferred agent, typically followed by VKAs in patients with acute PVT [47]. LMWH offers the advantage of a fixeddose regimen without the need for laboratory monitoring. However, daily subcutaneous LMWH administration may reduce patient compliance and require dose adjustment based on renal function, which is relatively poor in patients with advanced liver cirrhosis [47]. VKAs are usually considered for long-term anticoagulation; however, maintaining the INR within the therapeutic range throughout treatment and interference with the model for end-stage liver disease (MELD) score are challenging in patients administered VKAs [47].
Two recent meta-analyses reported that conventional anticoagulants significantly increased the PVT recanalization rate of 71% (odds ratio [OR], 4.16; 95% CI, 1.88–9.20) as compared to 42% in patients without anticoagulants, and lowered the PVT progression rate of 9% (OR, 0.06; 95% CI, 0.02–0.20) as compared to 33% in patients without anticoagulants [48,49]. Both LMWH and warfarin effectively prevented thrombosis progression; however, LMWH, but not warfarin, was significantly associated with complete PVT resolution [48]. Cessation of anticoagulation after PV repermeation led to recurrent thrombosis in up to 38% of patients after a few months [50]. A recent meta-analysis of 33 studies (n=1,696 patients with cirrhotic PVT who received conventional anticoagulants) reported that decompensated cirrhosis may be associated with lower PVR rates in patients who are administered anticoagulants [51]. Early anticoagulation initiation (risk ratio [RR], 1.58; 95% CI, 1.21–2.07; P<0.001) significantly increased PVR. Furthermore, decompensated cirrhosis (RR, 0.77; 95% CI, 0.62–0.95; P=0.02) and higher MELD scores (mean difference, -1.48; 95% CI, -2.20 to 0.76; P<0.001) were significantly associated with low PVR rates [51].
Bleeding, one of the most common complications of anticoagulation therapy, occurred in 5% of patients with cirrhosis and PVT who received anticoagulants [50]. A meta-analysis of six studies that included 257 patients with cirrhosis and PVT reported no difference in total bleeding rates between the anticoagulation and noanticoagulation groups (11% in both groups) [48]. Moreover, the research showed PVT progression rates of 9% and 33%, respectively, in patients with and without anticoagulation therapy [48]. Non-portal hypertensive bleeding complications following therapeutic anticoagulation were similar between patients with cirrhosis and the general population [19]. Anticoagulants do not tend to affect portal hypertension-induced bleeding in patients with cirrhosis [19].

Role of TIPS for PVT treatment

Indications for TIPS in patients with cirrhosis and PVT include a poor response to anticoagulation or acute PVT accompanied by gastroesophageal variceal bleeding [52,53]. TIPS accelerates the PV inflow and improves PVT recanalization [54]. There are clinical benefits of TIPS for PVT treatment in patients with cirrhosis, such as the following: 1) it achieves effective endovascular recanalization of the thrombosed PV, 2) simultaneously resolves symptomatic portal hypertension, and 3) prevents thrombus recurrence or extension owing to portosystemic shunt creation [55]. Although TIPS is recognized as technically feasible in patients with PVT, it is challenging in patients with extensive obliteration of intrahepatic PV branches and fine collateral vessels [56]. Trans-splenic TIPS is feasible for PVR in patients with complete PVT occlusion, who await liver transplantation [47].
A recent meta-analysis of 13 studies that included 399 patients reported technical feasibility of TIPS in 95% of patients, and that this procedure effectively achieved sustained PVT recanalization. However, it showed a moderate risk of major complications, such as hemoperitoneum (10%) [57]. A randomized controlled trial performed by Lv et al. [58] included patients with cirrhosis (94%, ChildPugh class A or B) concomitant with PVT, with a history of variceal bleeding in the preceding 6 weeks. The patients were randomly assigned to the TIPS group (n=24) or the endoscopic band ligation (EBL) plus propranolol group (EBL+drug, n=25) [58]. During a median follow-up of 30 months in both groups, the incidence rate of variceal rebleeding was significantly lower in the TIPS than in the EBL+drug group (15% vs. 45% at 1 year and 25% vs. 50% at 2 years; HR, 0.28; P=0.008). Moreover, the incidence rate of PVR in the TIPS group was significantly higher than that in the EBL+drug group (95% vs. 70%, P=0.03), and the re-thrombosis rate in the TIPS group was relatively lower than that in the EBL+drug group (5% vs. 33%, P=0.06) [58], which indicate that TIPS can effectively maintain long-term PV patency and obviate the need for anticoagulation.
The effects of anticoagulation therapy after TIPS in patients with cirrhosis and PVT are controversial. A recent randomized controlled study showed that anticoagulation may not be necessary since TIPS placement alone can achieve long-term recanalization [59]. In contrast, Yue-Meng et al. [60] reported that warfarin could effectively promote recanalization in approximately 50% of patients within 1 year in those with de novo post-TIPS PVT. The incidence of PVT in the warfarin group (15%) was 3-fold lower than that in the control group (43%) [60].

DOAC treatment for PVT in patients with cirrhosis

Approval uses for DOACs in the general population

Currently, the following Food and Drug Administration (FDA)- approved DOACs are available clinically: dabigatran (a direct thrombin inhibitor), rivaroxaban, apixaban, edoxaban, and betrixaban (all factor Xa inhibitors) [61]. DOACs are approved for the following indications: prevention of thromboembolic events in atrial fibrillation, VTE prevention in patients who undergo hip or knee replacement, in patients hospitalized for acute illness, and for recurrent VTE or pulmonary embolism prophylaxis and prevention [62].
Studies have confirmed that compared with conventional anticoagulants, DOACs are safer in the general population [16]. A fixed-dose user-friendly regimen without the need to monitor the PT, with lesser food and drug interactions compared with other anticoagulants, are some of the advantages of DOACs [63]. However, studies that investigated the safety and efficacy of DOACs excluded patients with cirrhosis, a condition that is associated with an increased risk of PVT [16]. Table 3 summarizes the inclusion and exclusion criteria used for phase III trials for each DOAC (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF trials) [64-67]. Clinical trials that investigated dabigatran and edoxaban have excluded patients with active liver disease, including viral hepatitis A, B, and C, and patients who showed abnormalities on hepatic biochemical testing [64,67]. Similarly, a clinical trial that investigated rivaroxaban excluded patients with significant liver disease, such as acute clinical hepatitis, chronic active hepatitis, and cirrhosis, in whom alanine aminotransferase levels were >3-fold the upper limit of normal [65]. Patients with abnormalities on hepatic biochemical testing were also excluded in a clinical trial using apixaban[66]. Additionally, phase III trials for dabigatran, apixaban, and edoxaban excluded patients with platelet counts ≤100,000/mm3 [64,66,67]. Rivaroxaban trials did not define a strict platelet threshold; however, this trial excluded patients with “hepatic disease, which is associated with coagulopathy leading to a clinically relevant bleeding risk.” This might have led to the inclusion of individuals with undiagnosed cirrhosis and portal hypertension [65]. In some ambiguous ways, all four DOACs are contraindicated in severe liver disease. Few studies have reported DOAC therapy in patients with cirrhosis, and limited data are available in the literature. The exclusion criteria adopted by clinical trials may prevent the expansion of research with regard to DOAC use in patients with cirrhosis and could serve as obstacles, as medical insurance does not cover PVT treatment in patients with cirrhosis.

Efficacy of DOACs for PVT resolution in patients with cirrhosis

No standard criteria are available to evaluate the “efficacy” of anticoagulants to treat PVT. Currently, the efficacy of DOACs in patients with cirrhosis and PVT has been evaluated only by means of various response states, such as recanalization rates (complete/partial resolution rates), PVT progression rates, or PVT recurrence (re-thrombosis) rates. Although response criteria of PVT in patients with cirrhosis were not standardized in each study, most previous studies have reported that DOAC efficacy was superior to that of conventional anticoagulants in patients with cirrhosis and PVT (Table 4) [68-75]. In a study that investigated DOAC efficacy in 36 patients with cirrhosis across 17 European centers [70], De Gottardi et al. [70] observed PVT in 61% of patients; these patients were treated with DOACs (rivaroxaban [83%], apixaban [11%], or dabigatran [5%]) with median follow-up of 15 months, and the post-DOAC PVT recurrence rates were low (4.5%) in patients who received these drugs [70]. Recently, a single-center study performed by Nagaoki et al. [71] compared the efficacy of edoxaban and warfarin as maintenance treatment in patients with cirrhosis concomitant with acute PVT. After 2-week intravenous danaparoid (a low molecular weight heparinoid devoid of heparin) administered at the time of diagnosis of acute PVT, all patients received edoxaban (n=20) or warfarin (n=30) for 6 months [71]. Comparison between the edoxaban vs. warfarin groups showed a significantly higher rate of complete PVT resolution (70% vs. 20%) and a lower rate of PVT progression (5% vs. 47%) in the edoxaban group [71]. In a recent randomized controlled trial that compared rivaroxaban with warfarin for the treatment of acute PVT in patients with hepatitis C-induced cirrhosis, who underwent splenectomy for symptomatic hypersplenism within 1 week prior to enrollment, Hanafy et al. [73] observed that PVR rates were higher in patients treated with rivaroxaban (85%) than in those treated with warfarin (45%). With regard to the efficacy of post-TIPS anticoagulation, a prospective observational study performed by Lv et al. [74] reported that compared to warfarin, post-TIPS enoxaparin or rivaroxaban administration was associated with a lower risk of re-thrombosis in patients with cirrhosis and PVT. During a median follow-up of 31.7 months, re-thrombosis rates were 2% in patients treated with TIPS+warfarin and 0% in those treated with TIPS+enoxaparin/rivaroxaban; these rates were 33.3% in those who received only warfarin and 0% in those who received only enoxaparin/rivaroxaban [74]. A prospective observational cohort study performed by Ai et al. [75] in patients with cirrhosis and PVT compared patients who received DOACs to those who did not receive anticoagulants. The post-DOAC complete/partial PVT recanalization rates were 12.8% in the DOAC group and 0% in the no-anticoagulant group at 3 months, and 28.2% in the DOAC group and 2.6% in the no-anticoagulant group at 6 months (P<0.05 for all) [75]. In this study, the baseline total bilirubin levels and Child-Pugh scores were improved, and the thromboelastography coagulation index was significantly improved in the DOAC group compared to the no-anticoagulant group (P<0.05) [75]. The efficacy of DOACs for PVT has mainly been investigated in patients with well-compensated cirrhosis; however, further studies are required to confirm whether DOACs show high efficacy against PVT even in patients with decompensated cirrhosis. There is a lack of conclusive evidence to prove that a specific type of DOAC is more effective for the treatment of PVT in patients with cirrhosis.

Safety of direct oral anticoagulants in patients with cirrhosis and PVT

Most previous studies have reported that DOACs had “at least” similar safety profiles as conventional anticoagulants in patients with cirrhosis; the rate of bleeding complications in patients who received DOACs was comparable to that observed in patients who received conventional anticoagulants (Table 4) [68-75]. Bleeding events were categorized as “total bleeding” and “major bleeding.” The most frequent definition of major bleeding was fatal bleeding or overt bleeding that led to a reduction of at least 20 g/L in the serum hemoglobin level, or bleeding that necessitated transfusion of at least 2 units of packed blood cells, or hemorrhage at a critical anatomical site (e.g., intracranial or retroperitoneal bleeding) [76]. Intagliata et al. [68] compared the major bleeding rates between cirrhosis patients treated with DOACs (rivaroxaban [55%] or apixaban [45%]) and those treated with conventional anticoagulants (warfarin or LMWH), and observed no significant intergroup differences in the major bleeding rates (5% [1 of 20] in the DOAC group and 11% [2 of 19] in the conventional anticoagulation group, P=0.99). Hum et al. [69] reported that major bleeding rates observed during 3-year follow-up were higher in the conventional anticoagulation group (28%) than in the DOAC group (4%) for thrombosis or prevention of stroke in patients with atrial fibrillation and cirrhosis (P=0.03); however, the “total bleeding” rates were similar in both groups. Nagaoki et al. [71] reported no significant difference in the prevalence of major GI bleeding between patients with cirrhosis and PVT treated with edoxaban (15%) and those treated with warfarin (7%) for 6 months (P=0.34).
Importantly, Hanafy et al. [73] reported no hepatic decompensation or mortality in patients with cirrhosis and concomitant PVT who received rivaroxaban (n=40), whereas those who received warfarin (n=40) showed higher incidence of hepatic decompensation manifested as ascites (41.0%), GI bleeding (43.3%), hepatic encephalopathy (31.8%), or death (20%).
Lv et al. [74] (n=396) recently reported that compared with warfarin, long-term anticoagulation using enoxaparin or rivaroxaban with or without TIPS did not increase the risk of major GI bleeding in patients with cirrhosis and PVT over a median follow-up of 31.7 months. The GI bleeding rates were 14.7% in the no-anticoagulation group (n=20/136), 14.2% in the warfarin group (n=31/218), and 14.2% in the enoxaparin/rivaroxaban group (n=6/42) (P=0.06) [74].
Upper GI bleeding was the most common cause of bleeding associated with DOAC therapy in patients with cirrhosis. Sasso et al. [77] recently reported that 18% of bleeding events, with upper GI bleeding (53%), occurred in patients with cirrhosis who received warfarin (n=183) or DOACs (n=133). Esophageal varices were significantly associated with a high risk of clinically relevant bleeding (OR, 5.7; 95% CI, 1.8–17.7; P<0.05) [77], which highlights the importance of accurate and early diagnosis and treatment of esophageal varices based on the guidelines [78-80], prior to the initiation of anticoagulation therapy for cirrhotic PVT.
Notably, few studies have discussed the safety of DOACs and compared the complications based on DOACs for the treatment of PVT in patients with decompensated cirrhosis. However, Mort et al. [81] recently reported potential DOAC-induced bleeding risk in patients with decompensated cirrhosis. The authors observed that patients with decompensated cirrhosis had a significant risk of bleeding (25.8%, n=24 of 93), and 21% of the patients in this study discontinued DOAC therapy for 6 months [81]. Major bleeding predominantly occurred in patients with hepatocellular carcinoma (54%, n=7/13) who received DOACs for the treatment of atrial fibrillation and splanchnic or non-splanchnic venous thrombosis [81]. Further well-designed comparative studies are warranted to confirm the safety among DOACs and to investigate safety profiles in patients with decompensated cirrhosis concomitant with PVT.

Hepatic metabolism of individual direct oral anticoagulants

Table 5 summarizes the mechanism of action, metabolism, half-life, and reversal agent for individual DOACs. Dabigatran is a direct thrombin inhibitor, which is eliminated through the kidneys (80%) and the liver (20%) [82]. Its terminal half-life is 14–17 hours in healthy individuals [83]. Dabigatran peak levels (Cmax) and exposure (area under the curve [AUC]) were slightly lower in patients with Child-Pugh class B than in healthy individuals [84]. The current guidelines do not include recommendations for dabigatran usage or dosing in patients with hepatic dysfunction. Idarucizumab is a humanized monoclonal antibody fragment approved by the FDA that has been developed as a specific reversal agent for dabigatran [85]. A phase 3 clinical trial, REVERSE-AD, showed that over 98% of 503 patients reached 100% reversal of dabigatran activity [85].
Rivaroxaban is a direct factor Xa inhibitor that undergoes renal elimination (unchanged drug) and metabolic degradation of the drug [82], and resulting metabolites are excreted via both renal and hepatobiliary routes. Its terminal half-life is 9–13 hours in healthy individuals [83]. Peak drug levels (Cmax) and drug exposure (AUC) of a single rivaroxaban dose are slightly elevated in patients with Child-Pugh class A and moderately elevated in patients with Child-Pugh class B [86]. Rivaroxaban was shown to prolong the PT in patients with Child-Pugh classes A and B [16].
Apixaban is a direct factor Xa inhibitor that is eliminated through the kidneys (25%) and the liver (75%) [82]. Its terminal half-life is 8–15 hours in healthy individuals [87]. Compared with healthy individuals, the peak drug levels of a single apixaban dose (5 mg) remained unchanged in patients with Child-Pugh classes A and B. Drug exposure (AUC) was slightly elevated in patients with cirrhosis. Apixaban does not require dose adjustment in patients with Child-Pugh class A [84].
Edoxaban is a direct factor Xa inhibitor that is eliminated through the kidneys (50%) and the liver (50%) [82]. Its terminal half-life is 9–10 hours in healthy individuals [83]. Peak levels and drug exposure of a single edoxaban dose were elevated in patients with Child-Pugh classes A and B compared to healthy individuals [88].
Andexanet-α is a recombinant modified factor Xa protein approved by the FDA for the reversal of apixaban and rivaroxaban (not yet FDA-approved for edoxaban) [89]. A phase 3 clinical trial, ANNEXA, showed that 79% of 47 patients who received apixaban, rivaroxaban, edoxaban, or enoxaparin treatment achieved effective homeostasis [89].
No study has described the specific DOAC type that may be effective and safe for PVT treatment in patients with cirrhosis. Dabigatran may be considered relatively safe among the available DOACs in patients with cirrhosis, as it undergoes relatively lesser hepatic metabolism; however, few clinical studies have investigated the role of dabigatran for PVT treatment in patients with decompensated cirrhosis. The FDA [90] and European Medicines Agency (EMA) [91] recommend Child-Pugh score evaluation to guide DOAC treatment. According to the FDA and EMA guidelines, any DOAC is contraindicated in patients with Child-Pugh class C disease. Although apixaban, dabigatran, and edoxaban can be used with caution and/or after dose adjustment in patients with ChildPugh classes A and B, rivaroxaban administration is contraindicated in patients with Child-Pugh class B. Furthermore, DOACs should not be used in patients with Child-Pugh class C; and renal insufficiency, drug-drug interactions, a history of bleeding, and thrombocytopenia should be confirmed before the initiation of DOAC therapy.

CONCLUSIONS AND FUTURE DIRECTIONS

Patients with liver cirrhosis tend to show a more complicated coagulation state than is usually recognized based on standard coagulation tests. Rebalanced hemostasis involves the activity of both pro- and anticoagulant factors, and occurs secondary to various precipitating events. Worsening severity of cirrhosis predisposes patients to PVT and consequent portal hypertension-induced bleeding. This condition, particularly in patients with decompensated cirrhosis, often leads to a clinical dilemma, as it is difficult to determine whether to treat PVT in this clinical scenario in which two critical challenges oppose each other, specifically the high risk of bleeding vs. ongoing hepatic insufficiency caused by PV obstruction.
PVT, a common thrombotic complication observed in patients with cirrhosis, is invariably associated with poor outcomes and warrants at least 6-month maintenance anticoagulation therapy using LMWH or warfarin, according to the guidelines. Unfortunately, cessation of anticoagulation may be followed by recurrent thrombosis even after complete repermeation; therefore, an individualized long-term anticoagulation regimen is warranted.
The efficacy and safety of DOACs in patients with cirrhosis have been reported predominantly by small-sized, retrospective studies that only focused on patients with well-compensated cirrhosis; however, compared to conventional anticoagulants, DOACs appear to be “at least” safe and efficacious to treat PVT in patients with well-compensated cirrhosis and PVT. Notably, a few recent studies have reported that DOACs may cause significant bleeding and lower the recanalization rates in patients with decompensated cirrhosis and PVT [51,81]; therefore, DOACs should be cautiously administered to patients with decompensated cirrhosis. Therefore, it is important to decide whether prophylactic anticoagulation should be administered to patients with compensated cirrhosis at high risk for PVT or PVT progression, and to determine the optimal time to commence DOAC treatment to prevent PVT before the onset of decompensation.
There is a lack of convincing data regarding the benefits associated with the treatment of PVT, as PVR does not necessarily improve the course of chronic liver disease. Furthermore, it is necessary to conclusively establish the type of DOAC that shows the best efficacy and safety and to determine the optimal drug, dose, and treatment duration for management of PVT in patients with cirrhosis. Prospective studies with well-defined outcomes in a well-characterized cohort are warranted to gain a deeper understanding of these clinical issues.

Acknowledgments

This study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number: 2017R1D1A1B03031499), and a grant from the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (grant number: 2020R1C1C1004112).

Footnotes

Authors’ contribution
Study concept and design: Minjong Lee; Acquisition of data: Minjong Lee, Ho Soo Chun, A Reum Choe, Yuri Cho, Hwi Young Kim, Kwon Yoo, Tae Hun Kim; Drafting of the manuscript: Minjong Lee, Ho Soo Chun, A Reum Choe; Critical revision of the manuscript for important intellectual content: Minjong Lee, Ho Soo Chun, A Reum Choe, Tae Hun Kim; All authors have read and approved the manuscript.
Conflicts of Interest: The authors have no conflicts to disclose.

Figure 1.
The concept of rebalanced hemostasis in patients with liver cirrhosis. Rebalance in the hemostatic system occurs at the level of primary and secondary hemostasis, and in the fibrinolytic system. However, since this new balance is less stable compared to the balance in healthy people, it may more easily tip toward either bleeding or thrombosis. vWF, von Willebrand factor; ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif-13; TAFI, thrombin activatable fibrinolysis inhibitor; tPA, tissue plasminogen activator.

cmh-2021-0109f1.jpg
Figure 2.
The pathogenesis of portal vein thrombosis in cirrhosis.

cmh-2021-0109f2.jpg
Table 1.
Summary of existing guidelines for management of PVT in patients with cirrhosis
Guideline EASL (2016) AASLD (2020)
Classification 1. Acute PVT in patients without malignancy and cirrhosis 1. Recent PVT (for <6 months)
2. Cirrhotic PVT 2. Chronic PVT (for >6 months)
Treatment Acute PVT in patients without malignancy and cirrhosis Recent PVT
Start LMWH + antibiotics if septic thrombophlebitis Medical anticoagulants ± local or systemic thrombolytic therapy (very selected cases)
Treat cause when accurate Recent thrombosis of small intrahepatic sub-branches, minimal occlusive (<50% of lumen) of main PV: observation by serial imaging every 3 months.*
Recent occlusive or partially occlusive (>50% obstruction of the lumen) thrombosis of the main PV or mesenteric veins: antithrombotic therapy should be considered to avoid thrombosis progression.*
Cirrhotic PVT Chronic PVT
Medical anticoagulants (applicability of TIPS to treat PVT unknown) Medical anticoagulants ± TIPS (with advanced PVT and recurrent bleeding and/or refractory ascites)
Anticoagulation must be started always after implementing an adequate prophylaxis for gastrointestinal bleeding.* Chronic complete occlusion of the main PV or cavernous transformation of the PV with established collaterals: no established benefit of anticoagulant or interventional therapy, and treatment should focus on the management of portal hypertension complications.*
Type of anticoagulants LMWH or VKAs (no information currently available for DOACs) LMWH, VKA, or DOACs (recommendations rely on smaller cohort studies for DOACs)
Treatment duration At least 6 months Depends on clinical condition
Side effect (most common) Bleeding Non-portal hypertensive bleeding
LT candidates Consider prolonging anticoagulation for some months and until transplantation, once PVT has been repermeated. Anticoagulation with the goal to recanalize the portal vascular system before LT.
Consider TIPS for those with progressive PVT who are not responding to anticoagulation. PV recanalization followed by TIPS should be considered.

PVT, portal vein thrombosis; EASL, European Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; LMWH, low molecular weight heparin; PV, portal vein; TIPS, transjugular intrahepatic portosystemic shunt; VKAs, vitamin K antagonists; DOACs, direct-acting oral anticoagulants; LT, liver transplantation.

* Specific precautions for each treatment of PVT.

Table 2.
Portal vein thrombosis grading system
Definition
Grade I <50% PV thrombosed with or without minimal extension into SMV
Grade II >50% PV thrombosed with or without minimal extension into SMV
Grade III Complete thrombosis of PV and proximal SMV
Grade IV Complete thrombosis of PV, proximal SMV, and distal SMV

PV, portal vein; SMV, superior mesenteric vein.

Table 3.
Comparison of inclusion and exclusion criteria in phase 3 clinical trials in DOACs
Study characteristic RE-LY (dabigatran) ROCKET-AF (rivaroxaban) ARISTOTLE (apixaban) ENGAGE-AF (edoxaban)
Study design Randomized open label Multi-center randomized doubleblind, double dummy Randomized control double-blind parallel arm Three-group, randomized doubleblind, double-dummy
Number of patients 18,113 14,264 18,201 21,105
Randomized groups Dose-adjusted warfarin vs. blinded doses of dabigatran (150 or 110 mg twice a day) Dose-adjusted warfarin vs. rivaroxaban 20 mg daily Dose-adjusted warfarin vs. apixapain 5 mg twice a day Dose-adjusted warfarin vs. high-dose or low-dose edoxaban strategy
Inclusion criteria 1. AF-documented patients 1. Men or women aged ≥18 years with non-valvular atrial fibrillation 1. Atrial fibrillation or flutter at enrollment, or two or more episodes of atrial fibrillation or flutter, as documented by electrocardiography, at least 2 weeks apart in the 12 months before enrollment 1. ≥21 years in age and has atrial fibrillation documented by means of an electrical tracing within the 12 months preceding randomization
2. Patients must have one of the following: 2. Atrial fibrillation must be documented by ECG evidence
a. History of previous stroke, TIA, or systemic embolism 3. History of prior ischemic stroke, TIA, or non-CNS systemic embolism believed to be cardioembolic in origin, or has 2 or more of the risk factors 2. Has at least one of the risk factors for stroke 2. A score of 2 or higher on the CHADS2 risk assessment
b. Ejection fraction <40% documented by echocardiogram, radionuclide, or contrast angiogram in the last 6 months 3. Anticoagulation therapy planned for the duration of the trial
c. Symptomatic heart failure, New York Heart Association class 2 or higher in the last 6 months 4. Female subjects must be postmenopausal (for at least 2 years), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control
d. Age ≥75 years
e. Age ≥65 years and one of the following:
i) Diabetes mellitus on treatment 5. Written, informed consent
ii) Documented coronary artery disease (any of: prior myocardial infarction, positive stress test, positive nuclear perfusion study, prior CABG surgery or PCI, angiogram showing ≥75% stenosis in a major coronary artery
iii) Hypertension requiring medical treatment
3. Age >18 years at entry
4. Written, informed consent
Exclusion criteria (liver-related) 1. Active liver disease, including but not limited to: 1. Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 times the ULN 1. ALT or AST >2 times the ULN, or a total bilirubin ≥1.5 times the ULN (unless an alternative causative factor [e.g., Gilbert’s syndrome] is identified) 1. Active liver disease or persistent (confirmed by repeat assessment within a week) elevation of liver enzymes/bilirubin:
a. Persistent ALT, AST, ALP >2×ULN a. ALT or AST ≥2 times the ULN
b. Known active hepatitis C (positive HCV RNA) b. Total bilirubin ≥1.5 times the ULN
c. Active hepatitis B (HBs antigen+, anti HBc IgM+) 2. Hepatic disease that is associated with coagulopathy leading to a clinically relevant bleeding risk 2. Platelet count ≤100,000/mm3 c. ALP ≥2 times the ULN
d. Active hepatitis A 2. History of positive hepatitis B antigen or hepatitis C antibody
2. Platelet count ≤100,000/mm3 3. Platelet count ≤100,000/mm3

DOACs, direct-acting oral anticoagulants; AF, atrial fibrillation; TIA, transient ischemic attack; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; ECG, echocardiogram; CNS, central nervous system; CHADS2, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke [double weight]; ALT, alanine amino-transferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; ULN, upper limit of normal; HCV, hepatitis C virus.

Table 4.
Anticoagulation with DOACs in patients with cirrhosis and PVT
Study Study design Aim of study Indication for anticoagulation therapy Number of patients Drug and doses Treatment duration Efficacy Safety
Intagliata et al. [68] (2016) 1. Retrospective To compare the rates of bleeding in cirrhotic patients (DOAC vs. traditional anticoagulants) Splanchnic thrombosis, non- splanchnic venous thromboembolism, and atrial fibrillation DOAC (n=20; PVT, n=12) vs. warfarin (n=19) Rivaroxaban 20 mg daily or apixaban 5 mg bid daily (n=15, 75%) 10.6 months (mean) Not studied Major bleeding (n=1)
2. Cirrhotic, CP A, B Rivaroxaban 10 mg daily or apixaban 2.5 mg bid daily (n=5, 25%)
3. DOAC (apixaban and rivaroxaban) vs. traditional anticoagulants (warfarin and LMWH)
Hum et al. [69] (2017) 1. Retrospective To identify of the efficacy and safety of DOAC vs. traditional anticoagulants in cirrhosis Atrial fibrillation or venous thromboembolism, including PVT and deep vein thrombosis DOAC (n=27; PVT, n=4) vs. warfarin/LMWH (n=18; PVT, n=3) Rivaroxaban 15 mg bid ±20 mg daily load (63%), apixaban 5 mg bid ±10 mg bid load (47%), no bridging 10.6 months (mean) Recurrence (n=1, 4%) 1. 10 bleeds in traditional group, 8 bleeds in DOAC group (P=0.12)
2. Cirrhotic, CP A, B & C 2. More major bleeds in traditional group (n=5) than in DOAC group (n=1) (P=0.03)
3. DOAC (apixaban and rivaroxaban) vs. traditional anticoagulants (enoxaparin and warfarin)
De Gottardi et al. [70] (2017) 1. Retrospective To identify indications and reasons for starting or switching to DOAC and report adverse effects, complications, and short-term outcomes Splanchnic vein thrombosis, deep vein thrombosis, atrial fibrillation, and others Total (n= 94) Cirrhotic: rivaroxaban 15 mg (range, 5–20; 83%), apixaban 5 mg (range, 2.5–10; 11%), and dabigatran 165 mg (range, 110–220; 5%) Cirrhotic: 9.6 months (mean) Cirrhotic: recurrent PVT (n=1, 4.5%) Cirrhotic: minor bleeding (n=4), major bleeding (n=1)
2. Both cirrhotic and non- cirrhotic, CP A, B Cirrhosis (n=36)
Cirrhosis with PVT (n=22)
Nagaoki et al. [71] (2018) 1. Retrospective To compare the efficacy and safety of edoxaban and warfarin for treatment of PVT following danaparoid sodium in cirrhotic patients Portal vein thrombosis Total (n=50) Edoxaban 60 mg (CrCl >50) (n=4), edoxaban 30 mg (CrCl 30–50) (n=16) 6 months (maximum) Recanalization: 90% (complete, n=14; partial, n=1; unchanged, n=1; progression, n=1) Major gastrointestinal bleeding: edoxaban (n=3) and warfarin (n=2) (P=0.335)
2. Cirrhotic, CP A, B Edoxaban (n=20) Edoxaban group had more complete resolution and less PVT progression than warfarin group
3. Edoxaban vs. warfarin following 2 weeks of danaparoid treatment in cirrhotic PVT Warfarin (n=30)
Scheiner et al. [72] (2018) 1. Retrospective To assess the course of nonmalignant PVT in patients receiving anticoagulants Portal vein thrombosis Total (n=10) Edoxaban 30 or 60 mg once daily, apixaban 5 mg bid daily, rivaroxaban 10 mg once daily, dabigatran 110 mg bid daily 9.2 months (median) 20% with regression/resolution of PVT, 80% with stable PVT including unchanged cavernous transformation Portal hypertensive gastropathy bleeding (n=1)
2. Both cirrhotic and noncirrhotic Cirrhosis (n=3; edoxaban [n=4], apixaban [n=3], rivaroxaban [n=2], dabigatran [n=1])
Hanafy et al. [73] (2019) 1. Prospective To evaluate the efficacy and safety of rivaroxaban compared to warfarin Portal vein thrombosis Rivaroxaban (n=40) vs. warfarin (n=40) Rivaroxaban 10 mg bid daily 6 months (maximum) Recanalization: 100% with rivaroxavan (complete, n=34; partial, n=6) vs. 45% with warfarin Eight deaths in the warfarin group; none in the rivaroxaban group
2. Cirrhotic, CP A, B
3. Rivaroxavan vs. warfarin for acute PVT
Ai et al. [75] (2020) 1. Prospective To investigate the efficacy and safety of DOACs compared to no anticoagulants Portal vein thrombosis DOACs (n=40; rivaroxaban [n=26], dabigatran [n=14]) vs. no anticoagulants (n=40) Rivaroxaban 20 mg once daily 6 months (maximum) Recanalization: DOACs vs. no anticoagulation: 12.8% (n=5/39) vs. 0% (n=0/40) at 3 months; 28.2% (n=11/39) vs. 2.6% (n=1/38) at 6 months DOACs: melena 1, hematuria 1, hemoptysis 1 case vs. no anticoagulation: melena 1 (P>0.05)
2. Cirrhotic, CP A Dabigatran 150 mg bid daily
3. Rivaroxaban or dabigatran vs. no anticoagulants
Lv et al. [74] (2021) 1. Prospective To evaluate the management using a waitand-see strategy, anticoagulation, and transjugular intrahepatic portosystemic shunt to treat PVT in cirrhosis Portal vein thrombosis Total (n=396) Rivaroxaban 10 mg daily 21.0 months (median) Recanalization: 0% with rivaroxavan only (all with PVT and SMV thrombosis), 100% with TIPS+rivaroxavan Major bleeding events: AC only (n=14, 22.2%)
2. Cirrhotic, CP A, B & C All anticoagulants (n=260)
3. Comparison of anticoagulants and/or TIPS, and no treatment AC only (n=63; warfarin [n=51], enoxaparin [n=8], rivaroxaban [n=4]) TIPS+AC (n=30, 15.2%)
TIPS only (n=88)
TIPS+AC (n=197; rivaroxaban+TIPS [n=18])

DOAC, direct-acting oral anticoagulant; PVT, portal vein thrombosis; CP, Child-Pugh; LMWH, low-molecular-weight heparin; bid, bis in die; CrCl, creatinine clearance; TIPS, transjugular intrahepatic portosystemic shunt; AC, anticoagulation; SMV, superior mesenteric vein.

Table 5.
Summary of the mechanism of action, metabolism, half-life, and reversal agent for individual DOACs
Type of DOAC Dabigatran Rivaroxaban Apixaban Edoxaban
Mechanism of action Direct thrombin (FIIa) inhibitor Direct FXa inhibitor Direct FXa inhibitor Direct FXa inhibitor
Hepatic clearance (%) 20 65 75 50
Renal clearance (%) 80 35 25 50
Half-life (hours) 12–17 7–13 ~12 10–14
Reversal agent Idarucizumab Andexanet-α Andexanet-α Andexanet-α (not yet FDAapproved)
Mechanism of action Humanized monoclonal antibody fragment that binds dabigatran with high affinity both to free and thrombin-bound dabigatran Inactive human FXa decoys protein that binds to FXa inhibitors in their active site with high affinity Inactive human FXa decoys protein that binds to FXa inhibitors in their active site with high affinity Inactive human FXa decoys protein that binds to FXa inhibitors in their active site with high affinity
Summary of major phase 3 randomized, double-blind, placebocontrolled trials REVERSE-AD showed that over 98% of 503 patients (mean age, 76.5 years) reached 100% reversal of dabigatran activity ANNEXA showed that 79% of 47 patients (mean age, 77 years) who received apixaban, rivaroxaban, edoxaban, or enoxaparin treatment achieved effective homeostasis ANNEXA showed that 79% of 47 patients (mean age, 77 years) who received apixaban, rivaroxaban, edoxaban, or enoxaparin treatment achieved effective homeostasis ANNEXA showed that 79% of 47 patients (mean age, 77 years) who received apixaban, rivaroxaban, edoxaban, or enoxaparin treatment achieved effective homeostasis
Coagulation monitoring No No No No
Coagulation assay Thrombin time Anti-FXa activity Anti-FXa activity Anti-FXa activity

DOAC, direct oral anticoagulant; FIIa, factor IIa; FXa, factor Xa; FDA, Food and Drug Administration.

Abbreviations

AASLD
American Association for the Study of Liver Diseases
AKI
acute kidney injury
AUC
area under the curve
CI
confidence interval
DOACs
direct-acting oral anticoagulants
EASL
European Association for the Study of the Liver
EBL
endoscopic band ligation
EMA
European Medicines Agency
FDA
Food and Drug Administration
GI
gastrointestinal
HR
hazard ratio
INR
international normalized ratio
LMWH
low-molecular-weight heparin
MELD
model for end-stage liver disease
OR
odds ratio
PT
prothrombin time
PVR
portal vein recanalization
PVT
portal vein thrombosis
RR
risk ratio
SMV
superior mesenteric vein
TIPS
transjugular intrahepatic portosystemic shunt
VKAs
vitamin K antagonists
VTE
venous thromboembolism

REFERENCES

1. Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost 2017;1:150-161.
crossref pmid pmc
2. Ghazaleh S, Beran A, Aburayyan K, Nehme C, Patel D, Khader Y, et al. Efficacy and safety of anticoagulation in non-malignant portal vein thrombosis in patients with liver cirrhosis: a systematic review and meta-analysis. Ann Gastroenterol 2021;34:104-110.
crossref pmid
3. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011;365:147-156.
crossref pmid
4. Kovalic AJ, Majeed CN, Samji NS, Thuluvath PJ, Satapathy SK. Systematic review with meta-analysis: abnormalities in the international normalised ratio do not correlate with periprocedural bleeding events among patients with cirrhosis. Aliment Pharmacol Ther 2020;52:1298-1310.
crossref pmid
5. Drolz A, Horvatits T, Roedl K, Rutter K, Staufer K, Kneidinger N, et al. Coagulation parameters and major bleeding in critically ill patients with cirrhosis. Hepatology 2016;64:556-568.
crossref pmid
6. Cholongitas E, Senzolo M, Patch D, Kwong K, Nikolopoulou V, Leandro G, et al. Risk factors, sequential organ failure assessment and model for end-stage liver disease scores for predicting short term mortality in cirrhotic patients admitted to intensive care unit. Aliment Pharmacol Ther 2006;23:883-893.
crossref pmid
7. Zheng K, Yoshida EM, Tacke F, Li Y, Guo X, Qi X. Risk of stroke in liver cirrhosis: a systematic review and meta-analysis. J Clin Gastroenterol 2020;54:96-105.
pmid
8. Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest 2010;137:1145-1149.
crossref pmid
9. Aldawood A, Arabi Y, Aljumah A, Alsaadi A, Rishu A, Aldorzi H, et al. The incidence of venous thromboembolism and practice of deep venous thrombosis prophylaxis in hospitalized cirrhotic patients. Thromb J 2011;9:1.
crossref pmid pmc
10. Zanetto A, Rinder HM, Campello E, Saggiorato G, Deng Y, Ciarleglio M, et al. Acute kidney injury in decompensated cirrhosis is associated with both hypo-coagulable and hyper-coagulable features. Hepatology 2020;72:1327-1340.
crossref pmid
11. Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014;89:228-232.
crossref pmid
12. O’Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA clinical practice update: coagulation in cirrhosis. Gastroenterology 2019;157:34-43.e1.
crossref pmid
13. Serag WM, Mohammed BSE, Mohamed MM, Elsayed BE. Predicting the risk of portal vein thrombosis in patients with liver cirrhosis and hepatocellular carcinoma. Heliyon 2020;6:e04677.
crossref pmid pmc
14. Stine JG, Shah PM, Cornella SL, Rudnick SR, Ghabril MS, Stukenborg GJ, et al. Portal vein thrombosis, mortality and hepatic decompensation in patients with cirrhosis: a meta-analysis. World J Hepatol 2015;7:2774-2780.
crossref pmid pmc
15. Gómez-Outes A, Suárez-Gea ML, Lecumberri R, Terleira-Fernández AI, Vargas-Castrillón E. Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives. Eur J Haematol 2015;95:389-404.
crossref pmid
16. Weinberg EM, Palecki J, Reddy KR. Direct-acting oral anticoagulants (DOACs) in cirrhosis and cirrhosis-associated portal vein thrombosis. Semin Liver Dis 2019;39:195-208.
crossref pmid
17. European Association for the Study of the Liver. EASL clinical practice guidelines: vascular diseases of the liver. J Hepatol 2016;64:179-202.
pmid
18. DeLeve LD, Valla DC, Garcia-Tsao G; American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009;49:1729-1764.
crossref pmid
19. Northup PG, Garcia-Pagan JC, Garcia-Tsao G, Intagliata NM, Superina RA, Roberts LN, et al. Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases. Hepatology 2021;73:366-413.
crossref pmid
20. Harmanci O, Bayraktar Y. How can portal vein cavernous transformation cause chronic incomplete biliary obstruction? World J Gastroenterol 2012;18:3375-3378.
crossref pmid pmc
21. Young K, Wong R. Evaluation and management of acute and chronic portal vein thrombosis in patients with cirrhosis. Clin Liver Dis (Hoboken) 2018;10:152-156.
crossref pmid pmc
22. Senzolo M, Garcia-Tsao G, García-Pagán JC. Current knowledge and management of portal vein thrombosis in cirrhosis. J Hepatol 2021;75:442-453.
crossref pmid
23. Zocco MA, Di Stasio E, De Cristofaro R, Novi M, Ainora ME, Ponziani F, et al. Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J Hepatol 2009;51:682-689.
crossref pmid
24. Stine JG, Wang J, Shah PM, Argo CK, Intagliata N, Uflacker A, et al. Decreased portal vein velocity is predictive of the development of portal vein thrombosis: a matched case-control study. Liver Int 2018;38:94-101.
crossref pmid
25. Maruyama H, Okugawa H, Takahashi M, Yokosuka O. De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes. Am J Gastroenterol 2013;108:568-574.
crossref pmid
26. Francoz C, Valla D, Durand F. Portal vein thrombosis, cirrhosis, and liver transplantation. J Hepatol 2012;57:203-212.
crossref pmid
27. Tripodi A, Primignani M, Lemma L, Chantarangkul V, Mannucci PM. Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis. J Hepatol 2013;59:265-270.
crossref pmid
28. Violi F, Basili S, Raparelli V, Chowdary P, Gatt A, Burroughs AK. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction? J Hepatol 2011;55:1415-1427.
crossref pmid
29. Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006;44:53-61.
crossref pmid
30. Moore KL, Andreoli SP, Esmon NL, Esmon CT, Bang NU. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 1987;79:124-130.
crossref pmid pmc
31. de Franchis R; Baveno VI Facult. Expanding consensus in portal hypertension: report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743-752.
pmid
32. Sarin SK, Philips CA, Kamath PS, Choudhury A, Maruyama H, Nery FG, et al. Toward a comprehensive new classification of portal vein thrombosis in patients with cirrhosis. Gastroenterology 2016;151:574-577.e3.
crossref pmid
33. Yerdel MA, Gunson B, Mirza D, Karayalçin K, Olliff S, Buckels J, et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 2000;69:1873-1881.
crossref pmid
34. Ogren M, Bergqvist D, Björck M, Acosta S, Eriksson H, Sternby NH. Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies. World J Gastroenterol 2006;12:2115-2119.
crossref pmid pmc
35. Noronha Ferreira C, Reis D, Cortez-Pinto H, Tato Marinho R, Gonçalves A, Palma S, et al. Anticoagulation in cirrhosis and portal vein thrombosis is safe and improves prognosis in advanced cirrhosis. Dig Dis Sci 2019;64:2671-2683.
crossref pmid
36. Violi F, Corazza GR, Caldwell SH, Talerico G, Romiti GF, Napoleone L, et al. Incidence and recurrence of portal vein thrombosis in cirrhotic patients. Thromb Haemost 2019;119:496-499.
crossref pmid
37. Nery F, Chevret S, Condat B, de Raucourt E, Boudaoud L, Rautou PE, et al. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology 2015;61:660-667.
crossref pmid
38. Noronha Ferreira C, Marinho RT, Cortez-Pinto H, Ferreira P, Dias MS, Vasconcelos M, et al. Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: a prospective study. Liver Int 2019;39:1459-1467.
crossref pmid
39. Abdel-Razik A, Mousa N, Elhelaly R, Tawfik A. De-novo portal vein thrombosis in liver cirrhosis: risk factors and correlation with the model for end-stage liver disease scoring system. Eur J Gastroenterol Hepatol 2015;27:585-592.
pmid
40. Zhang Y, Xu BY, Wang XB, Zheng X, Huang Y, Chen J, et al. Prevalence and clinical significance of portal vein thrombosis in patients with cirrhosis and acute decompensation. Clin Gastroenterol Hepatol 2020;18:2564-2572.e1.
crossref pmid
41. Mulloy B, Hogwood J, Gray E, Lever R, Page CP. Pharmacology of heparin and related drugs. Pharmacol Rev 2016;68:76-141.
crossref pmid
42. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133(6 Suppl):160s-198s.
crossref pmid
43. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126(3 Suppl):204s-233s.
crossref pmid
44. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002;45:1757-1766.
crossref pmid
45. Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007;98:155-162.
crossref pmid
46. Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood 2010;115:15-20.
crossref pmid
47. Rugivarodom M, Charatcharoenwitthaya P. Nontumoral portal vein thrombosis: a challenging consequence of liver cirrhosis. J Clin Transl Hepatol 2020;8:432-444.
crossref pmid pmc
48. Loffredo L, Pastori D, Farcomeni A, Violi F. Effects of anticoagulants in patients with cirrhosis and portal vein thrombosis: a systematic review and meta-analysis. Gastroenterology 2017;153:480-487.e1.
crossref pmid
49. Qi X, De Stefano V, Li H, Dai J, Guo X, Fan D. Anticoagulation for the treatment of portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis of observational studies. Eur J Intern Med 2015;26:23-29.
crossref pmid
50. Delgado MG, Seijo S, Yepes I, Achécar L, Catalina MV, García-Criado A, et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012;10:776-783.
crossref pmid
51. Wang L, Guo X, Xu X, De Stefano V, Plessier A, Noronha Ferreira C, et al. Anticoagulation favors thrombus recanalization and survival in patients with liver cirrhosis and portal vein thrombosis: results of a meta-analysis. Adv Ther 2021;38:495-520.
crossref pmid
52. Loudin M, Ahn J. Portal vein thrombosis in cirrhosis. J Clin Gastroenterol 2017;51:579-585.
crossref pmid
53. Zhao D, Zhang G, Wang M, Zhang C, Li J. Portal pressure gradient and serum albumin: a simple combined parameter associated with the appearance of ascites in decompensated cirrhosis treated with transjugular intrahepatic portosystemic shunt. Clin Mol Hepatol 2019;25:210-217.
crossref pmid pmc
54. Turon F, Hernández-Gea V, García-Pagán JC. Portal vein thrombosis: yes or no on anticoagulation therapy. Curr Opin Organ Transplant 2018;23:250-256.
pmid
55. Riggio O, Ridola L, Lucidi C, Angeloni S. Emerging issues in the use of transjugular intrahepatic portosystemic shunt (TIPS) for management of portal hypertension: time to update the guidelines? Dig Liver Dis 2010;42:462-467.
crossref pmid
56. Hepatobiliary Disease Study Group; Chinese Society of Gastroenterology; Chinese Medical Association. Consensus for management of portal vein thrombosis in liver cirrhosis (2020, Shanghai). J Dig Dis 2021;22:176-186.
pmid pmc
57. Rodrigues SG, Sixt S, Abraldes JG, De Gottardi A, Klinger C, Bosch J, et al. Systematic review with meta-analysis: portal vein recanalisation and transjugular intrahepatic portosystemic shunt for portal vein thrombosis. Aliment Pharmacol Ther 2019;49:20-30.
crossref pmid
58. Lv Y, Qi X, He C, Wang Z, Yin Z, Niu J, et al. Covered TIPS versus endoscopic band ligation plus propranolol for the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis: a randomised controlled trial. Gut 2018;67:2156-2168.
crossref pmid
59. Wang Z, Jiang MS, Zhang HL, Weng NN, Luo XF, Li X, et al. Is postTIPS anticoagulation therapy necessary in patients with cirrhosis and portal vein thrombosis? A randomized controlled trial. Radiology 2016;279:943-951.
crossref pmid
60. Yue-Meng W, Li YH, Wu HM, Yang J, Yang LH, Xu Y. Portal vein thrombosis in patients with cirrhosis undergoing elective transjugular intrahepatic portosystemic shunt: risk factors, warfarin efficacy, and clinical outcomes. Clin Appl Thromb Hemost 2018;24:462-470.
crossref pmid
61. Husted S, de Caterina R, Andreotti F, Arnesen H, Bachmann F, Huber K, et al. Non-vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel. Thromb Haemost 2014;111:781-782.
crossref pmid
62. Schwarb H, Tsakiris DA. New direct oral anticoagulants (DOAC) and their use today. Dent J (Basel) 2016;4:5.
crossref pmc
63. Helms TM, Silber S, Schäfer A, Masuhr F, Palm F, Darius H, et al. Consensus statement: management of oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation. Herzschrittmacherther Elektrophysiol 2016;27:295-306.
pmid
64. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151.
crossref pmid
65. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.
crossref pmid
66. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.
crossref pmid
67. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-2104.
crossref pmid
68. Intagliata NM, Henry ZH, Maitland H, Shah NL, Argo CK, Northup PG, et al. Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation. Dig Dis Sci 2016;61:1721-1727.
crossref
69. Hum J, Shatzel JJ, Jou JH, Deloughery TG. The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis. Eur J Haematol 2017;98:393-397.
crossref
70. De Gottardi A, Trebicka J, Klinger C, Plessier A, Seijo S, Terziroli B, et al. Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis. Liver Int 2017;37:694-699.
crossref pmid
71. Nagaoki Y, Aikata H, Daijyo K, Teraoka Y, Shinohara F, Nakamura Y, et al. Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis. Hepatol Res 2018;48:51-58.
crossref pmid
72. Scheiner B, Stammet PR, Pokorny S, Bucsics T, Schwabl P, Brichta A, et al. Anticoagulation in non-malignant portal vein thrombosis is safe and improves hepatic function. Wien Klin Wochenschr 2018;130:446-455.
crossref
73. Hanafy AS, Abd-Elsalam S, Dawoud MM. Randomized controlled trial of rivaroxaban versus warfarin in the management of acute nonneoplastic portal vein thrombosis. Vascul Pharmacol 2019;113:86-91.
crossref pmid
74. Lv Y, Bai W, Li K, Wang Z, Guo W, Luo B, et al. Anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis: a prospective observational study. Am J Gastroenterol 2021;116:1447-1464.
crossref pmid
75. Ai MH, Dong WG, Tan XP, Xu L, Xu C, Zhang Q, et al. Efficacy and safety study of direct-acting oral anticoagulants for the treatment of chronic portal vein thrombosis in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2020;32:1395-1400.
crossref pmid
76. Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692-694.
crossref pmid
77. Sasso R, Rockey DC. Anticoagulation therapy in patients with liver cirrhosis is associated with an increased risk of variceal hemorrhage. Am J Med 2019;132:758-766.
crossref pmid
78. Lesmana CRA, Raharjo M, Gani RA. Managing liver cirrhotic complications: overview of esophageal and gastric varices. Clin Mol Hepatol 2020;26:444-460.
crossref
79. Chung JW. Role of endoscopic treatment or balloon-occluded retrograde transvenous obliteration in patients with Child-Pugh class C end-stage liver cirrhosis and esophageal/gastric varices. Clin Mol Hepatol 2019;25:181-182.
crossref pmid
80. Yokoyama K, Yamauchi R, Shibata K, Fukuda H, Kunimoto H, Takata K, et al. Endoscopic treatment or balloon-occluded retrograde transvenous obliteration is safe for patients with esophageal/gastric varices in Child-Pugh class C end-stage liver cirrhosis. Clin Mol Hepatol 2019;25:183-189.
crossref pmid
81. Mort JF, Davis JPE, Mahoro G, Stotts MJ, Intagliata NM, Northup PG. Rates of bleeding and discontinuation of direct oral anticoagulants in patients with decompensated cirrhosis. Clin Gastroenterol Hepatol 2021;19:1436-1442.
crossref pmid
82. Elhosseiny S, Al Moussawi H, Chalhoub JM, Lafferty J, Deeb L. Direct oral anticoagulants in cirrhotic patients: current evidence and clinical observations. Can J Gastroenterol Hepatol 2019;2019:4383269.
crossref pmid pmc
83. Raymond J, Imbert L, Cousin T, Duflot T, Varin R, Wils J, et al. Pharmacogenetics of direct oral anticoagulants: a systematic review. J Pers Med 2021;11:37.
crossref pmid pmc
84. Graff J, Harder S. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin Pharmacokinet 2013;52:243-254.
crossref pmid
85. Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017;377:431-441.
crossref pmid
86. Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol 2013;76:89-98.
crossref pmid pmc
87. Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet 2019;58:1265-1279.
crossref pmid pmc
88. Mendell J, Johnson L, Chen S. An open-label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics and pharmacodynamics. J Clin Pharmacol 2015;55:1395-1405.
crossref pmid
89. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019;380:1326-1335.
crossref pmid pmc
90. Chen A, Stecker E, A Warden B. Direct oral anticoagulant use: a practical guide to common clinical challenges. J Am Heart Assoc 2020;9:e017559.
crossref pmid pmc
91. Salmonson T, Dogné JM, Janssen H, Garcia Burgos J, Blake P. Non-vitamin-K oral anticoagulants and laboratory testing: now and in the future: views from a workshop at the European Medicines Agency (EMA). Eur Heart J Cardiovasc Pharmacother 2017;3:42-47.
crossref pmid

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: kasl@kams.or.kr
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 595
TOTAL : 607828
Close layer