Periprocedural management of hemostatic alterations in patients with cirrhosis and vascular liver disorders: a step forward of the American Association for the Study of Liver Diseases

“Time flies over us, but leaves its shadow behind” (Nathaniel Hawthorne, 1860, The Marble Faun). The shadow that separates the latest guidance on vascular liver disorders of the American Association for the Study of Liver Diseases (AASLD) from its former counterpart is 12 years long (1,2). Along the course, several guidelines from different societies have been published on this topic (3-7). As acknowledged in the preamble, the lack of high-quality evidence in the field led the AASLD to commission a guidance from an expert panel based on formal review and analysis of the literature. It thus differs from other guidelines that perform systematic reviews with explicit methods of searching, selection, and rating the quality of evidence and, if appropriate, meta-analysis on certain clinical questions (2).

The most distinguished feature of this new guidance is probably the incorporation of statements regarding the periprocedural management of hemostatic alterations in patients with cirrhosis. This disease has long been perceived as an acquired bleeding disorder resulting from thrombocytopenia and abnormal routine coagulation tests. However, unlike hereditary coagulopathies, cirrhosis affects the whole spectrum of the coagulation cascade (i.e., procoagulant/anticoagulant factors, and antifibrinolytics/profibrinolytics proteins) and is associated with both platelet hyperactivity and increased levels of von Willebrand factor, all of which results in a “rebalanced hemostasis”. This new equilibrium is fragile and can easily be tipped towards either a prohemorrhagic or a prothrombotic phenotype. During the last 6 years several important scientific societies, some of them outside the field of Hepatology, have provided recommendations regarding the periprocedural management of hemostatic alterations in this setting (2,5,8-13) (Table 1). The common ground is an increasingly restrictive policy on transfusion of blood products. Indeed, all of them do not recommend implementing measures to reduce the international normalized ratio (INR) regardless of the bleeding risk, while the discussion on correcting or not the platelet count and fibrinogen levels is limited to high-risk procedures. The AASLD document is one of the most restrictive, as it does not recommend the routine preprocedural correction of either of them in both low- and high-risk procedures. Of note, this risk dichotomy is in line with previous guidelines and is based on the estimated risk of major bleeding (greater or less than 1.5%), the feasibility of local bleeding control, and the consequences of bleeding regardless of its amount (e.g., central nervous system hemorrhage). Despite some discrepancies in certain procedures (i.e., liver biopsy, percutaneous ablation of liver cancer, endoscopic variceal ligation or dental extraction), most of them share the same risk stratification across guidelines (2,10,11,13).

This restrictive policy is based on cumulative data showing that traditional coagulation tests and platelet count do not adequately assess the risk of bleeding secondary to invasive procedures, nor is there high-quality evidence that their correction reduces this risk. There is more data on the poor predictive value of the INR and, thus, the universal agreement among guidelines. Discrepancies regarding the need to treat the platelet count is explained by the lack of randomized controlled trials, in vitro data suggesting that platelet levels >55,000/µL ensure normal primary hemostasis and by conflicting data from observational studies on the predictive value of platelet count in procedural bleeding. However, the majority of the guidelines published in the last 2 years recommend not to routinely correct the platelet level due to the limited evidence available, ability to use effective interventions if bleeding occurs and potential risks of platelet transfusion (2,10,11,13). In this last regard, thrombopoietin receptor agonists (TPO-RA) (i.e., lusutrombopag and avatrombopag) are considered as a valid alternative to platelet transfusion in scheduled procedures by some guidelines (5,12). Others, including the AASLD document, do not support their use since no reduction in bleeding complications has been shown so far (2). Of note, around 20–25% of the patients treated with TPO-RA do not reach the hypothetical safe threshold of >50,000/µL. A similar controversy exists regarding the correction of low fibrinogen levels (<100–150 mg/dL). Scarce data suggest that they might be associated with increased bleeding risk in critically ill patients with cirrhosis. These patients may also be a higher risk of procedural bleeding and, therefore, even the most restrictive guidelines acknowledge that deviations from the formal recommendations may be justified in patients with extreme changes in the hemostatic system (13). Accordingly, the AASLD guidance recommends an individualized approach to patients with severe thrombocytopenia and fibrinogen levels <100 mg/dL (2). More consensus exists regarding global tests of hemostasis. Although these tests better capture the general hemostatic status of a patient with cirrhosis and can reduce the need of preprocedural intervention and guide treatment should a bleeding occur, all guidelines agree that further studies are needed to confirm their reliability in identifying patients at risk for procedural bleeding (2,5,8-11,13). A final remark on the real-world management. Recent surveys from Spain and Italy have shown a lack of compliance with guidelines (14,15) and this highlights not only the need for high-quality studies (unlikely to be performed in the foreseeable future given the large sample required due to the low incidence of bleeding) (13), but also for multidisciplinary intra-hospital protocols to implement the current recommendations regardless of its more or less restrictive nature.

The rest of the guidance deals with vascular liver disorders and the main recommendations are depicted in Table 2. As far as portal vein thrombosis (PVT) is concerned, the AASLD proposed the establishment of a standardized terminology to allow comparison and external validation of future studies since terminology and classification systems of PVT vary extensively in the literature. The proposal was backed up by the Baveno VII consensus and includes a systematic documentation of initial site, extent/degree of luminal obstruction, and chronicity of PVT (2,7). Other important statements include not performing an extensive evaluation for thrombophilic conditions in patients with cirrhosis and PVT, unless family history or routine laboratory testing raises other concerns, and the incorporation of direct oral anticoagulants (DOACs) and of new radiological techniques in the treatment of PVT. Regarding the former, data is conflicting and comes from a limited number of studies, mostly case-control studies with small sample sizes and different designs. Therefore, recommendations from guidelines vary from consider testing on an individual basis (3,4) to limiting it to certain cases (2,5). This in opposition to PVT in the absence of cirrhosis where a full investigation for myeloproliferative disorders or another thrombophilic condition is universally supported. Regarding anticoagulation, and in contrast to other guidelines (6,7), the AASLD document makes no strong recommendation on the use of DOACs in patients with PVT with and without cirrhosis due to the limited evidence on their safety and efficacy, and states that the choice of anticoagulant agent should be individualize. As better specified in Baveno VII, if prescribed, DOACs should be limited to Child-Pugh A patients, used with caution in Child-Pugh B patients and not used in Child-Pugh C patients outside study protocols (7). In the setting of portal cavernoma, there is no established benefit of anticoagulation and treatment should be targeted at management of portal hypertension complications. In this regard, and in line with other guidelines (5,7), the AASLD document supports the percutaneous recanalization of the portal vein (PVR) followed by transjugular intrahepatic portosystemic shunt (TIPS) in patients with refractory complications and in liver transplant candidates with chronic PVT that hinders a physiological anastomosis between the graft and recipient portal vein (2). It must be noted that some centers do not systematically add a TIPS after PVR in the absence of parenchymal disease [e.g., cirrhosis or portosinusoidal vascular disorder (PSVD)].

The term PSVD has been recently proposed, and endorsed by Baveno VII, to define a broad clinico-pathological entity encompassing a heterogeneous group of vascular liver diseases including idiopathic noncirrhotic portal hypertension (INCPH). In contrast to the latter, diagnosis of PSVD can be made in the absence of signs of portal hypertension, provided there are specific histological lesions and no cirrhosis (7). Despite mentioning this new proposal, the AASLD still favors the term and definition of INCPH and does not recommend screening for PVT as suggested by the Baveno VII consensus (2). PVT is a frequent event in these patients, but its impact on the natural history is uncertain, explaining these different recommendations. The guidance also performed an update on Budd-Chiari syndrome, sinusoidal obstruction syndrome, hereditary hemorrhagic telangiectasia, hepatic/splenic artery aneurisms and congenital disorders. Beyond some new recommendations, the AASLD document highlights that patients with these disorders should be referred to tertiary care centers with expertise in their management.

In conclusion, the AASLD guidance offers significant updates for best practice but is hampered by a paucity of robust evidence. Indeed, the research agenda is wide and due to the rarity of vascular disorders and preprocedural bleeding, multicenter collaboration is key to foster advances in the field. Hopefully, and regardless of the length of the shadow, the next AASLD document will shed some light on many of the current gaps of knowledge.

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-22-556/coif). The authors have no conflicts of interest to declare.

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