Editorial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 18, 2015; 7(14): 1818-1827
Published online Jul 18, 2015. doi: 10.4254/wjh.v7.i14.1818
Spontaneous bleeding or thrombosis in cirrhosis: What should be feared the most?
Kryssia Isabel Rodríguez-Castro, Alessandro Antonello, Alberto Ferrarese
Kryssia Isabel Rodríguez-Castro, Alberto Ferrarese, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
Alessandro Antonello, Veneto Oncological Institute (IOV-IRCCS), 35128 Padua, Italy
Author contributions: All the authors equally contributed to this work.
Conflict-of-interest statement: All Authors declare they have no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Kryssia Isabel Rodríguez-Castro, MD, PhD, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padua, Italy. kryssiarodriguez@yahoo.com
Telephone: +39-33-36167592 Fax: +39-49-8218727
Received: January 29, 2015
Peer-review started: March 2, 2015
First decision: March 6, 2015
Revised: March 30, 2015
Accepted: May 5, 2015
Article in press: May 6, 2015
Published online: July 18, 2015

Abstract

The more modern and accurate concept of a rebalanced hemostatic status in cirrhosis is slowly replacing the traditional belief of patients with cirrhosis being “auto-anticoagulated”, prone only to bleeding complications, and protected from thrombotic events. With greater attention to clinical thrombotic events, their impact on the natural history of cirrhosis, and with the emergence and increased use of point-of-care and global assays, it is now understood that cirrhosis results in profound hemostatic alterations that can lead to thrombosis as well as to bleeding complications. Although many clinical decisions are still based on traditional coagulation parameters such as prothrombin (PT), PT, and international normalized ratio, it is increasingly recognized that these tests do not adequately predict the risk of bleeding, nor they should guide pre-emptive interventions. Moreover, altered coagulation tests should not be considered as a contraindication to the use of anticoagulation, although this therapeutic or prophylactic approach is not at present routinely undertaken. Gastroesophageal variceal bleeding continues to be one of the most feared and deadly complications of cirrhosis and portal hypertension, but great progresses have been made in prevention and treatment strategies. Other bleeding sites that are frequently part of end-stage liver disease are similar to clinical manifestations of thrombocytopenia, with gum bleeding and epistaxis being very common but fortunately only rarely a cause of life-threatening bleeding. On the contrary, manifestations of coagulation factor deficiencies like soft tissue bleeding and hemartrosis are rare in patients with cirrhosis. As far as thrombotic complications are concerned, portal vein thrombosis is the most common event in patients with cirrhosis, but venous thromboembolism is not infrequent, and results in important morbidity and mortality in patients with cirrhosis, especially those with decompensated disease. Future studies and the more widespread use of point-of-care tests in evaluating hemostasis will aid the clinician in decision making when facing the patient with bleeding or with thrombotic complications, with both ends of a continuum being potentially fatal.

Key Words: Bleeding, Hemorrhage, Thromboembolism, Portal vein thrombosis, Coagulation, Cirrhosis

Core tip: The two-faced, dynamic, and fragile hemostatic and coagulation system of patients with cirrhosis is of increasing interest. Thrombotic complications, and not only the well-known bleeding complications such as gastroesophageal bleeding, are now recognized complications of cirrhosis. Whether confined to the portal vein, due to venous stasis but also to other yet poorly characterized local as well as systemic factors, or in the presence venous thromboembolism, these complications warrant prevention and treatment with anticoagulation. Future clinical studies, as well as the broader implementation of point-of-care instruments and results from studies using global coagulation assays will outline the best strategies, tailored to each patient according to the severity of liver disease and the particular hemostatic alterations present at a given timepoint.



INTRODUCTION

The traditional concept of an “auto-anticoagulated patient” has given way to the modern, and more accurate notion of a rebalanced hemostatic status in patients with cirrhosis. It is now accepted that classic determinations of the coagulation status such as prothrombin (PT) time, international normalized ratio (INR), and activated partial thromboplastin time (aPTT), although useful in the non-cirrhosis setting, are of much less value in patients with advanced chronic liver disease, firstly because they describe only a fraction of what is actually occurring in the hemostatic system, secondly because this system is fragile and dynamic, and thirdly because they do not predict neither thrombotic nor bleeding events.

Hand in hand with this new bulk of knowledge regarding both the pre-clinical as well as the clinical picture of hemostasis and coagulation in cirrhosis, therapeutic and preventive strategies that were routinely used in the non-cirrhotic population and rigorously avoided in the cirrhotic population, are being used with increasing frequency and confidence.

SPECIFIC ALTERATIONS OF THE HEMOSTATIC AND COAGULATION SYSTEM

Although the clinician might be misled to judging the state of a patient with cirrhosis as pro-hemorrhagic due to an alteration of traditional coagulation parameters, in cirrhosis actually both pro- as well as anti-coagulation factors are affected, the latter of which are not adequately reflected in these tests. Typical of cirrhosis are reduced levels of factors II, IX, XI, and XII, and the magnitude of the reduction correlates with the severity of liver disease. However, levels of anticoagulant factors including protein S, protein C, and antithrombin, are also decreased in cirrhosis, and procoagulant factor VIII is notably increased. Magnifying the complexity of hemostatic and coagulation abnormalities in cirrhosis, studies have demonstrated that liver damage increases plasminogen activator inhibitor (PAI-1) expression[1,2]. Increased to a greater extent than PAI-1, tissue plasminogen activator is elevated both due to reduced hepatic clearance and to enhanced release[3], which has been interpreted as a hyperfibrinolytic state in cirrhosis[4]. Moreover, levels of plasminogen and antiplasmin antiplasmin (α 2-antiplasmin) are reduced, as well as levels of thrombin-activatable fibrinolysis inhibitor (TAFI). Whether observed alterations such as elevated fibrin degradation products[5-7], abnormalities in thromboelastography (TEG) tracings[8], and a decrease in TAFI[9] actually correspond to a state of hyperfibrinolysis which would hypothetically be frequent even in compensated cirrhosis is still controversial, however. Other studies have suggested that actually fibrinolysis is not enhanced in cirrhosis, with a balanced reduction of both pro- as well as anti-fibrinolytic agents[10], and a lack of association between TAFI reduction and actual hyperfibrinolysis[11,12]. Moreover, elevated levels of D-dimer may be a consequence of the activation of the coagulation cascade, which might accumulate in the presence of diminished hepatic clearance[13-15].

Responsible for stabilization of the fibrin clot and its resistance to lysis, factor XIII (FXIII) correlates with the liver’s biosynthetic capacity, and has been shown to be diminished in nearly half of patients with advanced stages of cirrhosis (Child C); FXIII levels < 50% significantly correlated with an increased risk of severe upper gastrointestinal bleeding and mortality in a 6-year follow-up period[16]. Although this could be a reflection of the severity of liver disease, and despite reduced FXIII activity by itself is probably not sufficient to cause bleeding, the addition of this alteration upon the underlying multiple coagulation and hemostatic defects, might increase the risk of hemorrhage[16,17]. As the only method of detecting FXIII deficiency is at present measuring the factor itself, it is probably reasonable to perform this test in the event of uncontrolled bleeding in the presence of regular rotation thromboelastometry (ROTEM) patterns, and when bleeding cannot be explained by platelet count and serum fibrinogen within the normal ranges[18]. The combination of these events results in the establishment of a new - fragile and dynamic - thrombotic/hemostatic balance[10,11].

Regarding primary hemostasis, chronic liver disease is characterized by a variable degree of thrombocytopenia due to increased platelet destruction, increased splenic and/or hepatic sequestration, and to reduced levels of thrombopoietin. Moreover, not only platelet number, but also platelet function has been shown to be compromised due to defective thromboxane A2 synthesis, storage pool deficiency and abnormalities of the platelet glycoprotein Ib[19-22]. Different mechanisms compensate for reduced platelet number and function: von Willebrand factor is notably elevated in cirrhosis, probably as a result of its reduced clearance resulting from diminished levels of its cleaver ADAMTS13 and as a reflection of high levels of FXIII, to which it is bound when circulating in plasma[23].

In addition to these acquired hemostatic and coagulation defects, superimposed (or rather, underlying) genetic thrombophilias may play an important role in tilting the balance towards thrombosis. In a study by Amitrano et al[24], the frequencies of factor V Leiden and of PT A20210 polymorphism were reportedly 13% and 34.8% in cirrhotic patients with portal vein thrombosis (PVT), whereas frequencies were 7.5% and 2.5% in cirrhotic patients without PVT.

The actual hemostatic and coagulation changes in cirrhosis are not adequately reflected by traditional tests including the INR, aPTT, bleeding time, and platelet count, and are also imprecise in predicting bleeding episodes[25]. These tests are not able to detect natural anticoagulant deficiencies, nor do they reveal other pro-thrombotic alterations such as the elevation of von Willebrand factor. In addition, other aspects related to the risk of bleeding or thrombosis, such as clot formation, firmness, and degradation, are not assessed by conventional tests. Likewise, the determination of the individual factors does not provide a complete picture of hemostatic alterations occurring in vivo, either, since the intricate system strongly depends on the balance of pro- and anti-fibrinolytic as well as coagulation factors.

A test that is used ever less frequently, bleeding time correlates with platelet count[26], and is prolonged in nearly half of patients with cirrhosis, without, however a certain relationship with bleeding risk[27].

Whereas traditional coagulation tests measure only the initial 5% of thrombin that is generated and are insensible to detecting deficiencies in the anticoagulation mechanisms, global assays such as the thrombin generation test analyze more components of the hemostatic status and therefore offer a view that is closer to what is actually going on in vivo. When performed in the presence of thrombomodulin, which enables the activation of protein C, the amount of thrombin generated in plasma from patients with cirrhosis is at least equal to - even increased with respect to - that of healthy subjects[28,29]. Despite this test yields a more approximate view regarding generation as well as degradation of thrombin, this in vitro technique, apart from being impractical and complex, has the drawback of excluding platelets, which serve not only as a scaffold for coagulation, but play an active role in the process.

The “newcomers” in the field of bedside coagulation monitoring, which have actually been around for quite a while in other clinical scenarios, provide a more complete picture of what is going on in vivo. Point-of-care coagulation monitoring devices which assessing the viscoelastic properties of whole blood include TEG (Haemonetics Corporation, Braintree, MA, United States), ROTEM™ (Tem International, Munich, Germany), and theSonoclot coagulation and platelet function analyzer or Sonoclot (Sienco Inc., Arvada, CO, United States)[30]. The fact that analyses are performed in whole blood allow for platelets and red cells to be accurately reflected[31] and the interactions between plasmatic and cellular components of hemostasis to be analyzed. The rate of fibrin formation, clot strength, and clot lysis[32,33] can be determined by all three instruments. Moreover, TEG provides a more adequate characterization of hypofibrinogenemia and hyperfibrinolysis[34] than the clot lysis time and global fibrinolysis capacity[35].

At present, ROTEM™ or TEG™ are valuable tools that aid in decision making in the context of direct therapeutic interventions in the actual case of bleeding[18]. TEG is in fact currently employed to guide therapy during liver transplantation in many centers[36-38] and is gaining importance in the assessment of liver-disease associated hemostasis alterations[39,40], with a possible role in predicting variceal rebleeding[41] and guiding pre-procedural transfusions[42]. Intense correction of coagulation abnormalities should be avoided, and rather transfusions and other therapeutic interventions should be tailored to each patient’s specific case, hopefully guided by point-of-care testing. This is very important in order to avoid risks associated with transfusions (acute lung injury, increase in portal pressure, etc.) and the increased risk of thromboembolism with, for example, the use of recombinant factor VIIa[43].

GASTROESOPHAGEAL VARICEAL BLEEDING

Gastroesophageal variceal bleeding (GEVB) constitutes a landmark in the natural history of a patient with cirrhosis, represents decompensated disease, and is one of the most feared complications. Mortality reaches 15%-20% during the 6 wk that follow an episode of variceal bleeding and is closely related to the severity of the underlying liver disease, ranging from 0% in patients in Child-Pugh class A to 40% in Child-Pugh class C patients[44,45]. Mortality significantly correlates with the presence of ascites or encephalopathy (OR = 4.18, 95%CI: 1.58-11.06; P = 0.004), the finding of fresh blood in the upper gastrointestinal tract at endoscopy (OR = 2.40, 95%CI: 1.28-4.51; P = 0.01), the presence of INR > 1.5 and/or PT prolonged > 3 s (OR = 3.06, 95%CI: 1.29-7.26; P = 0.01), in-patient status at the time of bleeding (OR = 7.14, 95%CI: 3.45-14.3; P < 0.001), and the presentation with hemodynamic shock (OR = 2.10, 95%CI: 1.07-4.13; P = 0.03), as demonstrated in a large United Kingdom study[46]. The principal determinants of GEVB are the severity of liver disease - as expressed by a Child Pugh class B or C, the presence of portal hypertension, variceal wall tension, and the characteristics of the varix wall[47-50]. In fact, anticoagulants at a prophylactic dose do not seem to increase the risk of GEVB, even in patients with advanced stages of liver disease, while actually preventing thrombotic events and decompensation[51].

Rebleeding occurs in approximately 26% of cases and results in a dramatic increase in mortality of up to 39%. This event correlates with the presence of INR > 1.5 and/or PT prolonged > 3 s (OR = 2.23, 95%CI: 1.22-4.07; P = 0.01), as well as with the presence of high risk endoscopic stigmata (OR = 1.74, 95%CI: 1.02-2.99, P = 0.04)[46]. Moreover, an underlying bacterial infection, followed by the circulatory release of endogenous heparin-like substances with established anti-Xa activity[52] and abnormal thromboelastographic curves, appears to be an important trigger for bleeding, for the persistence of bleeding, and correlates with the impossibility of controlling bleeding[41,53-56]. Supporting this concept, a consistent reduction of both mortality and frequency of early rebleeding has been achieved with the use of antibiotics following GEVB[57].

The risk of bleeding from variceal ulcers following endoscopic band ligation seems to depend exclusively on the severity of liver disease, and not the hemostatic status, as demonstrated by thromboelastographic parameters and traditional coagulation tests[58]. As in the occurrence of a spontaneous event of GEVB, the use of anticoagulants - may it be vitamin k antagonists or heparins - does not seem to increase the risk further[59,60].

NON-VARICEAL SPONTANEOUS BLEEDING
Upper non-variceal gastrointestinal bleeding

Non-variceal upper gastrointestinal bleeding is not an infrequent cause of morbidity and mortality in patients with cirrhosis. In a recently published cross-sectional nationwide study conducted in the United States, of 96887 hospital discharges for peptic ulcer bleeding, 3574 (3.69%) occurred in patients with cirrhosis[61]. Mortality of peptic ulcer bleeding was significantly higher in patients with cirrhosis (5.5%) vs in the group without cirrhosis (2%, P = 0.01), and decompensated cirrhosis was associated with a significantly higher mortality than that of patients with compensated cirrhosis (6.6% vs 3.9%; P = 0.01). Moreover, multivariate analysis demonstrated that the presence of cirrhosis independently increased mortality (adjusted odds ratio) 3.3; 95%CI: 2.2-4.9)[61]. A prospective, 10-year study analyzing patients admitted for non-variceal upper gastrointestinal bleeding showed that of 2217 patients with upper gastrointestinal bleeding, 1077 patients had non-variceal bleeding (48.7%) patients, and amongst these, 160 (14.8%) were patients with cirrhosis[62]. Of note, within the group of cirrhosis patients with non-variceal upper gastrointestinal bleeding, rebleeding occurred in 3 patients (1.9%), and in-hospital mortality was 13.75% (22 of 160 patients). Although deaths were due to reasons other than hypovolemia in 12 patients, and other causes of death included renal, hepatic, or respiratory failure, amongst others, the initial reason for hospitalization had been the bleeding episode[62].

Portal hypertensive gastropathy, which has been described in as many as 80%-90% of patients with cirrhosis[63,64], has been shown to correlate with severity of liver disease and to hepatic venous portal gradient in patients with cirrhosis[63,65]. Bleeding from portal hypertensive gastropathy most often leads to chronic anemia, but can also cause important blood losses over a short period of time. In a multi-center Italian study published on behalf of the New Italian Endoscopic Club for the Study and Treatment of Esophageal Varices, the prevalence of portal hypertensive gastropathy was 80% and was associated to the duration of liver disease, past medical history of endoscopic variceal slerotherapy, and with the presence and size of esophagogastric varices. During the follow-up period of 18 mo (± 8 mo), acute bleeding from portal hypertensive gastropathy was observed in 2.5% of patients (8 of 315 patients), with bleeding-related mortality rate of 12.5%, and chronic bleeding in 10.8% (34 patients)[64]. Treatment and prevention consist primarily in reducing portal pressure, principally with the use of non-selective beta-blockers[66], although treatment with other vasoactive drugs such as long-acting somatostatin, TIPS placement[67], argon plasma coagulation[68], and newer therapies such as hemospray[69] are increasingly being used.

Lower gastrointestinal bleeding

According to the study design, including the population analyzed, portal hypertensive colopathy has been reported to occur in 50%-80% of patients with cirrhosis, and is apparently more frequent in patients with ascites[70-72]. In a study analyzing 60 cirrhosis patients who underwent colonoscopy before undergoing upper endoscopic variceal band ligation, hemorrhoids, anorectal varices, and portal hypertensive colopathy were found in 37%, 40%, and 57% of patients, respectively[73]. A higher prevalence (66%) of portal hypertensive colopathy was found in a Japanese study analyzing endoscopic findings in 47 patients with cirrhosis who underwent colonoscopy for positive fecal occult blood (34%), melena (23%), iron deficiency anemia (10%), diarrhea (4%), abdominal pain (4%), and screening (10%), amongst other causes[74]. Although large, prospective studies are lacking, the presence of portal hypertensive colopathy appears to correlate with severity of liver disease, and an increase in portal hypertension, as that induced by endoscopic esophageal variceal band ligation, does not seem to worsen preexisting colopathy or induce the appearance of new lesions[73]. Whether portal hypertensive colopathy is associated with the degree of portal hypertension as determined by hepatic vein pressure gradient, is yet controversial, however[74,75].

Regarding the ano-rectal tract, rectal varices have been reported in 8% to 56% of patients with cirrhosis and portal hypertension[72,76,77]. Although hemorrhoids and polyps do not seem to occur more frequently in cirrhotics with respect to non-cirrhotic subjects undergoing colonoscopic evaluation[76], others hypothesize that the degree of portal hypertension and/or disease severity seems to be associated with hemorrhoids but not with rectal varices[78,79]. However, the improvement of bleeding rectal varices seems to point out a role for portal hypertension[80]. Moreover, although hematochezia has been reported[79], and a few cases of massive, fatal bleeding[81], life-endangering hemorrhage from the lower gastrointestinal tract due to complications of cirrhosis is relatively infrequent. Large, prospective studies are warranted in order to accurately determine the incidence and prevalence of these clinical entities, as well as their associated morbidity. Although studies which evaluate the best treatment options are lacking, reduction of portal hypertension with the use of non-selective beta-blockers and the employment of vasoactive agents such as somatostatin, octreotide and terlipressin, have demonstrated some benefit[82,83]. More recently, the use of argon plasma coagulation and hemospray have also been advocated[69,84].

Other bleeding sites

Minor but frequent bleeding in patients with cirrhosis seems to be more akin to that observed in patients with platelet defects than that observed in patients with hemophilia or other disorders that affect coagulation. Thus, aside from variceal bleeding, in which local factors, portal pressure and severity of liver disease play preponderant roles, manifestations of primary hemostasis defects are most frequently encountered in patients with cirrhosis: recurrent and prolonged epistaxis, gingivorrhagia, purpuric skin lesions, menometrorrhagia, and excessive bleeding after dental extractions or other surgical procedures. On the contrary, coagulation-related clinical manifestations such as intracerebral bleeding, deep muscle bleeding, and hemartrosis, are no more frequent in cirrhosis that they are in the general population. Although only very rarely epistaxis[85] and oral cavity bleeding[86] (gum bleeding and dental root bleeding) have been reported to be the cause of bleeding that endangers life, minor but repeated episodes are commonly encountered in cirrhosis.

PVT

PVT is the most common thrombotic event in patients with cirrhosis, and although its frequency is higher in patients with hepatic malignancy (approximately 35%[87], with reportedly 40% of these cases having histological confirmation of neoplastic thrombosis[88]), it is also common in patients with cirrhosis and without malignancy, with a prevalence of reportedly 0.6% to 26%. Moreover, a systematic review analyzing PVT in patients with cirrhosis who underwent liver transplantation found that of 25753 liver transplants, 2004 were performed in patients with PVT, for a prevalence of 9.7% ± 4.5%[89].

The most important risk factor for the development of PVT seems to be the severity of liver disease[90,91], with “paradoxically” a greater frequency of PVT when coagulation factors are lowest, as shown by traditional coagulation tests. Locally, venous stasis favors the development of thrombosis, and a prospective study revealed that reduced portal flow velocity was the only independent variable that correlated with the risk of developing PVT at 1 year follow-up[92], but this finding has not been univocally confirmed[93]. Elevated levels of FVIII have been correlated with PVT both in the presence and in the absence of concomitant cirrhosis[94,95], finding which was confirmed in a larger cohort study demonstrating that the odds ratio for PVT was 6.0 for patients with cirrhosis in whom FVIII levels were above 129 UI/dL[96]. Moreover, genetic thrombophilias have been found in up to 34% of patients with cirrhosis and PVT[24], which is why every patient who present this complication warrants complete thrombophilic screening.

Not only is this complication frequent, but its clinical presentation can be deadly in some cases; in a study analyzing newly diagnosed PVT in 79 patients with cirrhosis, in 39% the initial presentation was gastrointestinal bleeding (from esophagogastric varices or portal hypertensive gastropathy), and abdominal pain was the cardinal symptom in 18% of cases, amongst which 70% had intestinal infarction due to the extension of the thrombosis into the superior mesenteric vein[97]. Although recently it has been reported that PVT, when diagnosed during routine imaging screening in patients with cirrhosis, may not cause clinical deterioration and may even resolve spontaneously[98,99], a recently published systematic review revealed that the presence of non-neoplastic PVT at liver transplant entails a greater 30-d mortality after surgery when compared to patients without PVT (10.5% vs 7.7%, respectively (P = 0.01)[89]. Moreover, the presence of PVT at liver transplantation also increases the one-year mortality with respect to that of patients with patent portal vein (18.8% vs 15.3%, respectively (P < 0.001), and this is especially true for cases in which PVT is complete and extends into the superior mesenteric vein and the splenic vein.

DEEP VEIN THROMBOSIS AND VENOUS THROMBOEMBOLISM

It has been some time now since the publication of Northup and collaborators’ important study demonstrating that not only “coagulopathy” does not protect cirrhosis patients from life-threatening venous thromboembolic events, but that these patients are actually at a greater risk for these events[100]. Low albumin, surrogate of a greater severity of liver disease, was associated with the greatest risk. Although large, prospective population studies considering out-patient subjects with cirrhosis are needed, it seems that compared to the general population, the incidence of unprovoked deep vein thrombosis and pulmonary embolism (DVT/PE) is increased. In a large, prospective cohort study with case-control analysis of 6550 patients with venous thromboembolism, the presence of chronic liver disease was associated with PE (OR = 1.75, 95%CI: 0.91-3.36) and with DVT/PE combined (OR = 1.65, 95%CI: 0.97-2.82)[101]. Moreover, a large Danish population-based study showed that cirrhosis and liver disease were associated with a greater risk of venous thromboembolism (OR = 2.10) amongst 99000 patients with thromboembolism[102]. Thus, the incidence of DVT/PE in patients with cirrhosis has been reported to be between 0.5% to 8.1%[101-105].

Already deadly in the non-cirrhotic population, venous thromboembolism is associated with increased mortality in patients with compensated cirrhosis (OR = 2.16, 95%CI: 1.96-2.38) and those with decompensated cirrhosis (OR = 1.66, 95%CI: 1.47-1.87), with an in-hospital mortality for patients with venous thromboembolism of 16.8% and 18.6% for patients with compensated and decompensated cirrhosis, respectively[106]. Moreover, although the risk of venous thromboembolism is reduced with prophylactic anticoagulation, it is not annulled, as demonstrated in a recent study in which a higher than expected rate of venous thromboembolism occurred while on prophylaxis with unfractioned heparin or low molecular weight heparin[107].

Although guidelines do not yet provide recommendations regarding anticoagulation neither as prophylaxis nor as therapy, evidence has been accumulating supporting the efficacy and safety of such interventions[108]. Future studies, including the use of new anticoagulants such as direct thrombin inhibitors are warranted to establish which patients will benefit most from treatment, the time after which the risk-benefit ratio becomes inclined towards a greater risk, the most adequate dose, the choice of anticoagulant, and the means of monitoring of anticoagulation[109].

In conclusion, the pro-hemorrhagic and pro-thrombotic alterations of patients with cirrhosis correlate principally with the severity of liver disease, that determine a reduction in both pro- and anti-coagulant factors and an increased derangement of physiological blood flow causing portal hypertension and localized venous stasis. Routine laboratory tests do not reliably predict the risk of bleeding and there is yet no optimal management strategy to foretell potential bleeding complications. Although point-of-care testing is slowly being introduced to avoid intensive correction of coagulation parameters and better guide therapeutic decisions tailored to each patient’s clinical and hemostatic status, more studies are clearly needed to determine the actual role of these new tools. A myriad of both thrombotic and bleeding complications can aggravate the clinical course of cirrhosis, but as for frequency and gravity, GEVB remains probably the most feared event. However, thrombotic complications should also be considered, especially in more advanced stages of disease, when anticoagulation prophylaxis and therapy might represent the less traveled, but proper, road to follow.

Footnotes

P- Reviewer: Otto G, Procopet B S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ

References
1.  Huber K, Kirchheimer JC, Korninger C, Binder BR. Hepatic synthesis and clearance of components of the fibrinolytic system in healthy volunteers and in patients with different stages of liver cirrhosis. Thromb Res. 1991;62:491-500.  [PubMed]  [DOI]
2.  Simpson AJ, Booth NA, Moore NR, Bennett B. The platelet and plasma pools of plasminogen activator inhibitor (PAI-1) vary independently in disease. Br J Haematol. 1990;75:543-548.  [PubMed]  [DOI]
3.  Leebeek FW, Kluft C, Knot EA, de Maat MP, Wilson JH. A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis. Gastroenterology. 1991;101:1382-1390.  [PubMed]  [DOI]
4.  Violi F, Leo R, Basili S, Ferro D, Cordova C, Balsano F. Association between prolonged bleeding time and gastrointestinal hemorrhage in 102 patients with liver cirrhosis: results of a retrospective study. Haematologica. 1994;79:61-65.  [PubMed]  [DOI]
5.  Páramo JA, Rocha E. Hemostasis in advanced liver disease. Semin Thromb Hemost. 1993;19:184-190.  [PubMed]  [DOI]
6.  Vukovich T, Teufelsbauer H, Fritzer M, Kreuzer S, Knoflach P. Hemostasis activation in patients with liver cirrhosis. Thromb Res. 1995;77:271-278.  [PubMed]  [DOI]
7.  Wilde JT, Kitchen S, Kinsey S, Greaves M, Preston FE. Plasma D-dimer levels and their relationship to serum fibrinogen/fibrin degradation products in hypercoagulable states. Br J Haematol. 1989;71:65-70.  [PubMed]  [DOI]
8.  Ben-Ari Z, Osman E, Hutton RA, Burroughs AK. Disseminated intravascular coagulation in liver cirrhosis: fact or fiction? Am J Gastroenterol. 1999;94:2977-2982.  [PubMed]  [DOI]
9.  Colucci M, Binetti BM, Branca MG, Clerici C, Morelli A, Semeraro N, Gresele P. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology. 2003;38:230-237.  [PubMed]  [DOI]
10.  Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy KR, Tripodi A, Sanyal AJ. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology. 2006;44:1039-1046.  [PubMed]  [DOI]
11.  Tripodi A, Primignani M, Mannucci PM. Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged. Intern Emerg Med. 2010;5:7-12.  [PubMed]  [DOI]
12.  Lisman T, Leebeek FW, Mosnier LO, Bouma BN, Meijers JC, Janssen HL, Nieuwenhuis HK, De Groot PG. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology. 2001;121:131-139.  [PubMed]  [DOI]
13.  Bennani-Baiti N, Daw HA. Primary hyperfibrinolysis in liver disease: a critical review. Clin Adv Hematol Oncol. 2011;9:250-252.  [PubMed]  [DOI]
14.  Prisco D, Grifoni E. The role of D-dimer testing in patients with suspected venous thromboembolism. Semin Thromb Hemost. 2009;35:50-59.  [PubMed]  [DOI]
15.  Violi F, Ferro D, Basili S, Quintarelli C, Musca A, Cordova C, Balsano F. Hyperfibrinolysis resulting from clotting activation in patients with different degrees of cirrhosis. The CALC Group. Coagulation Abnormalities in Liver Cirrhosis. Hepatology. 1993;17:78-83.  [PubMed]  [DOI]
16.  Tacke F, Fiedler K, von Depka M, Luedde T, Hecker H, Manns MP, Ganser A, Trautwein C. Clinical and prognostic role of plasma coagulation factor XIII activity for bleeding disorders and 6-year survival in patients with chronic liver disease. Liver Int. 2006;26:173-181.  [PubMed]  [DOI]
17.  Kłoczko J, Wereszczyńska U, Wojtukiewicz M, Gybryelewicz A, Bielawiec M. Fibrin stabilization, factor XIII transamidase activity and subunits “A” and “B” concentration in plasma of patients with liver cirrhosis. Folia Haematol Int Mag Klin Morphol Blutforsch. 1986;113:539-544.  [PubMed]  [DOI]
18.  Saner FH, Gieseler RK, Akız H, Canbay A, Görlinger K. Delicate balance of bleeding and thrombosis in end-stage liver disease and liver transplantation. Digestion. 2013;88:135-144.  [PubMed]  [DOI]
19.  Laffi G, Marra F, Gresele P, Romagnoli P, Palermo A, Bartolini O, Simoni A, Orlandi L, Selli ML, Nenci GG. Evidence for a storage pool defect in platelets from cirrhotic patients with defective aggregation. Gastroenterology. 1992;103:641-646.  [PubMed]  [DOI]
20.  Peck-Radosavljevic M. Thrombocytopenia in liver disease. Can J Gastroenterol. 2000;14 Suppl D:60D-66D.  [PubMed]  [DOI]
21.  Ordinas A, Escolar G, Cirera I, Viñas M, Cobo F, Bosch J, Terés J, Rodés J. Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: studies under flow conditions. Hepatology. 1996;24:1137-1142.  [PubMed]  [DOI]
22.  Goulis J, Chau TN, Jordan S, Mehta AB, Watkinson A, Rolles K, Burroughs AK. Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation. Gut. 1999;44:754-758.  [PubMed]  [DOI]
23.  Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, Leebeek FW. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44:53-61.  [PubMed]  [DOI]
24.  Amitrano L, Brancaccio V, Guardascione MA, Margaglione M, Iannaccone L, D’Andrea G, Marmo R, Ames PR, Balzano A. Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis. Hepatology. 2000;31:345-348.  [PubMed]  [DOI]
25.  Segal JB, Dzik WH. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion. 2005;45:1413-1425.  [PubMed]  [DOI]
26.  Blake JC, Sprengers D, Grech P, McCormick PA, McIntyre N, Burroughs AK. Bleeding time in patients with hepatic cirrhosis. BMJ. 1990;301:12-15.  [PubMed]  [DOI]
27.  Violi F, Leo R, Vezza E, Basili S, Cordova C, Balsano F. Bleeding time in patients with cirrhosis: relation with degree of liver failure and clotting abnormalities. C.A.L.C. Group. Coagulation Abnormalities in Cirrhosis Study Group. J Hepatol. 1994;20:531-536.  [PubMed]  [DOI]
28.  Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol. 2010;52:355-361.  [PubMed]  [DOI]
29.  Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005;41:553-558.  [PubMed]  [DOI]
30.  Saxena P, Bihari C, Rastogi A, Agarwal S, Anand L, Sarin SK. Sonoclot signature analysis in patients with liver disease and its correlation with conventional coagulation studies. Adv Hematol. 2013;2013:237351.  [PubMed]  [DOI]
31.  Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg. 2008;106:1366-1375.  [PubMed]  [DOI]
32.  Lisman T, Porte RJ, Leebeek FW, Caldwell SH. Methodological issues with coagulation testing in patients with liver disease. J Thromb Haemost. 2006;4:2061-2062.  [PubMed]  [DOI]
33.  Lang T, Johanning K, Metzler H, Piepenbrock S, Solomon C, Rahe-Meyer N, Tanaka KA. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia. Anesth Analg. 2009;108:751-758.  [PubMed]  [DOI]
34.  Tripodi A. Tests of coagulation in liver disease. Clin Liver Dis. 2009;13:55-61.  [PubMed]  [DOI]
35.  Rijken DC, Kock EL, Guimarães AH, Talens S, Darwish Murad S, Janssen HL, Leebeek FW. Evidence for an enhanced fibrinolytic capacity in cirrhosis as measured with two different global fibrinolysis tests. J Thromb Haemost. 2012;10:2116-2122.  [PubMed]  [DOI]
36.  Krzanicki D, Sugavanam A, Mallett S. Intraoperative hypercoagulability during liver transplantation as demonstrated by thromboelastography. Liver Transpl. 2013;19:852-861.  [PubMed]  [DOI]
37.  Salooja N, Perry DJ. Thrombelastography. Blood Coagul Fibrinolysis. 2001;12:327-337.  [PubMed]  [DOI]
38.  Wang SC, Shieh JF, Chang KY, Chu YC, Liu CS, Loong CC, Chan KH, Mandell S, Tsou MY. Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial. Transplant Proc. 2010;42:2590-2593.  [PubMed]  [DOI]
39.  Ben-Ari Z, Panagou M, Patch D, Bates S, Osman E, Pasi J, Burroughs A. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J Hepatol. 1997;26:554-559.  [PubMed]  [DOI]
40.  Senzolo M, Cholongitas E, Thalheimer U, Riddell A, Agarwal S, Mallett S, Ferronato C, Burroughs AK. Heparin-like effect in liver disease and liver transplantation. Clin Liver Dis. 2009;13:43-53.  [PubMed]  [DOI]
41.  Chau TN, Chan YW, Patch D, Tokunaga S, Greenslade L, Burroughs AK. Thrombelastographic changes and early rebleeding in cirrhotic patients with variceal bleeding. Gut. 1998;43:267-271.  [PubMed]  [DOI]
42.  De Pietri L, Bianchini M, Montalti R, De Maria N, Di Maira T, Begliomini B, Gerunda G, Villa E. Thrombelastography (TEG) decreases blood products requirement before invasive procedures in cirrhotic patients with coagulation tests derangement. A randomized controlled trial. Dig Liver Dis. 2014;46:e5-e6.  [PubMed]  [DOI]
43.  Bendtsen F, D’Amico G, Rusch E, de Franchis R, Andersen PK, Lebrec D, Thabut D, Bosch J. Effect of recombinant Factor VIIa on outcome of acute variceal bleeding: an individual patient based meta-analysis of two controlled trials. J Hepatol. 2014;61:252-259.  [PubMed]  [DOI]
44.  Villanueva C, Piqueras M, Aracil C, Gómez C, López-Balaguer JM, Gonzalez B, Gallego A, Torras X, Soriano G, Sáinz S. A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding. J Hepatol. 2006;45:560-567.  [PubMed]  [DOI]
45.  Abraldes JG, Villanueva C, Bañares R, Aracil C, Catalina MV, Garci A-Pagán JC, Bosch J. Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy. J Hepatol. 2008;48:229-236.  [PubMed]  [DOI]
46.  Jairath V, Rehal S, Logan R, Kahan B, Hearnshaw S, Stanworth S, Travis S, Murphy M, Palmer K, Burroughs A. Acute variceal haemorrhage in the United Kingdom: patient characteristics, management and outcomes in a nationwide audit. Dig Liver Dis. 2014;46:419-426.  [PubMed]  [DOI]
47.  Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navasa M, Alberts J, Rodes J, Fischer R, Bermann M. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology. 1990;99:1401-1407.  [PubMed]  [DOI]
48.  Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353:2254-2261.  [PubMed]  [DOI]
49.  D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology. 2006;131:1611-1624.  [PubMed]  [DOI]
50.  Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology. 1985;5:419-424.  [PubMed]  [DOI]
51.  Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S, Tata C, Zecchini R, Gitto S, Petta S. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012;143:1253-1260.e1-4.  [PubMed]  [DOI]
52.  Zambruni A, Thalheimer U, Coppell J, Riddell A, Mancuso A, Leandro G, Perry D, Burroughs AK. Endogenous heparin-like activity detected by anti-Xa assay in infected cirrhotic and non-cirrhotic patients. Scand J Gastroenterol. 2004;39:830-836.  [PubMed]  [DOI]
53.  Goulis J, Patch D, Burroughs AK. Bacterial infection in the pathogenesis of variceal bleeding. Lancet. 1999;353:139-142.  [PubMed]  [DOI]
54.  Goulis J, Armonis A, Patch D, Sabin C, Greenslade L, Burroughs AK. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology. 1998;27:1207-1212.  [PubMed]  [DOI]
55.  Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK. Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study. J Hepatol. 2002;37:463-470.  [PubMed]  [DOI]
56.  Senzolo M, Coppell J, Cholongitas E, Riddell A, Triantos CK, Perry D, Burroughs AK. The effects of glycosaminoglycans on coagulation: a thromboelastographic study. Blood Coagul Fibrinolysis. 2007;18:227-236.  [PubMed]  [DOI]
57.  Hou MC, Lin HC, Liu TT, Kuo BI, Lee FY, Chang FY, Lee SD. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology. 2004;39:746-753.  [PubMed]  [DOI]
58.  Vieira da Rocha EC, D’Amico EA, Caldwell SH, Flores da Rocha TR, Soares E Silva CS, Dos Santos Bomfim V, Felga G, Barbosa WF, Kassab F, Polli DA. A prospective study of conventional and expanded coagulation indices in predicting ulcer bleeding after variceal band ligation. Clin Gastroenterol Hepatol. 2009;7:988-993.  [PubMed]  [DOI]
59.  Senzolo M, M Sartori T, Rossetto V, Burra P, Cillo U, Boccagni P, Gasparini D, Miotto D, Simioni P, Tsochatzis E. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis. Liver Int. 2012;32:919-927.  [PubMed]  [DOI]
60.  Bajaj JS, Franco J. Endoscopic band ligation of esophageal varices in patients on anticoagulation. J Clin Gastroenterol. 2008;42:782-785.  [PubMed]  [DOI]
61.  Venkatesh PG, Parasa S, Njei B, Sanaka MR, Navaneethan U. Increased mortality with peptic ulcer bleeding in patients with both compensated and decompensated cirrhosis. Gastrointest Endosc. 2014;79:605-614.e3.  [PubMed]  [DOI]
62.  González-González JA, García-Compean D, Vázquez-Elizondo G, Garza-Galindo A, Jáquez-Quintana JO, Maldonado-Garza H. Nonvariceal upper gastrointestinal bleeding in patients with liver cirrhosis. Clinical features, outcomes and predictors of in-hospital mortality. A prospective study. Ann Hepatol. 2011;10:287-295.  [PubMed]  [DOI]
63.  Kim MY, Choi H, Baik SK, Yea CJ, Won CS, Byun JW, Park SY, Kwon YH, Kim JW, Kim HS. Portal hypertensive gastropathy: correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci. 2010;55:3561-3567.  [PubMed]  [DOI]
64.  Primignani M, Carpinelli L, Preatoni P, Battaglia G, Carta A, Prada A, Cestari R, Angeli P, Gatta A, Rossi A. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC). Gastroenterology. 2000;119:181-187.  [PubMed]  [DOI]
65.  Iwao T, Toyonaga A, Sumino M, Takagi K, Oho K, Nishizono M, Ohkubo K, Inoue R, Sasaki E, Tanikawa K. Portal hypertensive gastropathy in patients with cirrhosis. Gastroenterology. 1992;102:2060-2065.  [PubMed]  [DOI]
66.  Ripoll C, Garcia-Tsao G. Management of gastropathy and gastric vascular ectasia in portal hypertension. Clin Liver Dis. 2010;14:281-295.  [PubMed]  [DOI]
67.  Kamath PS, Lacerda M, Ahlquist DA, McKusick MA, Andrews JC, Nagorney DA. Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis. Gastroenterology. 2000;118:905-911.  [PubMed]  [DOI]
68.  Herrera S, Bordas JM, Llach J, Ginès A, Pellisé M, Fernández-Esparrach G, Mondelo F, Mata A, Cárdenas A, Castells A. The beneficial effects of argon plasma coagulation in the management of different types of gastric vascular ectasia lesions in patients admitted for GI hemorrhage. Gastrointest Endosc. 2008;68:440-446.  [PubMed]  [DOI]
69.  Smith LA, Morris AJ, Stanley AJ. The use of hemospray in portal hypertensive bleeding; a case series. J Hepatol. 2014;60:457-460.  [PubMed]  [DOI]
70.  Chen LS, Lin HC, Lee FY, Hou MC, Lee SD. Portal hypertensive colopathy in patients with cirrhosis. Scand J Gastroenterol. 1996;31:490-494.  [PubMed]  [DOI]
71.  Ganguly S, Sarin SK, Bhatia V, Lahoti D. The prevalence and spectrum of colonic lesions in patients with cirrhotic and noncirrhotic portal hypertension. Hepatology. 1995;21:1226-1231.  [PubMed]  [DOI]
72.  Bresci G, Gambardella L, Parisi G, Federici G, Bertini M, Rindi G, Metrangolo S, Tumino E, Bertoni M, Cagno MC. Colonic disease in cirrhotic patients with portal hypertension: an endoscopic and clinical evaluation. J Clin Gastroenterol. 1998;26:222-227.  [PubMed]  [DOI]
73.  Misra SP, Misra V, Dwivedi M. Effect of esophageal variceal band ligation on hemorrhoids, anorectal varices, and portal hypertensive colopathy. Endoscopy. 2002;34:195-198.  [PubMed]  [DOI]
74.  Ito K, Shiraki K, Sakai T, Yoshimura H, Nakano T. Portal hypertensive colopathy in patients with liver cirrhosis. World J Gastroenterol. 2005;11:3127-3130.  [PubMed]  [DOI]
75.  Yamakado S, Kanazawa H, Kobayashi M. Portal hypertensive colopathy: endoscopic findings and the relation to portal pressure. Intern Med. 1995;34:153-157.  [PubMed]  [DOI]
76.  Scandalis N, Archimandritis A, Kastanas K, Spiliadis C, Delis B, Manika Z. Colonic findings in cirrhotics with portal hypertension. A prospective colonoscopic and histological study. J Clin Gastroenterol. 1994;18:325-328; discussion 329.  [PubMed]  [DOI]
77.  Chawla Y, Dilawari JB. Anorectal varices--their frequency in cirrhotic and non-cirrhotic portal hypertension. Gut. 1991;32:309-311.  [PubMed]  [DOI]
78.  Rabinovitz M, Schade RR, Dindzans VJ, Belle SH, Van Thiel DH, Gavaler JS. Colonic disease in cirrhosis. An endoscopic evaluation in 412 patients. Gastroenterology. 1990;99:195-199.  [PubMed]  [DOI]
79.  Goenka MK, Kochhar R, Nagi B, Mehta SK. Rectosigmoid varices and other mucosal changes in patients with portal hypertension. Am J Gastroenterol. 1991;86:1185-1189.  [PubMed]  [DOI]
80.  Yeşilkaya Y, Çil B, Peynircioğlu B, Şimşek H. Successful treatment with transjugular intrahepatic portosystemic shunt (TIPS) of recurrent massive rectal bleeding due to portal hypertension: case report. Turk J Gastroenterol. 2013;24:363-366.  [PubMed]  [DOI]
81.  Wilson SE, Stone RT, Christie JP, Passaro E. Massive lower gastrointestinal bleeding from intestinal varices. Arch Surg. 1979;114:1158-1161.  [PubMed]  [DOI]
82.  Bini EJ, Lascarides CE, Micale PL, Weinshel EH. Mucosal abnormalities of the colon in patients with portal hypertension: an endoscopic study. Gastrointest Endosc. 2000;52:511-516.  [PubMed]  [DOI]
83.  Sugano S, Nishio M, Makino H, Suzuki T. Relationship of portal pressure and colorectal vasculopathy in patients with cirrhosis. Dig Dis Sci. 1999;44:149-154.  [PubMed]  [DOI]
84.  Gad YZ, Zeid AA. Portal hypertensive colopathy and haematochezia in cirrhotic patients: an endoscopic study. Arab J Gastroenterol. 2011;12:184-188.  [PubMed]  [DOI]
85.  Johal SS, Austin AS, Ryder SD. Epistaxis: an overlooked cause of massive haematemesis in cirrhosis. BMJ. 2003;326:440-441.  [PubMed]  [DOI]
86.  Abouelalaa K, Nadaud J, Caumes D, Esnaut P, Favier JC. [Haemorrhagic shock following a dental bleeding in a cirrhotic patient]. Ann Fr Anesth Reanim. 2007;26:714-715.  [PubMed]  [DOI]
87.  Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodés J. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421-430.  [PubMed]  [DOI]
88.  Sotiropoulos GC, Radtke A, Schmitz KJ, Molmenti EP, Schroeder T, Saner FH, Baba HA, Fouzas I, Broelsch CE, Malagó M. Liver transplantation in the setting of hepatocellular carcinoma and portal vein thrombosis: a challenging dilemma? Dig Dis Sci. 2008;53:1994-1999.  [PubMed]  [DOI]
89.  Rodríguez-Castro KI, Porte RJ, Nadal E, Germani G, Burra P, Senzolo M. Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review. Transplantation. 2012;94:1145-1153.  [PubMed]  [DOI]
90.  Yerdel MA, Gunson B, Mirza D, Karayalçin K, Olliff S, Buckels J, Mayer D, McMaster P, Pirenne J. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation. 2000;69:1873-1881.  [PubMed]  [DOI]
91.  Egawa H, Tanaka K, Kasahara M, Takada Y, Oike F, Ogawa K, Sakamoto S, Kozaki K, Taira K, Ito T. Single center experience of 39 patients with preoperative portal vein thrombosis among 404 adult living donor liver transplantations. Liver Transpl. 2006;12:1512-1518.  [PubMed]  [DOI]
92.  Zocco MA, Di Stasio E, De Cristofaro R, Novi M, Ainora ME, Ponziani F, Riccardi L, Lancellotti S, Santoliquido A, Flore R. Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J Hepatol. 2009;51:682-689.  [PubMed]  [DOI]
93.  Francoz C, Belghiti J, Vilgrain V, Sommacale D, Paradis V, Condat B, Denninger MH, Sauvanet A, Valla D, Durand F. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut. 2005;54:691-697.  [PubMed]  [DOI]
94.  Martinelli I. von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis. Semin Hematol. 2005;42:49-55.  [PubMed]  [DOI]
95.  Fimognari FL, De Santis A, Piccheri C, Moscatelli R, Gigliotti F, Vestri A, Attili A, Violi F. Evaluation of D-dimer and factor VIII in cirrhotic patients with asymptomatic portal venous thrombosis. J Lab Clin Med. 2005;146:238-243.  [PubMed]  [DOI]
96.  Martinelli I, Primignani M, Aghemo A, Reati R, Bucciarelli P, Fabris F, Battaglioli T, Dell’Era A, Mannucci PM. High levels of factor VIII and risk of extra-hepatic portal vein obstruction. J Hepatol. 2009;50:916-922.  [PubMed]  [DOI]
97.  Amitrano L, Guardascione MA, Brancaccio V, Margaglione M, Manguso F, Iannaccone L, Grandone E, Balzano A. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol. 2004;40:736-741.  [PubMed]  [DOI]
98.  Nery F, Chevret S, Condat B, de Raucourt E, Boudaoud L, Rautou PE, Plessier A, Roulot D, Chaffaut C, Bourcier V. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology. 2015;61:660-667.  [PubMed]  [DOI]
99.  Girleanu I, Stanciu C, Cojocariu C, Boiculese L, Singeap AM, Trifan A. Natural course of nonmalignant partial portal vein thrombosis in cirrhotic patients. Saudi J Gastroenterol. 2014;20:288-292.  [PubMed]  [DOI]
100.  Northup PG, McMahon MM, Ruhl AP, Altschuler SE, Volk-Bednarz A, Caldwell SH, Berg CL. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006;101:1524-1528; quiz 1680.  [PubMed]  [DOI]
101.  Huerta C, Johansson S, Wallander MA, García Rodríguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med. 2007;167:935-943.  [PubMed]  [DOI]
102.  Søgaard KK, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol. 2009;104:96-101.  [PubMed]  [DOI]
103.  García-Fuster MJ, Abdilla N, Fabiá MJ, Fernández C, Oliver V. [Venous thromboembolism and liver cirrhosis]. Rev Esp Enferm Dig. 2008;100:259-262.  [PubMed]  [DOI]
104.  Gulley D, Teal E, Suvannasankha A, Chalasani N, Liangpunsakul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci. 2008;53:3012-3017.  [PubMed]  [DOI]
105.  Ali M, Ananthakrishnan AN, McGinley EL, Saeian K. Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. Dig Dis Sci. 2011;56:2152-2159.  [PubMed]  [DOI]
106.  Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol. 2010;8:800-805.  [PubMed]  [DOI]
107.  Intagliata NM, Henry ZH, Shah N, Lisman T, Caldwell SH, Northup PG. Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding. Liver Int. 2014;34:26-32.  [PubMed]  [DOI]
108.  Rodriguez-Castro KI, Simioni P, Burra P, Senzolo M. Anticoagulation for the treatment of thrombotic complications in patients with cirrhosis. Liver Int. 2012;32:1465-1476.  [PubMed]  [DOI]
109.  Rodriguez-Castro KI. Anticoagulation for portal vein thrombosis in cirrhosis - Response to Naeshiro and collaborators. Hepatol Res. 2015;Epub ahead of print.  [PubMed]  [DOI]