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Abstract

Background

Hemostasis in cirrhosis is a dynamic, “rebalanced” state rather than a simple bleeding diathesis. Portal vein thrombosis (PVT) is a frequent complication linked to variceal bleeding, hepatic decompensation, and mortality. Anticoagulation can prevent thrombus progression, promote recanalization, and improve survival without a major increase in bleeding risk.

Objectives

To summarize the safety, efficacy, and pharmacologic considerations of direct oral anticoagulants (DOACs) for PVT in cirrhosis.

Methods

This narrative review is informed by a systematic literature search (Ovid Medline, Ovid EMBASE, Cochrane Central, Cochrane Database of Systematic Reviews, and Scopus) from 2010 to 17 July 2025. We included cohort, interventional, and meta-analytic studies evaluating DOACs in adults with cirrhosis and PVT, and synthesized these with pharmacokinetic data and international guidance.

Results

Fixed-dose oral DOACs, with generally favorable safety profiles, are promising alternatives to vitamin K antagonists (VKAs) and low-molecular-weight heparins. Regulatory guidance supports DOAC use in Child–Turcotte–Pugh (CTP) class A, recommends cautious use in selected CTP class B patients, and generally discourages use in CTP class C. Apixaban and edoxaban show relatively stable pharmacokinetics in compensated cirrhosis. Observational cohorts and network meta-analyses suggest that DOACs achieve at least comparable, and often higher, rates of portal vein recanalization than VKAs, with similar risks of major and variceal bleeding.

Conclusions

Overall, DOACs represent an effective and convenient anticoagulation option for carefully selected cirrhotic patients with PVT. Treatment should be individualized according to liver and renal function, variceal status, and transplant candidacy. High-quality prospective studies are still needed, particularly in CTP classes B/C cirrhosis.

Keywords

thrombosis portal vein thrombosis cirrhosis direct oral anticoagulants Child–Turcotte–Pugh Class

Introduction

Historically, cirrhosis was considered a bleeding diathesis due to thrombocytopenia and prolonged prothrombin time (PT). However, it is now understood as a rebalanced hemostatic state, in which both pro- and anti-coagulant factors are altered.¹ Despite an abnormal coagulation profile, such as prolonged PT, activated partial thromboplastic time (aPTT), and elevated international normalized ratio (INR), patients with cirrhosis are paradoxically at higher risk for thrombotic complications such as portal vein thrombosis (PVT), deep vein thrombosis, and pulmonary embolism.² PVT is a known complication of liver cirrhosis with an estimated prevalence ranging from 6%–11% and related to the severity of portal hypertension (PHTN).³ For many decades, the severity of liver cirrhosis has been classified using the Child–Turcotte–Pugh (CTP) score, which stratifies patients into classes A, B, and C based on five parameters: serum bilirubin, serum albumin, INR, and the presence and severity of ascites and hepatic encephalopathy.⁴ Each variable is scored from 1 to 3, giving a total score from 5 to 15, with CTP class A (5-6 points) indicating compensated disease, CTP class B (7-9 points) moderate impairment, and CTP class C (10-15 points) advanced decompensation. Because ascites and encephalopathy are partly subjective and examiner-dependent, many clinicians increasingly depend on the Model for End-Stage Liver Disease (MELD) and other modified forms of MELD such as MELD-Na, which use objective laboratory values (bilirubin, creatinine, INR, and serum sodium in MELD-Na) and are widely applied for prognosis and transplant allocation.⁵ Despite the broad adoption of MELD-based scores, the CTP classification remains in routine use for drug labeling, trial eligibility, and treatment decision-making in cirrhosis. Clinically, patients are considered decompensated once they develop ascites, variceal bleeding, or hepatic encephalopathy; some clinicians also use CTP late class B or C (score ≥8) as a threshold to indicate clinically significant decompensation.

Imbalance of hemostatic factors, as well as reduced flow within the portal vein, are predisposing factors for PVT among patients with cirrhosis.⁶ Other risk factors include metabolic syndrome and presence of hepatocellular carcinoma (HCC).⁷ The clinical consequences of PVT include progression or exacerbation of PHTN, which may lead to variceal bleeding, hepatic decompensation, and intestinal infarction.

Treatment of acute PVT is indicated to prevent clot extension and enhance recanalization, therefore preventing complications associated with PHTN. In a meta-analysis by Yao et al including sixteen studies with more than one thousand patients, treatment of PVT was associated with lower rate of PVT progression, higher rate of recanalization, and decreased all-cause mortality.⁸

Although bleeding risk is a major concern in cirrhosis, several studies have reported a lower incidence of bleeding among patients with PVT who received anticoagulation. In the meta-analysis by Yao et al. the use of anticoagulation was not significantly associated with bleeding events (odds ratio 0.80; 95% confidence interval 0.39-1.66).⁸ Similar findings were observed in a large national study from the USA, where anti-coagulation led to significantly lower in-hospital mortality (2.1% vs 9.7%), as well as reduced risk of variceal bleeding.⁹ This reduction in bleeding risk is likely attributable to improved portal flow following recanalization and the prevention of clot extension.

In clinical practice, initial anticoagulation for PVT typically includes heparin, particularly low molecular weight heparin (LMWH), followed by transition to a vitamin K antagonist (VKA) such as warfarin. However, due to the need for frequent laboratory monitoring, the difficult interpretation of INR in the setting of baseline elevation, and dietary restrictions associated with warfarin, many patients with PVT are now being managed with direct oral anticoagulants (DOACs), despite limited data on their efficacy in this setting.¹⁰ The clinical use of DOACs in patients with liver disease, particularly cirrhosis, remains complex and understudied.¹¹

This review aims to provide a comprehensive overview of the pharmacologic properties of DOACs and summarize current evidence supporting their use in patients with cirrhosis and PVT, with the goal of offering practical recommendations for clinical decision-making in cirrhosis.

Methods

This is a narrative review informed by a systematic literature search, designed to identify cohort and interventional studies on the use of DOACs in patients with cirrhosis and PVT. A comprehensive search of major databases was performed from early 2010 to July 17, 2025, in Ovid Medline, Ovid EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. The strategy used MeSH and EMTREE terms related to relevant keywords “liver cirrhosis”, “portal vein thrombosis” and “direct oral anticoagulants”. We included all cohort and interventional studies as well as meta-analyses describing the use of DOACs among patients with cirrhosis and describing clinical outcomes such as recanalization, bleeding, and mortality.

We excluded case reports and case series, non-cirrhotic populations, and studies where anticoagulant type could not be clearly ascertained. Studies published in abstract form where details of outcomes and safety were not available, were also excluded. The search was restricted to humans and the English language.

The search results were exported into an EndNote file, and duplicates were removed. Reference lists from eligible articles and review articles were cross-checked to identify any records that might have been missed in the search. Two independent reviewers screened the titles, abstracts, and full-texts to select the articles fulfilling the inclusion criteria. Any discrepancies were resolved by a third reviewer.

An Overview of DOACs

Since their introduction in the early 2010s, DOACs have been extensively used to treat thromboembolic complications. Their use is enhanced by their fixed dosing regimens, rapid onset of action, predictable pharmacokinetics, no requirement for routine monitoring, and fewer drug-drug interactions.¹²

Currently, there are four DOACs that have been approved by the U.S. Food and Drug Administration (FDA) including apixaban, rivaroxaban, edoxaban, and dabigatran.

Understanding the mechanism of action of DOACs requires a comprehensive knowledge of the coagulation cascade and the site of action of different DOACs within the coagulation cascade (Figure 1).

Figure 1.

Sites of action of direct oral anticoagulants within the coagulation cascade.

The coagulation cascade is classically divided into intrinsic and extrinsic pathways. The intrinsic pathway is typically activated by contact with negatively charged surfaces, such as those exposed during endothelial injury. In contrast, the extrinsic pathway is initiated by the exposure of tissue factor following vascular damage. Both pathways converge to form a common pathway, in which factor Xa plays a central role by catalyzing the conversion of prothrombin (factor II) to thrombin (factor IIa). Thrombin subsequently converts fibrinogen into fibrin, culminating in clot formation.¹³ DOACs exert their anticoagulant effect by targeting this common pathway through two principal mechanisms:

Blocking the activity of factor Xa by directly inhibiting it and therefore preventing thrombin generation. The Xa inhibitors include rivaroxaban, apixaban, and edoxaban.

Direct thrombin inhibition, which neutralizes thrombin's ability to convert fibrinogen to fibrin. This class includes a single agent, dabigatran.

DOACs are currently approved for a range of clinical indications, including stroke prevention in patients with nonvalvular atrial fibrillation (AF), treatment and secondary prevention of venous thromboembolism (VTE), and postoperative thromboprophylaxis following orthopedic surgery.¹⁴ However, their use in the setting of liver cirrhosis is further complicated by several factors:

Impaired hepatic metabolism: Cytochrome P450 (CYP450) enzymes, particularly CYP3A4, play a central role in the metabolism of several DOACs. Apixaban and rivaroxaban are primarily metabolized by CYP3A4, making them prone to significant drug–drug interactions when co-administered with CYP3A4 inhibitors or inducers. In contrast, dabigatran is not metabolized by the CYP450 enzymes, and edoxaban is partially metabolized by CYP3A4 enzymes. These metabolic differences have important clinical implications in patients with advanced liver disease and cirrhosis, where hepatic CYP3A4 activity is often reduced, potentially leading to reduced drug clearance and a heightened risk of bleeding. In such patients, impaired hepatic metabolism, in addition to altered hemostasis, requires a cautious and individualized approach to DOACs use. Additionally, the CTP classification of liver cirrhosis is commonly used to guide therapy decisions, as several DOACs are either not recommended or contraindicated in patients with advanced liver cirrhosis, such as those with Child-Pugh class B or C cirrhosis, due to insufficient safety data and concerns regarding drug accumulation.¹⁵

Altered drug clearance: Changes in protein binding, renal function, and hepatic blood flow can significantly affect DOACs pharmacokinetics in patients with cirrhosis.

Lack of robust clinical trial data: Most phase III, DOAC trials excluded patients with moderate-to-severe liver dysfunction, CTP class B and C, leading to uncertainty about safety and efficacy in this population.

Nevertheless, emerging real-world evidence, retrospective studies, and several meta-analyses suggest that some DOACs, particularly apixaban, are safe in selected patients with advanced compensated cirrhosis.^16–18 The convenience of oral administration, fixed dosing, and relatively predictable pharmacologic profiles makes DOACs attractive alternatives to LMWH and VKAs in specific clinical scenarios such as PVT, provided that liver function is carefully monitored.

Regulatory, Hepatic and Renal Function Guidance

Regulatory agencies such as FDA and the European Medicines Agency (EMA) generally recommend that DOACs may be used in patients with compensated liver disease, CTP class A, based on available pharmacokinetic and safety data.^19–22

The hepatic metabolism and drug clearance are mildly impaired in patients with CTP class A cirrhosis. Therefore, the benefit-risk profile remains favorable.¹⁵ However, in patients with more advanced liver dysfunction, particularly those with CTP class B or C, the administration of DOACs is more complex and drug-specific.²³ For example, apixaban does not require dose adjustment in mild hepatic impairment, but its use in moderate impairment, CTP class B, should be approached with caution. It is not recommended in severe hepatic dysfunction, CTP class C, due to increased systemic exposure and bleeding risk.²⁴

In addition to hepatic considerations, regulatory guidance emphasizes the importance of renal function assessment before prescribing DOACs, as these medications are excreted by the kidneys in various degrees. As DOACs differ in their degree of renal clearance, ranging from approximately 27% for apixaban to over 80% for dabigatran, careful assessment of renal function is essential before initiation and throughout treatment.²⁵ Renal impairment is common in cirrhotic patients and may fluctuate due to factors such as hepatorenal physiology, infections, and volume shifts.²⁶ Yet assessing renal function in cirrhosis is particularly challenging, as serum creatinine is an unreliable marker due to reduced hepatic synthesis and diminished muscle mass. Consequently, creatinine-based estimations such as estimated glomerular filtration rate (eGFR) and creatinine clearance (CrCl) often overestimate true renal function and may obscure the presence of clinically significant dysfunction. Although direct GFR measurement using exogenous filtration markers such as iohexol or iothalamate remains the gold standard, these methods are not routinely available in clinical practice, limiting their widespread use.²⁷

Dose adjustments or even avoidance of certain DOACs may be warranted in moderate to severe renal dysfunction, especially given the elevated bleeding risk in this population. Chan et al. reported that dialysis patients treated with dabigatran or rivaroxaban had a significantly higher risk of hospitalization or death due to bleeding compared to those on warfarin (p = .0001 and p = .04, respectively).²⁸ While rivaroxaban, apixaban, and edoxaban may require dose adjustment based on CrCl, they are not absolutely contraindicated unless CrCl falls below 15 mL per minute. Renal function should be re-evaluated periodically, especially in patients with worsening hepatic status or acute illness. For clinical decision-making, both CrCl thresholds and serum creatinine–based dose-adjustment criteria (e.g., for apixaban) are summarized together in Table 1, rather than described separately by drug in the text.

Table 1.

DOACs use in PVT Based on CTP Classes and Renal Function Categories.

Condition	Apixaban	Edoxaban	Rivaroxaban	Dabigatran
CTP-A	No dose adjustment	Standard dose	No dosing recommendation*	Standard dose
CTP-B	No dosing recommendation	Not recommended	Avoid use	No dose adjustment
CTP-C	Not recommended	Not recommended	Avoid use	Avoid use^†
CrCl > 50 mL/min	Standard dose	Standard dose	Standard dose	Standard dose
CrCl 30–50 mL/min	No dose adjustment	Reduced dose	Standard dose	Standard dose
CrCl 15– < 30 mL/min	No dose adjustment	Reduced dose	Reduced dose	No dose recommendation
CrCl < 15 mL/min	No dose adjustment	Not recommended	Avoid use	No dose recommendation

Abbreviations: Cr Cl, creatinine clearance; CTP, child-turcotte-pugh; CTP-A/B/C, child-turcotte-pugh class A/B/C; DOACs, direct oral anticoagulants; PVT, portal vein thrmbosis.

†

FDA does not provide any dosing recommendation

* Avoid use with coagulopathy

Dabigatran is primarily excreted by the kidneys and therefore is contraindicated in patients with severe renal impairment with CrCl less than 30 mL per minute.²⁹ Rivaroxaban and edoxaban also require dose adjustments in moderate renal impairment (CrCl 15 to 50 mL per minute) in patients with AF. However, no dose adjustment is required for venous thromboembolism.³⁰ Apixaban has a more favorable renal profile but still necessitates caution in patients with advanced renal impairment. Dose reduction is recommended if two of the following are met: Creatinine ≥133 µmol/L, age ≥ 80, or weight ≤ 60 Kilogram.³¹ Regulatory authorities and international societies recommend assessing renal function at baseline and periodically during therapy, particularly in patients at risk of renal decline.³² The selection and dosing of DOACs must therefore be individualized, balancing thrombotic risk with potential for drug accumulation and bleeding in the context of renal impairment.

Although data remain limited, current evidence supports the cautious use of DOACs in selected patients with PVT who have stable renal function and compensated cirrhosis classified as CTP class A. However, robust data are lacking for patients with more advanced liver disease or fluctuating renal function. A systematic review and meta-analysis of nine randomized controlled trials involving 54, 667 patients with renal impairment demonstrated a significantly lower risk of major bleeding among those treated with DOACs when CrCl ranged between 50 and 80 mL per minute (risk ratio 0.87; 95% confidence interval 0.81 to 0.93). In contrast, only a non-significant reduction in bleeding risk was observed in patients with more severe renal dysfunction, defined by a serum creatinine level of ≥177 μmol/L, or in those undergoing dialysis.³³ Table 1 summarizes the current regulatory recommendations for DOACs use across CTP classes and renal function categories, as per EMA and FDA.

Pharmacologic Profiles of DOACs in Cirrhosis

The use of DOACs in cirrhotic patients with PVT presents unique therapeutic benefits. They are easier to manage than VKAs and LMWHs due to their oral administration, fixed dosing, lack of routine need for therapeutic drug monitoring, and they are less influenced by concomitant medications and dietary intake.³⁴

Although three of the four currently approved DOACs target factor Xa (rivaroxaban, apixaban, edoxaban) they all differ significantly in their metabolism and pharmacokinetic profiles. Rivaroxaban is eliminated through both hepatic and renal pathways, with approximately two-thirds of the drug metabolized in the liver by CYP3A4 isoenzymes into inactive metabolites, and about one-third excreted unchanged in the urine. Kubitza et al. demonstrated in their study that compared to healthy controls, a single dose of rivaroxaban results in slightly increased exposure, with an area under the curve (AUC) of 1.15 in CTP class A cirrhosis but a moderately increased exposure in those with CTP class B impairment (AUC: 2.27).³⁵ Prolonged factor Xa inhibition and increased PT were also observed in CTP class B patients, suggesting a potential for over-anticoagulation in advanced liver cirrhosis.

Apixaban undergoes both hepatic metabolism through multiple CYPs with intestinal excretion (around 75%) as well as renal excretion. Pharmacokinetic studies have shown a slightly increased AUC after a single dose of apixaban in CTP class A and CTP class B compared with healthy controls with slightly elevated drug exposure (AUC: 1.03 and 1.09, respectively).^24,36 Apixaban also leads to increased PT in both CTP class A and CTP class B.³⁶ These findings suggest that apixaban may be safe for use in patients with compensated cirrhosis.

Edoxaban is metabolized in the liver through CYP3A4 and undergoes renal excretion (50%-50%). Despite having significant hepatic metabolism, it is gaining interest in cirrhotic patients, as its anticoagulant potency appears to diminish with increasing severity of liver cirrhosis.^37,38 A pharmacokinetic study demonstrated that edoxaban exposure does not significantly increase in CTP class A and CTP class B cirrhosis compared with healthy controls.³⁷

Dabigatran, unlike the other DOACs, is a direct thrombin inhibitor. It is an oral prodrug activated by esterases in multiple tissues, including the liver, but is not metabolized by CYP450 enzymes. Approximately 80% of dabigatran is renally excreted.³⁹ In a pharmacokinetic study, after a single dose of 150 mg dabigatran, compared to healthy controls, dabigatran peak levels (Cmax) and exposure (AUC) were slightly lower (but not statistically significant) in CTP class B cirrhosis.³⁶ However, dabigatran exhibits a stronger in vitro anticoagulant effect in patients with cirrhosis compared to healthy controls, including those with CTP class A cirrhosis.^40,41

Based on pharmacological profiles, apixaban and edoxaban appear to be particularly favorable in patients with cirrhosis. Table 2 summarizes the key pharmacologic characteristics of each DOAC and their relevance to cirrhotic populations.

Table 2.

Comparison of DOAC Metabolism, Renal Excretion, and use in Cirrhosis.

DOAC	Hepatic Metabolism	Renal Excretion	T 1/2	Key Notes in Cirrhosis
Apixaban	Moderate (via CYP3A4 /others)	∼27%	8–15 H	Mild ↑ AUC in CTP class-A/B Safe in compensated cirrhosis
Edoxaban	Moderate (via CYP3A4)	∼50%	10–14 H	Minimal change in AUC in CTP class -A/B
Rivaroxaban	High (via CYP3A4/2J2)	∼33%	5–9 H	↑ AUC in CTP-B. Not recommended in moderate/severe cirrhosis (CTP class B/C)
Dabigatran^‡	Low (non-CYP esterases)	∼50%	12–17 H	Contraindicated in severe renal impairment

‡

Dabigatran in the only DOAC that is direct thrombin inhibitor, the rest are factor Xa inhibitors

Abbreviations: DOAC, direct oral anticoagulant; CYP, cytochrome P; AUC, area under the curve; CTP, child-turcotte-pugh; H, hours; T ½, elimination half-life.

Decision-Making in Cirrhosis with Portal Vein Thrombosis (PVT)

There is increasing evidence supporting the safety of anticoagulant therapy in patients with cirrhosis and PVT.^16,42–44 A recent individual patient data meta-analysis (IMPORTAL) demonstrated that anticoagulation significantly reduced all-cause mortality in this population, with a hazard ratio of 0.59 (95% CI 0.49-0.70), indicating that approximately nineteen patients needed treatment to prevent one death.⁴⁴ In a prospective observational cohort by Ai et al. patients with cirrhosis and PVT were evaluated based on whether they received DOACs or no anticoagulation. At three months, complete or partial PVT recanalization was achieved in 12.8% of the DOACs group versus none in the non-anticoagulated group. By six months, recanalization rates increased to 28.2% and 2.6%, respectively, with statistically significant differences ( p < 0.05).¹⁶

There is growing evidence that DOACs are promising alternative to conventional anticoagulants in the setting of cirrhosis.^45–48 A network meta-analysis by Ng Ch et al. demonstrated that DOACs were more effective than LMWH (risk ratio 2.30; 95% CI 1.04-5.09; p = 0.04), warfarin (risk ratio 1.76; 95% CI 1.02-3.05; p = 0.04), and no treatment (risk ratio 3.49; 95% CI 1.39-8.73; p = 0.01) in achieving complete recanalization.⁴⁵ Although DOACs did not show statistically significant superiority over other treatments for partial recanalization, they ranked highest in likelihood of achieving recanalization according to surface under the cumulative ranking curve (SUCRA) analysis. Bleeding risk and overall mortality were comparable across all treatment options.⁴⁸

In a systematic review and meta-analysis, Jim Hean Koh et al. reported that DOACs were associated with higher rates of portal vein recanalization and reduced PVT progression compared with VKAs, while major bleeding, variceal bleeding, and overall mortality remained similar between groups.⁴⁹

In cirrhosis, treatment is typically recommended for cases of PVT that may contribute to worsening portal hypertension, as well as for liver transplant candidates with extensive thrombus involvement that could jeopardize their eligibility for transplantation and negatively impact post-transplant outcomes.^1,45,50 In liver transplant candidates, greater clot burden is linked to increased morbidity and mortality, while anticoagulation in these patients has been associated with better post-transplant survival outcomes.⁵⁰ Meanwhile, the decision to initiate treatment for chronic PVT in patients with cirrhosis is individualized, taking into account key factors such as eligibility for liver transplantation and the patient's risk of bleeding.^1,46,51 The 2016 guidelines from the European Association for the Study of the Liver (EASL) on vascular liver disorders recommend assessing for high-risk varices and starting appropriate treatment, such as band ligation or nonselective β-blockers, before initiation of anticoagulation therapy for PVT in patients with cirrhosis.⁵²

Therefore, anticoagulation decisions in this setting should be informed by endoscopic findings, the chronicity and extent of thrombosis, the degree of portal vein occlusion, and transplant candidacy.⁵³ Additional factors such as the presence of varices, platelet count, and risk of hepatic encephalopathy must also be considered before initiating therapy.

Figure 2 illustrates key factors to assess prior to initiating anticoagulation in patients with cirrhosis and PVT.

Figure 2.

Factors to consider before PVT anticoagulation in patients with cirrhosis. Abbreviations: PV, Portal vein; SV, Splenic vein; SMV, Superior Mesenteric Vein.

Which DOAC is Most Suitable in Cirrhosis?

In cirrhosis, the choice of DOAC should be driven by two major factors: severity of liver disease (CTP class) and renal function, in addition to other factors presented in Figure 2. Both regulatory agencies, the FDA and the EMA, as well as available pharmacokinetic data agree that CTP class A is the group with the strongest evidence and most favorable benefit–risk profile.^54,55 Patients with CTP class B represent an intermediate zone where use is off-label and must be individualized, and CTP class C is generally considered a contraindication for DOACs because of advanced hepatic dysfunction and marked coagulopathy with high bleeding risk.

Across DOACs, apixaban and edoxaban currently have the most supportive data in cirrhosis, while rivaroxaban is specifically contraindicated in CTP class B because of hepatotoxicity and further decompensation.⁵⁶

Dabigatran is primarily limited by renal clearance and a lack of cirrhosis-specific data. Key pharmacologic differences relevant to cirrhosis are summarized in Table 2, and integrated hepatic/renal use recommendations are shown in Table 1.

Apixaban

Among available agents, apixaban appears best suited for use in CTP class A and carefully selected early CTP class B cirrhosis based on its pharmacological profile. There are currently no data supporting its use in CTP class C patients; such use would be off-label and is not recommended as routine practice.

A retrospective study evaluated the safety and effectiveness of reduced-dose apixaban (2.5 mg twice daily) compared to VKAs for secondary prevention of chronic PVT in patients with cirrhosis. Among 498 patients (67% were CTP class B and C), apixaban was associated with lower rates of PVT recurrence/progression (2.1% vs 6.7%), fewer major bleeding events (1.7% vs 8.2%), and better survival at 1 and 2 years compared to VKAs.⁵⁷ These results suggest that apixaban may be a safer and more effective alternative to VKAs in selected cirrhotic patients, including some of those with CTP class C cirrhosis, for long-term PVT management. However, this remains off-label, observational evidence and does not override labeling cautions in CTP C.

A larger retrospective study by Intagliata et al. showed similar rates of major bleeding in CTP class A and CTP class B cirrhosis when compared to healthy controls.⁵⁸ Moreover, Weinberg et al. synthesizing pharmacodynamic data from multiple trials, concluded that apixaban would be the preferred DOAC in patients with CTP class B cirrhosis, citing its minimal alterations in pharmacokinetics and lower potential for drug-induced liver injury compared with other DOACs.⁴⁶ These data support apixaban as the most favorable agent in compensated cirrhosis and selected CTP class B patients, recognizing that evidence remains non-randomized.

Edoxaban

Edoxaban is an emerging option with the most evidence in cirrhosis patients.¹⁸ In a retrospective study by Nagaoki et al. patients with cirrhosis and acute PVT were initially treated with intravenous danaparoid for two weeks, followed by either edoxaban (n = 20) or warfarin (n = 30) for six months. The edoxaban group showed significantly higher complete PVT resolution (70% vs 20%) and lower rates of PVT progression (5% vs 47%), with no major differences in safety between the two groups.⁵⁹ Similarly, Tadokoro et al. demonstrated that edoxaban, when used as monotherapy, achieved long-term portal vein recanalization without compromising hepatic reserve and could be conveniently initiated in outpatient settings.⁶⁰

Overall, available data support edoxaban as a reasonable alternative to apixaban in CTP class A and selected CTP class B patients, again acknowledging that evidence is retrospective and off-label in more advanced disease.

Rivaroxaban

Rivaroxaban is dependent on hepatic metabolism through the CYP3A4/2J2 system, with a marked increase in exposure and prolonged factor Xa inhibition in CTP B. Regulatory guidance and post-marketing experience indicate a higher risk of hepatotoxicity and decompensation in patients with moderate liver dysfunction.²⁰ Therefore, rivaroxaban is acceptable in CTP class A with preserved liver function, but not recommended in advanced cirrhosis such as CTP classes B and C, where use should generally be avoided.

Dabigatran

Dabigatran is a direct thrombin inhibitor with minimal hepatic metabolism and predominant renal excretion (>80%).¹⁹ Pharmacokinetic changes in CTP class B appear modest, but its strong dependence on renal clearance, coupled with frequent and fluctuating renal dysfunction in cirrhosis, significantly constrains its use. Severe renal impairment (CrCl <30 mL/min) is a formal contraindication.⁶¹ In cirrhotic PVT, clinical data remain limited compared with apixaban and edoxaban. Dabigatran may be considered in CTP class A patients with stable, preserved renal function, but is generally less attractive in advanced cirrhosis or chronic kidney disease.

This narrative review has several strengths. It incorporates pharmacologic, regulatory, real-world, and clinical outcome data to provide a practical framework for using DOACs in cirrhotic PVT, including structured comparisons across different DOACs (Tables 1 and 2) and a decision-focused figure to support individualized prescribing. The review is informed by a systematic literature search across multiple databases and includes data from recent meta-analyses and real-world cohort studies, with the latter offering high-value evidence because they reflect routine practice without the strict exclusion criteria of randomized trials. However, important limitations must be acknowledged: most available studies are retrospective cohorts with heterogeneous PVT definitions, outcome measures, and follow-up duration, and patients with advanced (CTP class B/C) cirrhosis or unstable renal function were underrepresented. In addition, this is a narrative rather than quantitative systematic review, restricted to English-language publications, so residual selection and publication bias cannot be excluded. These factors constrain the certainty of our conclusions and justify our emphasis on cautious, individualized use of DOACs in patients with CTP class B and C cirrhosis.

Conclusion and Clinical Guidance

The use of DOACs in patients with cirrhosis and PVT is increasingly supported by real-world data and evolving clinical evidence. While VKAs and LMWHs have long been standard therapies, DOACs offer notable advantages, including oral administration, fixed dosing, and no requirement for routine laboratory monitoring. Among the available DOACs, apixaban and edoxaban appear most suitable in patients with compensated liver disease (CTP class A) and select patients with moderate impairment (early CTP class B), given their favorable pharmacokinetic and observational safety profiles. In contrast, CTP class C and unstable or advanced CTP class B patients remain a group in which DOACs should generally be avoided.

In all patients, the use of DOACs should be individualized, accounting for hepatic function, renal status, bleeding risk, and liver transplant candidacy as summarized in Tables 1, 2 and Figure 2. Despite encouraging outcomes from retrospective studies and meta-analyses, high-quality prospective trials in patients with advanced cirrhosis are still lacking. Until such data are available, the use of DOACs in cirrhosis-associated PVT should be guided by a multidisciplinary approach, with careful patient selection and close monitoring.

Footnotes

ORCID iDs

Khalid M. Al Naamani

Bader Al Rawahi

Author Contributions

All authors participated in the development of this review and approved the final version of the manuscript. Khalid M. Al Naamani, Mohamed El-Kassa, and Siham Al Sinani contributed to the conception and design of the review, formulation of research questions, and overall supervision of the project.

Sundus Rizwan and Sheikha AlMa’mari conducted the initial literature search, performed article screening, and extracted data relevant to the scope of the review. Khalid M Al Naamani, Mohamed El-Kassa and Bader Al Rawahi contributed significantly to the critical appraisal of included studies and interpretation of findings.

Khalid M Al Naamani, Sundus Rizwan, Siham Al Sinani, and AlMa’mari drafted major sections of the manuscript. Khalid M. Al Naamani, revised the manuscript for intellectual content, harmonized all sections, and coordinated correspondence with co-authors and the journal.

All authors contributed to the writing, critical review, and final approval of the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Direct Oral Anticoagulants for Portal Vein Thrombosis in Cirrhosis: From Pharmacology to Clinical Practice

Abstract

Background

Objectives

Methods

Results

Conclusions

Keywords

Introduction

Methods

An Overview of DOACs

Regulatory, Hepatic and Renal Function Guidance

Pharmacologic Profiles of DOACs in Cirrhosis

Decision-Making in Cirrhosis with Portal Vein Thrombosis (PVT)

Which DOAC is Most Suitable in Cirrhosis?

Apixaban

Edoxaban

Rivaroxaban

Dabigatran

Conclusion and Clinical Guidance

Footnotes

ORCID iDs

Author Contributions

Funding

Declaration of Conflicting Interests

References