Portal Vein Thrombosis Treatment: Clinical Considerations

Portal vein thrombosis (PVT) is being increasingly diagnosed in patients both with and without cirrhosis, as contrast enhanced imaging has continued to evolve and improve.  The portal vein represents the confluence of the splenic (drains the spleen) and superior mesenteric veins (drains the small bowel).  Regardless of whether a PVT is an incidental finding or not, a frequently encountered question is if and how to treat

Depending on the extent and time course, patients with PVT can be asymptomatic or present with a multitude of symptoms including abdominal pain, diarrhea, gastrointestinal bleeding (GIB), ascites and infectious symptoms (if the thrombus becomes infected).¹  Although patients do not need to be cirrhotic to develop a PVT, those with cirrhosis are typically the most common type of patient diagnosed on a day to day basis.  Prevalence of PVT in patients with cirrhosis is as high as 50%, with an increased risk as the liver decompensates further.^1,2 

A PVT can be identified on contrast enhanced imaging such as computerized tomography (CT) or magnetic resonance imaging (MRI), but can also be seen on an abdominal ultrasound with dopplers.  Once diagnosed, it is important to be able to classify the PVT as acute vs chronic, occlusive vs nonocclusive, cirrhotic vs noncirrhotic and malignant vs nonmalignant.¹   Noncirrhotic etiologies include malignancy, thrombophilias, and hypercoaguable states, such as protein C and S deficiencies. 

Unfortunately, many currently available guidelines offered by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) provide relatively vague recommendations on the treatment of PVT.^3,4  Therefore, many gastroenterologists and hepatologists struggle with the decision on whether or not to treat it.  Prior to making this decision and considering anticoagulation, many gastroenterologists and hepatologists would recommend an endoscopy to rule out and subsequently band esophageal varices, if indicated, in order to mitigate any potential bleeding risk.  In addition, an endoscopy may also identify other potential bleeding risks including gastric varices or ulcers.  Patients who are deemed to be high risk for bleeding based on their endoscopy findings may be considered poor candidates for anticoagulation.  Even if patients do not have high risk findings on endoscopy, the baseline bleeding risk encountered in patients with cirrhosis further complicates an anticoagulation decision. 

In 2017, Loffredo et al published a systematic review and meta-analysis evaluating anticoagulants (ATCs) in patients with cirrhosis and PVT.²  This study included a total of 353 patients from 8 studies, with patients receiving low molecular weight heparin (LMWH) or warfarin compared with controls receiving no therapy.  The primary efficacy endpoint was complete or partial recanalization of the portal vein, although not all studies included this endpoint. 

Patients receiving ATC had significantly higher rates of PVT recanalization compared with controls (71% vs 42; P <.0001).  Additionally, those studies that included complete PVT recanalization found that the ATC group also had higher rates of improvement compared with controls (53% vs 33%; P =.002).   Patients in the control group had higher rates of PVT progression compared with the ATC group (33% vs 9%; P <.0001).   

There were no differences between groups in either major or minor bleeding, with both groups having 11% of patients report bleeding.  Interestingly, patients in the ATC group had lower rates of spontaneous variceal bleeding compared with control patients (2% vs 12%; odds ratio [OR], 0.232; 95% CI, 0.06-0.94; P =.04) which was primarily derived from the patients receiving LMWH and not warfarin.  LMWH but not warfarin was associated with complete recanalization of PVT.  However both LMWH and warfarin were associated with reducing PVT progression.  It is important to note that this study did not include patients treated with direct acting oral anticoagulants (DOACs) and that duration of ATC therapy had no impact on clinical outcomes. 

As DOACs have become increasingly used in clinical practice, there is evolving data regarding their use in PVT management.  Naymagon et al conducted a retrospective study evaluating DOACs (rivaroxaban, apixaban, dabigatran) for treatment of noncirrhotic PVT (ncPVT).⁵   Patients receiving DOACs had the highest rates of complete radiography resolution (CRR) at approximately 66% among the three agents included, which was similar to enoxaparin at 57%.  There was no statistical difference in number of patients developing chronic portal hypertensive symptoms (new varices on endoscopy or new ascites requiring diuretics) among the groups.  Only when the DOACs were grouped together was there a significant difference found in major bleeding, which showed a lower risk in DOACs compared with warfarin (hazard ratio [HR] DOACs:warfarin, 0.20; 95% CI, 0.05-0.86; P =.0307).  

Although the research evaluating DOACs to treat PVT in patients with cirrhosis is relatively limited, the early evidence from small studies does suggest they are safe and effective.¹   It should be kept in mind that DOACs are typically more expensive compared with other ATCs. Additionally, some agents within the class do not have an agent-specific antidote and/or easily available clotting factor products (eg, prothrombin complex concentrates).  Although these agents typically do not routinely require international normalized ratio (INR) monitoring, rivaroxaban, apixaban and dabigatran have been reported to increase INR.¹  This makes interpreting the INR in a patient who also has cirrhosis extremely challenging. 

There are mixed data regarding the hepatotoxicity and pharmacokinetics (PK) of using DOACs in patients with cirrhosis, especially rivaroxaban, secondary to concerns for hepatoxicity.¹  Patients taking rivaroxaban who are concomitantly receiving acetaminophen, statins, or amiodarone may have the highest risk for drug induced liver injury (DILI).  Special consideration of bleeding and hepatotoxicity for DOACs should be given to those patients who are older (eg, > 75 years) and with impaired renal function.¹  The decision on whether or not to anticoagulate patients with PVT will continue to be challenging until there are larger, well-controlled clinical trials.

References

1. Weinberg EM, Palecki J, Reddy KR. Direct-acting oral anticoagulants (DOACs) in cirrhosis and cirrhosis-associated portal vein thrombosis. Semin Liver Dis. 2019;39(2):195-208. doi: 10.1055/s-0039-1679934
2. 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. Gastroenterol. 2017;153(2):480-487.  doi: 10.1053/j.gastro.2017.04.042
3. DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver. Hepatol. 2009;49(5):1729-64.  doi: 10.1002/hep.22772
4. Garcia-Pagan JC, Buscarini E, Janssen HLA, et al.  EASL clinical practice guidelines: vascular diseases of the liver. J Hepatol. 2016;64(1):179-202. doi: 10.1016/j.jhep.2015.07.040
5. Naymagon L, Tremblay D, Zubizarreta N, et al. The efficacy and safety of direct oral anticoagulants in noncirrhotic portal vein thrombosis.  Blood Adv. 2020;4(4):655-666. doi: 10.1182/bloodadvances.2019001310