High risk of thrombosis recurrence in people with idiopathic or only locally caused non-cirrhotic splanchnic vein thrombosis: it is time for guidelines’ revision

Portal hypertension caused by non-cirrhotic and non-neoplastic splanchnic vein thrombosis (NC-SVT) is responsible for 5–10% of portal hypertension cases in the western world (1). Chronic myeloproliferative neoplasms (MPN) or systemic prothrombotic disorders are in cause in about 40% of subjects, while in about 30% a local condition, such as recent abdominal surgery or infection/inflammation triggers the event. The local condition, however, can only be the precipitating cause, since a thorough screening allows identifying the co-occurrence of systemic thrombophilia in about 30% of such cases. Hence, screening is mandatory even in cases where the cause of NC-SVT seems obvious. Nevertheless, about 30% of cases of NC-SVT remains unexplained and defined idiopathic (1).

NC-SVT frequently causes the development of gastroesophageal or ectopic varices that entail a severe risk of bleeding. In this setting, anticoagulant therapy, if not strictly needed, might be deemed as contraindicated. However, the absence of anticoagulant treatment exposes to a risk of thrombosis recurrence or progression, with possible harmful consequences such as mesenteric ischemia or further increase in portal hypertension and worsening of liver function. In general, both gastrointestinal bleeding and splanchnic vein thrombosis (SVT) recurrence are fearsome events, which negatively affect survival (2,3).

Current guidelines (4,5) recommend long-term anticoagulant therapy if a systemic thrombophilia is identified, assuming a high risk of thrombotic recurrence. Conversely, anticoagulant therapy just for a limited period is recommended if NC-SVT has been triggered by a local cause no longer persistent (as surgery or abdominal infection) and in the absence of other thrombophilia, or if no cause at all is identified, assuming in such cases a low risk of recurrence or progression of thrombosis. Such caution partly depends on the deemed increased risk of bleeding associated with the frequent occurrence of gastroesophageal varices, further augmented by the frequently occurring thrombocytopenia due to the ensued hypersplenism. However, long-term anticoagulant therapy is certainly associated with a general hemorrhagic risk, but portal hypertensive bleeding mainly depends on hemodynamic causes. Of note, recent studies do not find a relationship between anticoagulation and risk of portal hypertension bleeding in patients with cirrhosis and portal vein thrombosis. Instead, though contra intuitively, anticoagulation is associated with lower rates of variceal bleeding (6). Moreover, if variceal bleeding occurs, its outcome is not worse in patients on anticoagulants (7). Although such studies refer to subjects with cirrhosis and portal vein thrombosis, this data is reasonably plausible even for subjects with NC-SVT. Contrariwise, the progression of splanchnic thrombosis certainly worsens portal hypertension and its related bleeding risk. Lastly, the risk of thrombosis recurrence in such subjects with idiopathic or exclusively locally caused SVT is assumed low by the guidelines, but is actually unknown.

The study of Baiges et al. recently published in the Journal of Hepatology (8) addresses the important issue of the risk of recurrent thrombosis (RT) in subjects with idiopathic or only isolated cause NC-SVT. Baiges et al. performed a multicentric, observational retrospective study of consecutive subjects with NC-SVT with well-defined inclusion criteria, managed according to a predefined protocol. This included the assessment of thrombosis extension by angio-computed tomography (CT) scan or angio-magnetic resonance imaging (MRI) at diagnosis and at scheduled follow-up periods, an exhaustive thrombophilia study even in patients with a recognized local factor, and the exclusion of patients with severe initial thrombotic event (portal vein thrombosis with intestinal ischemia) or previous thrombotic events. The study enrolled 64 patients with the characteristics described above, and therefore not on anticoagulant treatment according to the guidelines.

Of note, the study gives an operative definition of SVT recurrence as “the development of a thrombus in a segment of the splanchnic venous axis not previously involved or progression from an incomplete to complete thrombosis proved by angio-CT scan, angio-MRI or by Doppler-US examination”. Such definition, together with the decision of performing abdominal imaging studies at scheduled intervals in the follow-up, allowed an adequate evaluation of the incidence of thrombosis recurrence/progression in such subgroup of subjects with idiopathic or isolated cause NC-SVT, which usually accounts for about half of subjects with NC-SVT.

The results challenge the indications of the guidelines. In fact, the overall incidence of thrombosis recurrence/progression was not low as previously supposed, but rather high: 26% of patients had recurrence of splanchnic or extra splanchnic thrombosis during follow-up, with a cumulative incidence: 2%, 10%, 19% and 34% at 1, 2, 5 and 10 years. Moreover, as for NC-SVT, such recurrence/progression was asymptomatic in over half of cases, thus implying that most recurrences would have missed if not actively investigated. Therefore, the guidelines indication to stop anticoagulation in people with idiopathic or only isolated cause NC-SVT should be reconsidered.

Interestingly, the relapse rate of thrombosis observed in the study is very similar to that of unprovoked proximal lower limbs deep vein thrombosis and pulmonary embolism. In such cases, guidelines recommend long-term anticoagulation (9). Since the sequelae of recurrence/progression of NC-SVT are potentially more severe than those of lower limbs deep vein thrombosis, one may ask why refrain from long-term anticoagulation in such subjects, even if without an identified risk factor, now having data demonstrating such an high recurrence rate.

Then the question is whether we should treat all patients with idiopathic or exclusively local cause NC-SVT, without considering both the presence of portal hypertension and a potentially severe bleeding risk. Conversely, should we treat all such patients because the potential risk of recurrence/progression of splanchnic vein thrombosis and the ensued severe sequelae entail a more severe prognosis as compared to the sequelae of recurrent deep vein thrombosis of the lower limbs, for which long-term anticoagulation is now recommended? The Baiges’ study sought to answer these questions evaluating, in a subgroup of 48 subjects, the potential value of further parameters of thrombophilia already recognized useful in stratifying the risk of recurrence of venous thrombosis of the lower limbs. Such additional parameters are increased levels of factor VIII (10-12) or Von Willebrand Factor (13,14), previously identified as risk factors for extra-hepatic portal vein obstruction (10) or lower limb venous thrombosis and pulmonary embolism (11-13). Moreover, the possible protective role of d-dimer levels <500 ng/mL against recurrent SVT in people without thrombophilia or with low-risk prothrombotic disorders, as pointed out at the recent Baveno VII consensus, was also evaluated (14).

Though no clinical or biochemical parameters predicted overall-RT, in the 48 patients factor VIII ≥150% was the only independent factor predicting overall RT [hazard ratio (HR) 7.10; 95% confidence interval (CI): 2.17–23.17; P<0.01]. Such result was confirmed in the validation cohort, where about one third of subjects had overall-RT that was also independently predicted by factor VIII >150% (HR 3.71; 95% CI: 1.31–10.5; P<0.01). Of note, the predictive value of factor VIII was confirmed both in patients with idiopathic and with local etiology.

These data, although obtained on a limited number of patients, are confirmed in a validation cohort, which confers reliability. Moreover, they are already validated in other venous thrombosis setting, and are biologically plausible, since FVIII is an important procoagulant factor released after endothelial activation.

Thus, after analyzing Baiges’ data, the question arise if we should treat with long-term anticoagulation all the subjects with idiopathic or isolated local etiology NC-SVT or only those with a higher risk of thrombosis recurrence, i.e., those with factor VIII >150% at diagnosis, in order to balance the risks and benefits of long-term anticoagulant therapy. The number of such subjects with factor VIII >150% may actually be high (23% in the training cohort and 50% in the validation cohort in the Baiges’ series).

The Baiges’ study cannot fully answer the question, since the enrolled subjects, given their previously assumed low risk of thrombosis recurrence, were not long-term anticoagulated. Future studies will assess the benefit/risk ratio of long-term anticoagulation in such subjects, taking into account the influence of levels of coagulation factors. For sure, the Baiges’ study, by showing that the risk of recurrence thrombosis in subjects with idiopathic or only isolated cause NC-SVT is high (particularly in those with factor VIII >150%) and not low as previously assumed, paves the way for such prospective studies.

Waiting for prospective studies, a therapeutic option for the time being to pursue a reasonably favourable risk/benefit ratio in subjects with idiopathic or only local cause NC-SVT and gastroesophageal varices and/or severe thrombocytopenia could be long-term low-dosage direct oral anticoagulant (DOAC) treatment, drugs with a very favourable benefit/risk ratio. Indeed, a recent randomized open label controlled trial (15) showed that rivaroxaban at the prophylactic dose of 15 mg once daily decreased the recurrence rate of thromboembolic events or death in subjects with non-cirrhotic portal vein thrombosis without a strong risk factor for thrombosis recurrence, and without increasing the occurrence of major bleeding.

A last consideration refers to the thrombophilia screening. How extensive should it be?

At present, a comprehensive thrombophilia screening includes the search for gain-of-function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia (10). According to the Baiges’ study, factor VIII levels must be included in the list.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-292/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Garcia-Pagán JC, Hernández-Guerra M, Bosch J. Extrahepatic portal vein thrombosis. Semin Liver Dis 2008;28:282-92. [Crossref] [PubMed]
2. Amitrano L, Guardascione MA, Scaglione M, et al. Prognostic factors in noncirrhotic patients with splanchnic vein thromboses. Am J Gastroenterol 2007;102:2464-70. [Crossref] [PubMed]
3. Spaander MC, Hoekstra J, Hansen BE, et al. Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding. J Thromb Haemost 2013;11:452-9. [Crossref] [PubMed]
4. European Association for the Study of the Liver. Electronic address: easloffice@easloffice. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol 2016;64:179-202. [Crossref] [PubMed]
5. de Franchis R, Baveno VI. Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743-52. [Crossref] [PubMed]
6. Loffredo L, Pastori D, Farcomeni A, et al. Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis: A Systematic Review and Meta-analysis. Gastroenterology 2017;153:480-487.e1. [Crossref] [PubMed]
7. Cerini F, Gonzalez JM, Torres F, et al. Impact of anticoagulation on upper-gastrointestinal bleeding in cirrhosis. A retrospective multicenter study. Hepatology 2015;62:575-83. [Crossref] [PubMed]
8. Baiges A, Procopet B, Silva-Junior G, et al. Incidence and factors predictive of recurrent thrombosis in people with non-cirrhotic portal vein thrombosis. J Hepatol 2023;78:114-22. [Crossref] [PubMed]
9. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest 2021;160:e545-608. [Crossref] [PubMed]
10. Martinelli I, Primignani M, Aghemo A, et al. High levels of factor VIII and risk of extra-hepatic portal vein obstruction. J Hepatol 2009;50:916-22. [Crossref] [PubMed]
11. Kyrle PA, Minar E, Hirschl M, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000;343:457-62. [Crossref] [PubMed]
12. Timp JF, Lijfering WM, Flinterman LE, et al. Predictive value of factor VIII levels for recurrent venous thrombosis: results from the MEGA follow-up study. J Thromb Haemost 2015;13:1823-32. [Crossref] [PubMed]
13. Koster T, Blann AD, Briët E, et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995;345:152-5. [Crossref] [PubMed]
14. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VII - Renewing consensus in portal hypertension. J Hepatol 2022;76:959-74. [Crossref] [PubMed]
15. Plessier A, Goria O, Cervoni JP, et al. Rivaroxaban Prophylaxis in Noncirrhotic Portal Vein Thrombosis. NEJM Evid 2022;1:EVIDoa2200104.