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
Authors: Patrick G. Northup, Juan Carlos Garcia‐Pagan, Guadalupe Garcia‐Tsao, Nicolas M. Intagliata, Riccardo A. Superina, Lara N. Roberts, Ton Lisman, Dominique C. Valla
Journal: Hepatology (2020)

Previous guidelines reviewing vascular disorders of the liver(1-3) focused on thrombosis of large vessels, such as the portal vein (PV) and hepatic vein (HV). However, increased understanding and research in hemostasis and bleeding in patients with cirrhosis has led to more diagnostic and therapeutic opportunities targeting prevention of bleeding, especially procedural bleeding. Therefore, this Guidance covers bleeding related to disturbances in the hemostatic system predisposed by chronic liver disease as well as thrombosis, especially in the splanchnic vasculature. This American Association for the Study of Liver Diseases (AASLD) Guidance provides a data-supported approach to the management of vascular liver disorders, portal (PVT) and hepatic vein thrombosis (HVT), and procedural bleeding in patients with liver disease. It differs from AASLD Guidelines, which are supported by systematic reviews of the literature, formal rating of the quality of evidence and strength of the recommendations, and, if appropriate, meta-analysis of results using the Grading of Recommendations Assessment Development and Evaluation system. In contrast, this document was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics with oversight provided by the AASLD Practice Guidelines Committee at all stages of Guidance development. The AASLD Practice Guidelines Committee chose to commission a guidance on this topic because a sufficient number of randomized controlled trials were not available to support the development of a meaningful guideline. Patients with cirrhosis have multiple alterations in their hemostatic system.(4) First, defective hepatic synthetic capacity results in decreased plasma levels of coagulation factors, inhibitors of coagulation, and fibrinolytic factors. Second, circulating platelet numbers are decreased because of a combination of decreased thrombopoietin (TPO) synthesis, splenomegaly with sequestration, accelerated platelet turnover, and decreased megakaryocyte production.(5) Third, plasma levels of hemostatic proteins that are primarily synthesized by endothelial cells are substantially elevated.(6) Fourth, low-grade intrahepatic and/or systemic activation of the hemostatic system results in consumption of hemostatic proteins.(7) Fifth, acquired disorders in platelet function and posttranslational modification of hemostatic proteins (e.g., fibrinogen) result in altered function.(8) There are many more hemostatic changes in patients with cirrhosis that are as yet unknown or not adequately characterized. Such changes include newly discovered roles of neutrophils(9) and red blood cells(10) in hemostasis and thrombosis; endothelial changes, including alterations in the endothelial glycocalyx(11, 12); and alterations in circulating levels of procoagulant microparticles.(13) Figure 1 provides an overview of the current understanding of the cellular-based hemostasis system in cirrhosis. Hemostatic changes promoting bleeding and clotting occur simultaneously in any individual patient, and some of these changes counteract each other. For example, thrombocytopenia in cirrhosis is alleviated by elevated levels of the platelet adhesive protein, von Willebrand factor (VWF),(6) decreased levels of procoagulant proteins are counteracted by decreased levels of natural anticoagulant proteins,(14) and decreased levels of antifibrinolytic proteins are counteracted by decreased levels of profibrinolytics,(15) except in critically ill patients.(16) In view of these changes and clinical observations, cirrhosis is no longer considered a condition associated with an overall bleeding tendency, but rather both prohemostatic and antihemostatic pathways are disturbed in complex ways, such that it is difficult to determine in an individual patient exactly where the balance is using currently available clinical tests. Traditional laboratory measures of coagulation, such as prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT), have proven inadequate and often misleading in the evaluation of hemostasis in cirrhosis because these measures only partially evaluate the hemostasis system and neglect the counterbalanced factors mentioned above (Table 1). Global tests of hemostasis, including plasma-based thrombin generation tests, plasma-based fibrinolysis assays, and whole-blood viscoelastic tests of clot formation, have been instrumental in developing the current concept of rebalanced hemostasis. For example, although traditional laboratory measures of coagulation may suggest a bleeding tendency, more advanced hemostasis tests, including plasma-based thrombin generation tests and whole-blood viscoelastic tests such as thromboelastography (TEG) or rotational thromboelastometry (ROTEM), have shown that patients with cirrhosis have normal to elevated thrombin-generating capacity and near-normal whole-blood clot formation.(4) Details of strengths and weaknesses of TEG and ROTEM in liver disease have been published.(17) Nevertheless, all currently available global hemostasis tests have limitations and should be interpreted cautiously because the predictive value of all available tests for spontaneous or procedural bleeding is unproven (Table 2). Whether global hemostasis tests are able to identify patients at risk for procedural bleeding has been poorly studied. Published data on viscoelastic tests, in particular, are contradictory because of a heterogeneous collection of subjects and procedures tested, a predominance of study procedures with a low risk of bleeding, poorly defined bleeding endpoints, and the use of fresh frozen plasma (FFP) transfusion in the standard-of-care arms.(18-22) However, because these tests are frequently within normal ranges in patients with cirrhosis, they may be useful in selecting which patients do not need preprocedural intervention. Because of the systematic underestimation of coagulation capacity by currently available viscoelastic testing methods,(23) abnormal preprocedural viscoelastic testing may still not require correction. Further study of viscoelastic testing with standardized clinical bleeding endpoints is needed.(24) Although there are simultaneous changes in prohemostatic and antihemostatic pathways that have been interpreted to result in a reset in the hemostatic balance,(25) there are poorly understood distinct hypercoagulable and hypocoagulable features that may contribute to thrombosis or bleeding in any individual patient (Table 1). Procedure-related bleeding in patients with cirrhosis may be a consequence of hemostatic failure, but many bleeding events arise as a consequence of unrelated factors, such as portal hypertension or vessel rupture/puncture. These types of bleeding events are therefore not preventable with preprocedural manipulation of the hemostasis system, although major nonhemostatic bleeding events may eventually turn into hemostatic bleeds because of the consumption of hemostatic proteins. Consequently, clinicians routinely face complex dilemmas when assessing procedural bleeding risk because bleeding can occur from different underlying causes (Fig. 2). Interventions directed at preventing and treating bleeding should specifically target the expected or actual source of bleeding (e.g., vessel rupture, portal hypertension, or hemostatic failure). Assessment of bleeding risk for any particular procedure is dependent on numerous factors that can be broadly grouped into procedural- or technical-related factors, disease-state characteristics inherent to cirrhosis, and systemic factors.(26-32) Although these factors are interdependent and vary over time, understanding each component's relative contribution to bleeding risk is important when estimating risk. Past studies have grouped both low- and high-risk procedure types together to derive broader conclusions with respect to an overall bleeding risk,(18, 33-35) but procedure risk stratification should be based on specific procedure type when data are available. In previous guidance statements and expert opinion documents, procedure bleeding risk has been categorized as low or high (Table 3).(26, 28, 29) Low-risk procedures constitute all procedures whereby major bleeding is expected to occur in <1.5% of cases and/or significant bleeding, if it occurs, can be easily controlled. Conversely, high-risk procedures have increased risk of bleeding (estimated >1.5% risk of major bleeding) and/or hemorrhage, if it occurs, can be difficult to control or may lead to catastrophic consequences, even in small amounts (e.g., central nervous system bleeding).(26, 28) This risk dichotomy is based on expert opinion and generally grounded in the context of periprocedural therapeutic anticoagulation, but provides a useful framework when engaging in multidisciplinary planning before procedures. An individual procedure will involve different technical risks. Both provider experience and technique directly affect outcomes. For example, the use of imaging with ultrasound guidance for thoracentesis in patients with abnormal coagulation parameters reduces the risk of bleeding.(36) Similarly, the use of ultrasound guidance for PV access during transjugular intrahepatic portosystemic shunt (TIPS) reduces the risk of capsule perforation, a known precipitant of intraperitoneal hemorrhage.(37) Although factors such as technique and operator experience are often discussed, they are difficult to quantify and study systematically, but should be considered in procedure risk stratification. Another important factor inherent to each individual procedural technique is the ability to control active bleeding if it occurs. For example, significant bleeding after dental extractions is often prevented with local hemostatic measures, even in patients with advanced cirrhosis, significant thrombocytopenia, and elevated INR.(38, 39) Patients with cirrhosis can present with a wide spectrum of diseases, from well-compensated cirrhosis to chronic decompensation to acute decompensation with multiorgan failure.(40) Advanced liver disease is associated with thrombocytopenia attributable to portal hypertension and a prolonged INR as a result of an impaired synthesis of coagulation factors. Although these coagulation indices are historically used to assess bleeding risk, they are misleading in patients with cirrhosis. Advanced portal hypertension is an independent risk factor for procedure-related bleeding, even in low-risk procedures,(41, 42) but there are factors that may confound this finding. The hemostatic system is affected by hepatic decompensation, and patients with cirrhosis are at risk of becoming critically ill, requiring exposure to multiple procedures and potentially increasing the risk of bleeding complications.(43, 44) Acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) directly alter the hemostatic system.(16, 45, 46) A retrospective case-control study demonstrated that patients with ACLF had a higher risk of hemorrhage after paracentesis, and low fibrinogen levels were associated with this risk.(47) Of note, there were no significant differences between platelet and INR levels between matched controls and patients with bleeding, and neither factor was predictive of bleeding on multivariable analysis. The systemic inflammatory response and association with concurrent infection alter hemostatic function, as measured by global hemostasis testing, and may be associated with an increased risk of bleeding, particularly in the setting of invasive procedures. Overall, data remain sparse on the independent influence of advanced portal hypertension, acute decompensation, and ACLF in hemostasis; however, it is likely that patients with these disorders are at higher risk of procedural bleeding, and careful consideration in preprocedural planning is recommended. Patients with cirrhosis often have multiple medical comorbidities that may affect overall bleeding risk. Among these, acute and chronic kidney disease (CKD) have been most extensively studied as risk factors for bleeding. Underlying alteration in coagulation factors may play a role in the association of bleeding risk and acute kidney injury (AKI).(48, 49) One study examined patients with postparacentesis hemorrhage and found an association between AKI and bleeding, independent of infection.(50) In a large retrospective analysis of large-volume paracentesis, nine bleeding events out of 4,729 procedures were reported, and renal dysfunction was reported in 89% of patients (8 of 9 patients) with bleeding events.(51) A study examining postbanding ulcer bleeding after endoscopic variceal ligation (EVL) demonstrated that patients who developed bleeding (n = 6) compared to those who did not (n = 259) had significantly higher serum creatinine (2.2 mg/dL bleeders vs. 1.0 mg/dL nonbleeders; P = 0.001).(52) In this study, there was no significant difference in platelet level and INR between patients with bleeding and those without bleeding. Based on these data, addressing acute and/or chronic kidney dysfunction as much as possible before elective procedures is recommended. Medications, in particular antiplatelet therapy and anticoagulation, alter the risk of bleeding during procedures and should be carefully considered in the periprocedural period. In a retrospective cohort analysis comparing hospitalized patients with cirrhosis receiving venous thromboembolism (VTE) prophylaxis to those who did not, there was a trend of increased nongastrointestinal bleeding events in patients receiving VTE prophylaxis (64% of nongastrointestinal bleeding events were procedure-related bleeding).(53) On multivariable analysis, the use of VTE prophylaxis in this cohort (OR, 2.36; CI, 1.12-4.97; P = 0.025) was associated with overall in-hospital bleeding, yet platelet count, INR, and Model for End-Stage Liver Disease (MELD) score were not predictive of bleeding. However, in a study examining post-EVL ulcer bleeding, the use of therapeutic low-molecular-weight heparin (LMWH) was not associated with bleeding.(52) More data are needed to better understand the effect of anticoagulation on bleeding risk with specific procedures in patients with cirrhosis. Procedures are routinely performed in patients with cirrhosis (e.g., paracentesis and endoscopy) with very low risk of bleeding in the presence of elevated INR and thrombocytopenia.(41, 54, 55) Therefore, the use of prophylactic transfusions of FFP and/or platelets based on preprocedural laboratory tests is not routinely indicated.(56) For example, a study of 1,100 therapeutic paracenteses in 628 patients (513 with cirrhosis) and no prophylactic transfusion before the procedure showed no bleeding or complications requiring hospitalization in any patient (292 patients with INR > 2; 598 patients with platelets <50,000/µL).(55) EVL can lead to delayed postbanding ulcer bleeding in patients with cirrhosis. In one study of 150 patients with cirrhosis undergoing EVL, traditional hemostasis testing (elevated INR and thrombocytopenia) was not predictive of EVL bleeding, but advanced cirrhosis (Child-Turcotte-Pugh [CTP] C) was the most important factor associated with risk of post-EVL ulcer bleeding.(42) This finding has been reproduced in other studies.(57) Because EVL bleeding is typically delayed by several days, prophylactic measures before or during the procedure will likely not alter post-EVL bleeding risk. As such, the use of prophylaxis, based on traditional measures of hemostasis before EVL, is not recommended. The risk of bleeding with liver biopsy, either percutaneous or transjugular, is low in the general population, but may be higher in patients with cirrhosis.(58-61) Historically, traditional hemostasis studies do not correlate with bleeding risk in patients undergoing liver biopsy.(58, 62) One study of 2,740 percutaneous liver biopsies performed in patients with advanced fibrosis or well-compensated cirrhosis documented a 0.6% bleeding rate with no bleeding-related deaths.(61) Data from this study suggest an association with thrombocytopenia (<60,000/µL) and elevated INR (>1.3) and postbiopsy hemorrhage.(61) Because of the conflicting data in the literature, current AASLD guideline recommendations on liver biopsy do not identify a specific INR or platelet cutoff in which the risk of bleeding is substantially increased, but suggest individualized approaches and assessment of other risk factors that may increase bleeding risk,(60) as discussed above. The preparation and intraoperative management of patients with cirrhosis undergoing major surgery, including liver transplantation (LT), has been described.(63) However, it is important to note that data suggest that LT surgery can be safely performed without prophylactic or protocol-driven preprocedural administration of blood, FFP, or platelets.(64) In the general medical population, it has been well established that preprocedural hemostasis laboratory testing serves little purpose unless patients have a history of bleeding or an inherited bleeding disorder or are using antithrombotic drugs.(65) Because patients with cirrhosis often do have a bleeding history and because of the known hemostatic abnormalities of these patients, preprocedural hemostasis testing is very common. In the following sections, we argue that there is little evidence that correction of hemostatic laboratory abnormalities before common procedures decreases bleeding risk. In vitro data have been interpreted to suggest platelet levels >55,000/μL(66) improve hemostasis in patients with cirrhosis. However, these in vitro data have only assessed platelet procoagulant activity and have not accounted for potential compensation by VWF and other endothelial-based components. In addition, this threshold has not been validated clinically. Data suggest that platelet transfusions do not substantially improve thrombin generation capacity or viscoelastic markers of bleeding risk.(67) Furthermore, despite modest rises in absolute platelet counts, they carry a potential for the transfusion-related lung injury syndromes.(68) The data on a threshold platelet level for bleeding risk minimization before procedures are mixed. Some studies have shown no predictive value of preprocedural peripheral platelet count on procedural bleeding complications.(69, 70) In a prospective cohort study of critically ill patients, of whom 211 had cirrhosis, the most common bleeding events were spontaneous gastrointestinal or variceal bleeding; however, 10 events (occurring in 4.7% of the entire cohort of patients with cirrhosis) were postprocedural or postoperative.(71) In this cohort, although a peripheral platelet count of <30,000/μL was associated with bleeding, most of the bleeding was attributable to portal hypertension. Another study of 50 LT candidates with platelet counts <125,000/μL (52% with counts <75,000/μL) were followed for procedural complications.(33) There were 10 (20%) bleeding complications after procedures, all of which occurred in patients with a platelet count <75,000/μL. Despite this finding, patients in this study who received prophylactic platelet transfusion before the procedures were paradoxically more likely to experience bleeding. Therefore, this suggests that the low platelet count may have been merely a reflection of advanced portal hypertension and not a causative risk factor for bleeding. There are three medications approved by the U.S. Food and Drug Administration (FDA) for increasing platelet counts in patients with cirrhosis. All of these agents are TPO receptor agonists and stimulate bone marrow production of platelets. Eltrombopag has the obsolete indication for treatment of thrombocytopenia related to interferon-based hepatitis C therapy and is now rarely used in the prophylactic role. However, an early study of this agent designed to produce platelet counts in the "healthy normal" range before invasive procedures in patients with cirrhosis was discontinued early because of excess thrombotic events, particularly PVT, in the treatment arm, possibly related to excessively high platelet counts.(72) Avatrombopag(35) and lusutrombopag(34) are indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Each of these oral agents requires completion of a 2- to 8-day course preceding the scheduled procedure. These agents are superior to placebo in achieving a target platelet count ≥50,000/μL before the procedure, with no statistical differences in thrombotic complications compared to placebo. Of note, there were no statistical differences in postprocedural bleeding events in these studies between treatment arm and placebo, and therefore routine use of these agents to prevent procedure-related bleeding cannot be recommended. There are no high-quality data on appropriate platelet thresholds before procedures, and general interventions to increase platelet counts to prevent bleeding are not evidence based and cannot be recommended. Given the low bleeding risk of many common procedures, potential risks of platelet transfusion, lack of evidence that elevating the platelet count reduces bleeding risk, and ability to use interventions, including transfusion and hemostasis procedures on an as-needed basis if bleeding occurs, it is reasonable to perform both low- and high-risk procedures without prophylactically treating the platelet count. This recommendation deviates from recommendations by other societies (Table 4), and, ideally, studies with clinical bleeding endpoints and placebo controls are required to examine the best strategy for periprocedural platelet management. Understanding the inconsistency of various societal recommendations and multidisciplinary nature of procedural health care, an individualized approach to patients with severe thrombocytopenia before procedures is recommended because of the lack of definitive evidence for safety and efficacy of interventions intended to increase platelet counts in patients with cirrhosis. 1-Deamino-8-d-arginine vasopressin (DDAVP) increases release of endothelial VWF. A randomized controlled trial using intranasal administration of DDAVP showed equivalent postprocedural bleeding rates compared with platelet and FFP transfusions preceding dental extractions in patients with cirrhosis with INR between 2 and 3 and/or platelet count between 30,000 and 50,000/μL.(73) The mechanism of action of DDAVP in this study was not clear, and DDAVP was shown to not affect primary hemostasis or platelet adhesion in another study of patients with cirrhosis.(74) As discussed above, the PT and its derivative, the INR, are widely available traditional measures of coagulation. However, because the INR only assesses quantitative defects in procoagulant clotting factors (Tables 1 and 2), it is not a reliable indicator of hemostatic balance in patients with cirrhosis and is unable to predict procedural bleeding risk. The literature on the INR's poor predictive value in procedural bleeding is extensive.(42, 55, 60, 75-77) However, INR is a surrogate indicator of protein synthetic functional capacity of the liver and may correlate with bleeding risk related to severity of liver disease, rather than bleeding risk related directly to hemostatic failure. FFP transfusions carry important risks: (1) a potential for developing transfusion-related lung injury syndromes(68) and (2) increases in portal pressures directly proportional to the volume transfused.(78) Importantly, FFP transfusions show minimal efficacy in improving thrombin generation capacity in vitro.(79) Outside of advanced malnutrition states or chronic cholestasis, vitamin K replacement has no measurable effect on the INR in patients with cirrhosis. Determination of factor V levels can aid the practitioner in differentiating vitamin K deficiency from impaired liver function if the diagnosis is in question. Given the lack of effect of FFP on hemostatic capacity in the population of patients with cirrhosis, we advise against prophylactic FFP transfusion before common procedures and await studies with clinically relevant endpoints to yield further guidance. This recommendation is consistent with the AASLD practice guidelines for management of ascites(56) and portal hypertensive bleeding(80) as well as other professional society guidelines.(3, 28, 81, 82) Recombinant factor VIIa is effective in normalizing the INR in patients with cirrhosis, yet a randomized clinical trial showed no benefit in controlling esophageal variceal hemorrhage.(83) Its use in a prophylactic setting before invasive procedures is not recommended, and the use of this agent in nonhemophilia patients has been associated with increased risks of thrombosis, including arterial thromboses.(84) Prothrombin complex concentrates targeting both the deficiency of the procoagulant system as well as the acquired deficiency of the innate anticoagulant system are under study in patients with liver disease,(85, 86) but efficacy and safety data are lacking to date. Plasma fibrinogen levels <100 mg/dL are associated with spontaneous and procedure-related bleeding in patients with cirrhosis,(71, 87) but causal relationships are not established. Low fibrinogen levels may reflect critical illness and do not directly cause bleeding in most cases. In a case series of critically ill surgical patients without cirrhosis, a fibrinogen level of ≥100 mg/dL resulted in greater mechanical clot stability compared to lower levels of fibrinogen, but the relationship was relatively linear without an obvious threshold effect.(88) The literature on fibrinogen replacement for bleeding is derived from trauma literature or advanced fibrinolytic states during cardiac surgery and LT. Diagnostic laboratory tests for hyperfibrinolysis are not readily available in clinical practice, and current viscoelastic testing is not sensitive for moderate or mild hyperfibrinolysis. The diagnosis of hyperfibrinolytic postprocedural bleeding is made clinically because laboratory testing is not reliable for this condition. Typical manifestations include continuous venous oozing from skin puncture sites and persistent mucosal or submucosal bleeding. Epsilon-aminocaproic acid (EACA), a lysine analogue that prevents plasminogen and tissue plasminogen activator (tPA) from binding to fibrin, has shown benefit in stopping fibrinolytic bleeding without major toxicity in an uncontrolled case series.(89) In patients without cirrhosis, some benefits of antifibrinolytic therapy are observed after dental extractions in patients on continuous therapeutic anticoagulants.(90) There are no definitive data supporting the use of EACA for prevention of bleeding in cirrhosis, although elective procedures should be delayed during states of clinically apparent pathological fibrinolysis. Tranexamic acid has antifibrinolytic activity through a similar mechanism as EACA. A recent international multicenter, randomized, double-blind, placebo-controlled trial of high-dose tranexamic acid as an adjunctive therapy in patients presenting with acute gastrointestinal bleeding showed no reduction in death or bleeding in the tranexamic acid arm.(91) This study population included a minority of patients with cirrhosis, and a subgroup analysis showed the risk of VTE events to be higher in patients with cirrhosis receiving the tranexamic acid. Until further supportive data are published, the prophylactic use of EACA or tranexamic acid to prevent procedural bleeding cannot be recommended. Because fibrin and its precursor, fibrinogen, are key components of functional clot formation, until definitive clinical trial data are available, it is logical to maintain blood levels of this factor to promote the ability to form strong and functional clots. Therefore, correction of plasma fibrinogen to levels >100 mg/dL using cryoprecipitate or fibrinogen concentrate before high-risk procedures could be considered for patients with cirrhosis, but data to support this strategy reducing bleeding complications are lacking. Regardless, levels of fibrinogen of <100 mg/dL are rare in patients with cirrhosis outside of acute critical illness. PVT is a heterogeneous condition with respect to etiology, manifestations, natural history, and therapeutic options. For this reason, terminology and classification systems also vary extensively in the literature. It is desirable to establish standardized terminology in describing PVT to allow comparison and external validation of future studies. In regard to the time course of thrombosis, the term "recent" is preferred to the term "acute" because the latter implies both clinical symptoms as well as recent-onset thrombosis, yet not all patients with a recent PVT develop symptoms. Precise dating can be impossible in patients without recent suggestive symptoms or previous abdominal imaging and is often done retrospectively. The term "chronic" should be applied to a PV obstruction persisting longer than 6 months after presumed onset. Although somewhat arbitrary, 6 months has some justification based on a pivotal prospective, longitudinal study in 100 patients with recent PVT followed up until 1 year. In this study, recanalization that did not take place within 6 months did not occur between 6 and 12 months, and cavernous transformation developed in most such patients despite anticoagulation therapy.(92) Following the onset of a PV obstruction that is not followed by regression, cavernous transformation may develop within a few weeks regardless of the cause of obstruction. Therefore, when portal cavernous transformation is present, this term should be preferred to "chronic portal vein thrombosis" for descriptive and systematic categorization. Table 5 outlines a simplified nomenclature system that can be used