Summary: Background: Given the lack of long‐term prospective studies, it is challenging for clinicians to make informed decisions about screening and treatment decisions regarding the risk of hepatocellular carcinoma (HCC) in patients with non‐alcoholic steatohepatitis (NASH) who do not have cirrhosis.Aim: To characterise the pooled risk of HCC in the non‐cirrhosis population.Methods: Published studies were identified through April 2016 in MEDLINE, Scopus, Science Citation Index, AMED and the Cochrane Library. Two independent reviewers screened citations and extracted data. Random effect odds ratios (OR) were calculated to obtain aggregate estimates of effect size between NASH and non‐NASH groups. Between‐study variability and heterogeneity were assessed.Results: Nineteen studies with 168 571 participants were included. Eighty‐six per cent of included subjects had cirrhosis. The prevalence of HCC in non‐cirrhotic NASH was 38.0%; among other aetiologies in non‐cirrhotics, it was 14.2% (P < 0.001). Non‐cirrhotic NASH subjects were at greater odds of developing HCC than non‐cirrhotic subjects of other aetiologies (OR 2.61, 95% CI 1.27‐5.35, P = 0.009). When examining all NASH subjects either with or without cirrhosis, those with NASH as the underlying liver disease did not have a significantly increased risk of HCC (OR 1.43, 95% CI 0.77‐2.65, P = 0.250).Conclusions: In non‐cirrhotic subjects, those with NASH have a higher risk of HCC compared to other aetiologies of liver disease. Further study investigating the risk factors of HCC among non‐cirrhotic NASH patients is needed.

Patients with acute and chronic liver disease frequently acquire unique changes in haemodynamic and haemostatic pathways that may result in life-threatening bleeding and thrombosis. Additionally, activation of haemostatic pathways may play a role in disease progression through parenchymal extinction, organ atrophy, recruitment of inflammatory cells and activation of stellate cells. In the setting of a previously entrenched set of clinical perceptions, the slowly evolving evidence-based paradigms of haemostasis in cirrhosis are now more carefully scrutinized. The 7th International Conference on Coagulation in Liver Disease (held biennially since 2005) met in October of 2017 in Rome, Italy, to discuss and debate important topics in this field. This document provides a statement-based thematic summary of the meeting presented here amid a framework of the most current evidence. The review of the literature, preparation of the document and presentation of each summary statement below are based on systematic approaches used in published guidance documents.[1] In particular, recognition of the potential disconnect between existing evidence and actual practice, we utilized a questionnaire and real-time poll of the conference attendees to compare actual clinical practice to the evidence-based support for each statement. The final section summarizes the results of the most salient results of the poll. 1. Traditional coagulation measures, including pro-thrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR) and bleeding time (BT) do not measure bleeding risk in cirrhosis. Conventional in vitro tests of the coagulation system are of limited value in estimating haemostatic competency in cirrhosis and current literature emphasizes these limitations when compared with global assays of coagulation.[2] [3] [4] [5] PT/INR, aPTT and BT are generally prolonged in patients with cirrhosis in direct relationship to the degree of hepatic decompensation. While useful for predicting prognosis in chronic liver disease, these tests do not predict bleeding or thrombosis in patients with chronic liver disease. For the PT/INR and aPTT, a trigger reagent (tissue factor for extrinsic pathway or kaolin for the intrinsic pathway), phospholipids and calcium are added to patient plasma in a test tube and the time to the formation of fibrin is recorded. The PT/INR test performs poorly in assessing coagulation capacity in patients with liver disease[6] and suffers from high inter-laboratory variability.[7] [8] The PT/INR measures only pro-thrombotic pathways without measuring counter-balancing anticoagulation (AC) pathways including protein C. Numerous studies and clinical experience now clearly demonstrate that these tests do not measure in vivo activity of the coagulation system in cirrhosis.[9] [10] [11] [12] [13] 2. Platelet count alone provides an incomplete guide to bleeding risk in cirrhosis. However, values below 50,000/μL may be associated with higher risk of bleeding. Thrombocytopenia is common in patients with advanced cirrhosis and indirectly correlates with the degree of portal hypertension and hepatic decompensation.[14] In vitro evidence indicates that platelet-dependent thrombin generation is preserved in patients with cirrhosis with platelet levels 56,000/μL or greater.[15] Notably, however, other important aspects of platelet function are not assessed by thrombin generation assay (TGA). Severe thrombocytopenia is associated with procedural-related bleeding events in some, but not all studies.[16] [17] While there is no evidence that prophylactic platelet transfusion improves haemostatic potential,[18] current guidelines and expert opinion recommend consideration of platelet transfusion prior to high-risk procedures or when active bleeding is encountered in patients with platelet counts below 50,000/μL.[4] [19] A notable exception is liver transplant surgery, in which platelet counts below 50,000/μl are accepted by many centres. 3. Global viscoelastic tests (VETs) provide a more physiologic assessment of coagulation, VETs are not standardized in patients with liver disease and do not appear to predict bleeding or thrombosis. Application of VETs in patients with liver disease remains controversial. VETs measure clot strength and integrity in whole blood under low shear conditions, attempting to more closely recreate the environment in vivo during clot formation.[20] VETs are considered point-of-care tests and provide the clinician with information regarding the kinetics of clot formation and strength of the clot with the ability to distinguish contributions from fibrinogen, platelets and the fibrinolytic system. VETs are most extensively studied in patients with cirrhosis undergoing liver transplantation.[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] More recently VETs have been employed to examine the haemostatic system in a wide variety of patients with liver disease, including well-compensated patients,[40] [41] [42] patients with acute liver failure[43] and in acutely ill patients with liver disease.[44] [45] [46] A recent randomized control trial compared transfusion-directed prophylactic therapy in patients with cirrhosis undergoing procedures using VETs as a guide versus standard coagulation tests.[47] While significantly less blood product was used in the group undergoing VETs screening, the low rate of bleeding events, lack of control arm and inclusion of relatively low risk procedures significantly limits conclusions from these data.[48] Specific nuances of VETs such as test performance without stimulators (‘native’ VETs) and optimal duration of test remain uncertain in cirrhosis. 4. TGA provides a more comprehensive assessment of the haemostatic system in cirrhosis. However, the clinical utility of TGA in patients with cirrhosis is unexplored with current use confined mainly to research. TGA is a valuable research tool that has led to important insights in liver disease and coagulation.[9] [10] [11] [12] [13] [15] [18] [49] [50] [51] [52] [53] [54] It measures the rate of production and decay of thrombin after introduction of a triggering agent (tissue factor and phospholipid).[55] [56] [57] [58] With the addition of thrombomodulin (required for thrombin-mediated activation of protein C), the integrity of the protein C anticoagulant system is measured. Tripodi et al demonstrated that thrombin generation is preserved in cirrhosis despite prolonged conventional coagulation assays due to decreased protein C.[10] [13] Automation and standardization of TGA is incomplete and clinical use is not currently available. Efforts at standardization and development of a point-of-care whole blood thrombin generation test are in progress with the hope for future clinical utility.[52] [59] [60] 5. Available laboratory tests of hyperfibrinolysis are of limited value in cirrhosis and clinical diagnosis is often necessary (see also anti-fibrinolytic therapy below). Identifying the presence of hyperfibrinolysis in cirrhosis is challenging with limited clinically available and laboratory testing.[61] [62] [63] [64] [65] Reliance on clinical assessment and empiric therapy are currently recommend (see the “Pre-Procedure Prophylaxis and Treatment of Non-Portal Hypertension-Related Bleeding in Patients with Cirrhosis” section). The fibrinolytic system regulates clot remodelling and breakdown and is likely rebalanced in cirrhosis. With exogenous disruption (e.g. infection), hyperfibrinolysis, a state of abnormal fibrin degradation mediated by plasmin, can lead to delayed bleeding and has been a recognized clinical feature of cirrhosis for over a century.[66] [67] [68] [69] [70] [71] [72] [73] [74] Joist, who coined the term ‘AICF’ or ‘accelerated intravascular coagulation and fibrinolysis’, recognized the entity of bleeding in cirrhosis similar to, but distinct, from disseminated intravascular coagulation (DIC).[75] This condition was seen in a clinical series where laboratory evidence of hyperfibrinolysis was detectable in a third of hospitalized cirrhosis patients, but clinically evident in only 6% of patients.[76] However, the divergent results of two key studies which examined the mechanistic role of liver synthesized thrombin activatable fibrinolysis inhibitor has resulted in on-going controversy regarding the clinical significance of AICF.[61] [62] These studies have failed to resolve the long known and clinically evident occurrence of diffuse mucosal bleeding or delayed post-procedure bleeding and efficacy of anti-fibrinolytic therapy.[71] [77] On the other hand, further laboratory-based studies have shown increased fibrinolytic capacity in cirrhosis patients[64] suggesting a precariously balanced system more prone to clot lysis. Both endotoxemia[78] and ascites fluid egress into the systemic circulation[79] have been postulated as mechanisms of increased clot lysis. Procedure-related bleeding is common in cirrhosis patients, but estimates of incidence vary widely.[16] For many years, the PT/INR served as a surrogate marker for estimating bleeding risk in cirrhosis. However, use of the INR and arbitrary ‘cut-offs’ as a clinical target is not recommended or supported by scientific evidence. Nonetheless, medical-legal concerns have dominated this field over scientific considerations for many years. This situation is exacerbated by the limited connection between the detached clinician performing the procedure and the ordering provider. This issue likely contributed to early termination of the well-conceived S.H.I.P. trial (Study of Hemostasis and Invasive Procedures NCT00233246) which did not enroll any patients. However, the field has substantially evolved since 2005.[80] This now allows for more refined recommendations based on recent data. Assessment of individual patient characteristics is also essential as clinical factors, such as acute kidney injury[81] or infection[82] may alter bleeding risk in certain clinical scenarios. Global tests, such as VETs, have offered particular insight into potential pathophysiologic mechanism in patients with cirrhosis and active bacterial infection where release of endogenous heparinoids may contribute to an anticoagulant effect placing patients at higher risk to bleed.[83] [84] Large clinical studies examining bleeding outcomes are needed to provide clinicians with better data to assess risk. 6. Pre-procedure testing of plasma fibrinogen and platelet level is recommended for high-risk procedures (see [Table 1]) and pre-procedure correction is recommended for high risk procedures. Clinicians performing the procedure should define the level of risk. Single test assessments and even multi-parameter measures are unlikely to capture the nuances of a complicated physiology. Nonetheless, there are data suggesting that platelet level and the level of fibrinogen correlates to effective haemostasis, although it has not been established whether correction of low levels actually reduces bleeding risk.[85] Evidence is very limited regarding any measure as a guide to prophylactic measures and is mainly inferred from bleeding risk associative studies. Again, many centres do not correct low fibrinogen or platelets prior to liver transplantation, and a clinical trial has failed to demonstrate a beneficial effect of pre-emptive fibrinogen supplementation.[60] Despite the limitations and lack of firm data, with our current knowledge in the field, these parameters are currently considered to be useful in predicting bleeding in cirrhosis patients. 7. Routine prophylaxis for low or moderate risk procedures (see [Table 1]) is generally not recommended. However, individualized approaches are often necessary. The most consistent finding with whole blood VETs (such as thromboelastography or rotational thromboelastometry) has been the demonstration of intact haemostatic mechanisms in cirrhosis with evidence that haemostatic support with blood products is not required despite abnormal PT or platelet count.[86] [87] Unfortunately, the majority of studies in this field have lacked a placebo control arm which limits our understanding of the overall baseline risk in patients without prophylaxis. To this end, we conducted a poll to assess actual current practice in potential contradistinction to rational-based therapy—see below. The most important point to remember is that prophylactic measures PT/INR can paradoxically increase bleeding risk by engorging the collateral bed without any haemostatic benefit. Greater recognition of the baseline bleeding risk and the limitations of prediction, by both clinicians that perform procedures and other clinicians, will improve patient outcomes. 8. Platelet transfusion prior to high-risk procedures or with active bleeding has a rational in vitro basis, but lacks high level supportive data. Within the same limitations, thrombopoetin agonists may have a role in pre-planned procedural prophylaxis. Conflicting data exists regarding bleeding risk and cirrhosis-related thrombocytopenia. The divergence in the literature likely reflects the complexity of haemostasis in cirrhosis and marked study design variation. Among patients undergoing liver transplant evaluation, procedure-related bleeding in one study was closely correlated to platelet levels < 75,000/µL.[16] Similarly, bleeding risk was higher in a retrospective study of cirrhosis patients undergoing dental extractions when platelets were < 40,000/µL.[88] Platelet levels < 30,000/µL were also an independent predictor of major bleeding among critically ill cirrhosis patients in the intensive care unit setting.[89] On the other hand, post-procedure bleeding in cirrhosis was not predicted by baseline platelet levels in another prospective study[90] and the platelet-related risk of post-banding ulcer bleeding has been variably reported.[91] [92] Compensatory mechanisms which may alter overall platelet performance, such as elevated von Willebrand factor (VWF),[93] increased circulating activated platelets[94] and platelet-derived microvesicles,[95] may also be significant factors which balance the bleeding risk related to thrombocytopenia. Additional factors may also contribute to platelet physiology.[96] [97] [98] Limited yield of platelet infusion in cirrhosis is well known and raises the question of whether platelet transfusion prior to high-risk procedures is more ‘cosmetic’ to cover procedure-related liability or an actual effective strategy—this is an understandable conundrum that remains unresolved. More definitive studies require placebo-controlled trials which present clinical investigators with almost insurmountable ethical hurdles at the current state of the art. In elective and planned settings, such as planned dental extractions or other invasive procedures with moderate or high risk, oral thrombopoetin agonists are an alternative means to increase platelets prior to invasive procedures. Concern for a transient hypercoagulable state due to thrombocytosis with eltrombopag, with early reports of increased risk of portal vein thrombosis (PVT), have tempered enthusiasm for these agents.[99] [100] [101] However, new agents are in development, such as avatrombopag and lusutrombopag, which appear to predictably raise platelets to a range associated with improved thrombin production without apparent increased thrombosis risk.[102] [103] 9. The use of desmopressin in patients with cirrhosis lacks a sound physiological basis and does not appear to significantly alter risk of bleeding. Desmopressin (1-deamino-8-arginine vasopressin or DDAVP) has been shown to be as effective as human blood products in cirrhosis patients undergoing dental extractions.[104] Notably, bleeding was very infrequent in both groups raising the question of actual efficacy and no control arm without prophylaxis was studied. Other studies show no benefit in variceal bleeding, liver biopsy in dialysis patients with chronic hepatitis C and with partial hepatectomy.[105] [106] [107] A recent report further demonstrated lack of significant pro-haemostatic effects in cirrhosis patients receiving a conventional dose of intravenous DDAVP compared with a control group of patients with haemophilia A.[108] These concerns raise the question again of the need for placebo controls to more definitively define the utility of various prophylactic strategies. 10. Fibrinogen replacement, pro-thrombin complex concentrates (PCC), and recombinant factor VIIa (rVIIa) may have a role in treatment of significant bleeding in patients with cirrhosis in specific clinical scenarios, but the utility of these agents is undefined. Fibrinogen replacement: The clearest data regarding fibrinogen replacement in clinical bleeding is associated with non-cirrhosis conditions of severe trauma where fibrinogen levels > 200 mg/dL are associated with more effective haemostasis.[109] Although based on very limited data, levels below 120 mg/dL in active bleeding patients with cirrhosis have historically required correction. However, much remains to be learned about fibrinogen replacement in cirrhosis.[110] Replacement has conventionally involved cryoprecipitate, a plasma-derived product rich in VWF, fibrinogen and fibronectin, made by freezing and slow thawing human plasma and reconstituting the precipitate in 10 to 20 mL plasma. In contrast, fibrinogen concentrates are derived from a similar cryoprecipitation process of pooled plasma which then undergo isolation, viral exclusion and lyophilization.[111] The very low volume, standardization of fibrinogen content and lack of need for cross matching favour its use in cirrhosis. Recent in vitro data also suggests a clear improvement in haemostasis in cirrhosis.[112] However, further clinical studies are needed to justify the expense which currently limits wider application. PCC: PCC have been studied in cirrhosis sporadically for over 40 years.[113] [114] However, recommended dosing is linked to AC therapy as the dose is based on factor IX content of the agent, INR (while on vitamin K antagonist [VKA]) and body weight. Data are emerging that lower doses may be effective in cirrhosis, but needs further study.[112] A typical dose is 25 to 30 units of factor IX per kilogram of body weight. The low volume needed for VKA-treated patients is attractive to avoid volume overload and collateral bed engorgement in cirrhosis, however concerns over increasing the risk of thrombosis remain. rFVIIa: rFVIIa has mainly been studied in cirrhosis and variceal bleeding. No definitive survival benefit was evident in patients treated with rFVIIa as an adjunct in variceal bleeding.[115] [116] However, the use of this agent as a rescue agent in uncontrolled haemorrhage in cirrhosis remains unsettled by randomized trials.[117] 11. In delayed and diffuse mucosal bleeding in decompensated cirrhosis (hyperfibrinolysis physiology), consider use of anti-fibrinolytic therapy. Optimal treatment of patients with suspected hyperfibrinolysis lacks well-controlled prospective trials to delineate risks and points of effective intervention. There are two available anti-fibrinolytics that block the lysine binding site on plasminogen preventing its attachment to fibrin and subsequent activation: trans-p-aminomethyl-cyclohexane carboxylic acid or tranexamic acid and epsilon-aminocaproic acid (EACA).[118] [119] Both agents can be given orally or intravenously. Neither are felt to be significantly pro-thrombotic based on studies in cardiac surgery of EACA versus placebo.[120] Several points of caution include the possibility of thrombotic issues if there is superimposed DIC, possible increased risk of central line related thrombosis[121] and the high concentration of the agent excreted in...

Portal vein thrombosis (PVT) is a common complication of cirrhosis sometimes implicated in hepatic decompensation. There are no consistent epidemiologic data to suggest an increased risk of thrombotic complications in nonalcoholic steatohepatitis (NASH); however, research suggests an increased risk of thrombosis. Our aim was to examine the independent association between NASH cirrhosis and PVT in patients who underwent liver transplantation (LT) in a cross‐sectional study. Data on all LTs occurring in the United States between January 1, 2003 and December 31, 2012 were obtained from the United Network for Organ Sharing. Multivariable models were constructed to assess the statistical associations and risk factors for the development of PVT. A total of 33,368 patients underwent transplantation. Of these, 2096 (6.3%) had PVT. Of the patients with PVT, 12.0% had NASH. When we compared these patients to a composite of all other causes of cirrhosis, an increased prevalence of PVT was again found, with 10.1% having PVT at the time of transplantation versus 6.0% without NASH (P < 0.001). The strongest risk factor independently associated with a diagnosis of PVT in a multivariable analysis was NASH cirrhosis (odds ratio, 1.55; 95% confidence interval, 1.33‐1.81; P < 0.001). NASH cirrhosis appears to predispose a patient to PVT independently of other risk factors. These epidemiological findings provide support for the idea that NASH is a prothrombotic state, and they should lead to more research in treatment and prevention in this population. Liver Transpl 21:1016‐1021, 2015. © 2015 AASLD.

AIM: To determine the clinical impact of portal vein thrombosis in terms of both mortality and hepatic decompensations (variceal hemorrhage, ascites, portosystemic encephalopathy) in adult patients with cirrhosis. METHODS: We identified original articles reported through February 2015 in MEDLINE, Scopus, Science Citation Index, AMED, the Cochrane Library, and relevant examples available in the grey literature. Two independent reviewers screened all citations for inclusion criteria and extracted summary data. Random effects odds ratios were calculated to obtain aggregate estimates of effect size across included studies, with 95%CI. RESULTS: A total of 226 citations were identified and reviewed, and 3 studies with 2436 participants were included in the meta-analysis of summary effect. Patients with portal vein thrombosis had an increased risk of mortality (OR = 1.62, 95%CI: 1.11-2.36, P = 0.01). Portal vein thrombosis was associated with an increased risk of ascites (OR = 2.52, 95%CI: 1.63-3.89, P < 0.001). There was insufficient data available to determine the pooled effect on other markers of decompensation including gastroesophageal variceal bleeding or hepatic encephalopathy. CONCLUSION: Portal vein thrombosis appears to increase mortality and ascites, however, the relatively small number of included studies limits more generalizable conclusions. More trials with a direct comparison group are needed.