• chronic liver failure
• cirrhosis
• consumption coagulopathy
• disseminated intravascular coagulation

• Humans
• Disseminated Intravascular Coagulation/blood
• Disseminated Intravascular Coagulation/diagnosis
• Disseminated Intravascular Coagulation/etiology
• Liver Cirrhosis/blood
• Liver Cirrhosis/complications
• Liver Cirrhosis/diagnosis
• Blood Coagulation
• Hemostasis
• Fibrin Fibrinogen Degradation Products/metabolism

• Advanced cirrhosis
• Ascites
• D-dimers

• Humans
• Fibrin Fibrinogen Degradation Products/analysis
• Fibrin Fibrinogen Degradation Products/metabolism
• Liver Cirrhosis/blood
• Liver Cirrhosis/complications
• Liver Cirrhosis/diagnosis
• Biomarkers/blood
• Venous Thromboembolism/blood
• Venous Thromboembolism/diagnosis
• Venous Thromboembolism/etiology
• Disseminated Intravascular Coagulation/diagnosis
• Disseminated Intravascular Coagulation/blood
• Disseminated Intravascular Coagulation/etiology

• Agreement analysis
• Hemodynamic monitoring
• Liver transplantation
• PiCCO
• Pulmonary artery catheterization
• Trending ability.

• Liver Transplantation/methods
• Humans
• Catheterization, Swan-Ganz/methods
• Cardiac Output/physiology
• Male
• Middle Aged
• Female
• Hemodynamics/physiology
• Monitoring, Intraoperative/methods
• Aged
• Adult
• Pulmonary Artery/physiology

• bleeding
• cirrhosis
• liver disease
• thrombosis
• viscoelastometry

In blood vessels there is a balance between clot formation and its dissolution. Fibrinolysis normally allows the breakdown of blood clots during the healing of injured blood vessels. This process is mediated by the activation of a blood enzyme (plasmin) which breaks down a meshed protein (fibrin) which holds blood clots at the site of the vessel injury. In some diseases, the activation of plasmin becomes excessive, leading to bleeding tendencies (hyperfibrinolysis). Under normal conditions, abdominal and thoracic cavities are filled with a small amount of fluid deriving from the blood. The results of recent studies have shown that, in dogs, all types of pathologic intracavitary fluids have an increased fibrinolytic activity. This increased fibrinolytic activity is also present in their blood, in some cases reaching a hyperfibrinolytic state. Hyperfibrinolysis and bleeding tendencies have also been documented in cardiopathic dogs with ascites. The latter result is surprising considering that thrombotic events are commonly documented in humans and cats with some cardiac diseases.

Physiologic fibrinolysis is a localized process in which stable fibrin strands are broken down by plasmin in response to thrombosis. Plasmin activation can also take place separately from the coagulation process, resulting in pathologic fibrinolysis. When plasmin activation exceeds the neutralizing capacity of plasmin inhibitors, severe bleeding can potentially take place. Although the processes which regulate coagulation and fibrinolysis in the blood are well known, it is less clear as to what extent the same processes take place in the body cavities and whether they influence systemic hemostasis. The results of the studies herein cited demonstrate that coagulation followed by fibrinogenolytic/fibrinolytic activity takes place in all kinds of canine ascitic and pleural fluids. Moreover, systemic clotting abnormalities suggesting primary fibrinolysis/primary hyperfibrinolysis (i.e., elevated plasma fibrin/fibrinogen degradation products [FDPs] and normal D-dimer concentrations with fibrinogen concentrations ≤ 100 mg/dL or above this cut-off, respectively) occur in dogs with intracavitary effusion. Enhanced fibrinolytic activity in dogs with intracavitary effusion can also be detected using rotational thromboelastometry (ROTEM), although the degree of agreement between ROTEM and FDPs, D-dimer and fibrinogen concentrations is poor. Finally, contrary to the thrombotic events commonly documented in some humans and cats with cardiac diseases, bleeding tendencies due to primary fibrinolysis/primary hyperfibrinolysis have been documented in dogs with cardiogenic ascites.

• Fibrinolysis
• heart disease
• oedema
• thrombosis

• Animals
• Cat Diseases/epidemiology
• Cats
• Cross-Sectional Studies
• Heart Diseases/veterinary
• Heart Failure/complications
• Heart Failure/veterinary
• Pleural Effusion/epidemiology
• Pleural Effusion/veterinary
• Pulmonary Edema/complications
• Pulmonary Edema/veterinary
• Thromboembolism/epidemiology
• Thromboembolism/veterinary

Von-Willebrand factor (vWF) disposes certain prognostic value in patients with liver cirrhosis, but its relation to other prognostic indicators has not been fully investigated.

To analyze the relation between vWF and other prognostic indicators in cirrhotic patients and to evaluate its prognostic value for mortality.

This analytic prospective study was carried out in a tertiary center and initially enrolled 71 patients with liver cirrhosis and portal hypertension. It analyzed the relation between vWF and the stage of the disease and several inflammatory and prognostic indicators. The prospective analysis, performed on a sample of 63 patients, evaluated the association between the selected variables [vWF, Model for End-stage Liver Disease (MELD) score, C-reactive protein (CRP), ferritin, vitamin D, activated partial thromboplastin time, thrombin time, D-dimer concentration] and the survival time as well as their predictive value in terms of 3-mo, 6-mo and 1-year mortality.

vWF was significantly higher in patients with higher Child-Turcotte-Pugh class (P = 0.0045), MELD group (P = 0.0057), ferritin group (P = 0.0278), and D-dimer concentration (P = 0.0232). vWF significantly correlated with D-dimer concentration, ferritin, CRP, International Normalized Ratio, and MELD, Child-Turcotte-Pugh, Sequential Organ Failure Assessment, and CLIF-consortium organ failure (CLIF-C OF) scores. vWF, MELD score, and CRP were significantly associated with death and were significant predictors of 3-mo, 6-mo, and 1-year mortality. Each vWF unit significantly increased the probability for 3-mo mortality by 1.005 times (P = 0.008), for 6-mo mortality by 1.006 times (P = 0.005), and for 1-year mortality by 1.007 times (P = 0.002). There was no significant difference between the diagnostic performance of vWF and MELD score and also between vWF and CRP regarding the 3-mo, 6-mo, and 1-year mortality.

In patients with liver cirrhosis, vWF is significantly related to other prognostic indicators and is a significant predictor of 3-mo, 6-mo, and 1-year mortality similar to MELD score and CRP.

• von-Willebrand factor
• Cirrhosis
• Mortality
• C-reactive protein
• D-dimer

Coagulation and fibrinolysis disorders are major prognostic factors in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients. Here, we aimed to clarify the role of disseminated intravascular coagulation (DIC) scores in predicting HBV-ACLF patient prognosis. We assessed the DIC score from HBV-ACLF patients at Huashan Hospital in Shanghai, China from June 2013 to May 2021 and evaluated it in relation to short-term mortality, clinical course, and infection. A novel prognostic scoring model was proposed based on DIC scores. A total of 163 transplant-free HBV-ACLF patients were enrolled. DIC scores were higher in non-survivors than survivors (6 vs. 4, P = 0.000) and were independently associated with short-term mortality [hazard ratio (HR): 1.397, 95% confidence interval (95% CI): 1.040–1.875, P = 0.026]. DIC scores were associated with ACLF grade, clinical course, and infection. Moreover, they were correlated with model for end-stage liver disease (MELD) scores (r = 0.521, P < 0.001). The area under the receiver operating curve (auROC) of CLIF-C OF-DICs [a novel prognostic score based on age, DIC score, and Chronic liver failure-consortium organ function score (CLIF-C OFs)] for 90-day mortality was 0.936, which was higher than six other generic prognostic scoring models. These results were confirmed in a validation cohort (n = 82). In conclusion, elevated DIC score is associated with poor prognosis in HBV-ACLF patients, and can be used jointly with CLIF-C OFs to improve the accuracy of prognosis prediction.

• National Major Science and Technology Projects of China
• National Natural Science Foundation of China
• Shanghai Shen Kang Hospital Development Center

• D-dimer
• ascites
• concentrated ascites reinfusion therapy
• deep vein thrombosis-pulmonary embolism
• ovarian cancer

• Children
• Fibrinolysis
• Hypercoagulability
• Idiopathic nephrotic syndrome
• Rotational thromboelastometry

• Ascites
• Fibrinolysis
• Liver
• Rotational thromboelastometry Cirrhosis

Prognostic models of cirrhosis underestimate disease severity for patients with cirrhosis and ascites. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein linked to hepatic neoangiogenesis and fibrogenesis. We investigated ascites MFAP4 as a predictor of transplant-free survival in patients with cirrhosis and ascites.

A dual-centre observational study of patients with cirrhosis and ascites recruited consecutively in relation to a paracentesis was carried out. Patients were followed up for 1 year, until death or liver transplantation (LTx). Ascites MFAP4 was tested with the model for end-stage liver disease (MELD-Na), CLIF Consortium Acute Decompensation (CLIF-C AD), and Child-Pugh score in Cox regression models.

Ninety-three patients requiring paracentesis were included. Median ascites MFAP4 was 29.7 U/ml [22.3–41.3], and MELD-Na was 19 [16–23]. A low MELD-Na score (<20) was observed in 49 patients (53%). During follow-up, 20 patients died (22%), and 6 received LTx (6%). High ascites MFAP4 (>29.7 U/ml) was associated with 1-year transplant-free survival (p = 0.002). In Cox regression, ascites MFAP4 and MELD-Na independently predicted 1-year transplant-free survival (hazard ratio [HR] = 0.97, p = 0.03, and HR = 1.08, p = 0.01, respectively). Ascites MFAP4 and CLIF-C AD also predicted survival independently (HR = 0.96, p = 0.02, and HR = 1.05, p = 0.03, respectively), whereas only ascites MFAP4 did, controlling for the Child-Pugh score (HR = 0.97, p = 0.03, and HR = 1.18, p = 0.16, respectively). For patients with MELD-Na <20, ascites MFAP4 but not ascites protein predicted 1-year transplant-free survival (HR 0.91, p = 0.02, and HR = 0.94, p = 0.17, respectively).

Ascites MFAP4 predicts 1-year transplant-free survival in patients with cirrhosis and ascites. In patients with low MELD-Na scores, ascites MFAP4, but not total ascites protein, significantly predicted 1-year transplant-free survival.

Patients with cirrhosis who have fluid in the abdomen, ascites, are at an increased risk of death and in need for liver transplantation. Our study identified patients with ascites and a poor prognosis by measuring microfibrillar associated protein 4 (MFAP4), a protein present in the abdominal fluid. Patients with low levels of the MFAP4 protein are at particularly increased risk of death or liver transplantation, suggesting that clinical care should be intensified in this group of patients.

•

MFAP4 is a protein linked to liver fibrosis that can be found in the ascitic fluid in patients with cirrhosis.

• Biomarker
• CLIF-C AD, CLIF Consortium Acute Decompensation
• CPS, Child-Pugh score
• CRP, C-reactive protein
• CT, computed tomography
• Decompensated
• ECM, extracellular matrix
• Fibrosis
• GFR, glomerular filtration rate
• HR, hazard ratio
• INR, internationalised normal ratio
• LTx, liver transplantation
• Liver disease
• MELD-Na, model for end-stage liver disease
• MFAP4, microfibrillar associated protein 4
• Mortality
• NASH, non-alcoholic steatohepatitis
• Prognosis
• SBP, spontaneous bacterial peritonitis
• eGFR, estimated GFR

• blood coagulation
• hemostasis
• humans
• liver cirrhosis
• thrombosis

Development of ascites is the most common form of decompensation of cirrhosis. We aimed to investigate the coagulation system in ascitic fluid and plasma of patients with cirrhosis. We determined coagulation parameters and performed clotting and fibrinolysis experiments in ascitic fluid and plasma of thoroughly characterized patients with cirrhosis and ascites ( n  = 25) and in plasma of patients with cirrhosis but without ascites ( n  = 25), matched for severity of portal hypertension. We also investigated plasma D-dimer levels in an independent cohort of patients ( n  = 317) with clinically significant portal hypertension (HVPG ≥ 10 mmHg), grouped according to ascites severity. Ascitic fluid was procoagulant in a clotting assay. The procoagulant potential of ascitic fluid was abolished by depletion of extracellular vesicles from ascitic fluid by filtration or by addition of a tissue factor-neutralizing antibody. Compared with plasma, extracellular vesicle-associated tissue factor activity was high in ascitic fluid, while activities of other coagulation factors were low. The extracellular vesicle-depleted fraction of ascitic fluid induced fibrinolysis, which was prevented by aprotinin, indicating the presence of plasmin in ascitic fluid. Plasma peak thrombin generation and parameters reflecting fibrinolysis were independently associated with the presence of ascites. Finally, plasma D-dimer levels were independently linked to ascites severity in our second cohort comprising 317 patients. In conclusion, coagulation and fibrinolysis become activated in ascites of patients with cirrhosis. While tissue factor-exposing extracellular vesicles in ascitic fluid seem unable to pass the peritoneal membrane, fibrinolytic enzymes get activated in ascitic fluid and may re-enter the systemic circulation and induce systemic fibrinolysis.

The study aimed to investigate serum and ascitic fluid D-dimer level in patients with liver cirrhosis with and without ascites and to evaluate the impact of spontaneous bacterial peritonitis (SBP) on circulating serum and ascitic fluid D-dimer levels.

This study was conducted on 60 subjects who were further subdivided into group I comprising 15 patients with liver cirrhosis and no ascites, group II comprising 15 cirrhotic patients with ascites, group III comprising 15 cirrhotic patients with ascites and SBP, and group IV comprising 15 healthy controls. All patients were subjected to full history taking, physical examination, laboratory investigations, and measurement of serum D-dimer in all groups and ascitic fluid D-dimer in groups II and III. The diagnostic performance of serum D-dimer was tested to detect SBP.

Serum D-dimer differed significantly between groups III and IV, whilst no significant differences were detected between the other groups and group IV. Moreover, group III showed a significantly higher level of serum D-dimer. Ascitic fluid D-dimer mean levels showed no statistically significant differences. A statistically significant positive correlation was found between serum D-dimer level and ascitic fluid D-dimer in group III, r = 0.682. Using a sensitivity and specificity level of 80%, a cut-off value (COV) of > 323.2 ng/ml could differentiate between patients with SBP and patients with ascites only.

Serum D-dimer significantly correlated with ascitic fluid D-dimer in patients with SBP, whereas no significant correlation was found in patients with cirrhotic ascites without bacterial infection. D-dimer showed good diagnostic performance for SBP among patients with liver cirrhosis.

• D-dimer
• ascites
• liver cirrhosis
• spontaneous bacterial peritonitis

Prognostic models of cirrhosis underestimate disease severity for patients with cirrhosis and ascites. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein linked to hepatic neoangiogenesis and fibrogenesis. We investigated ascites MFAP4 as a predictor of transplant-free survival in patients with cirrhosis and ascites.

A dual-centre observational study of patients with cirrhosis and ascites recruited consecutively in relation to a paracentesis was carried out. Patients were followed up for 1 year, until death or liver transplantation (LTx). Ascites MFAP4 was tested with the model for end-stage liver disease (MELD-Na), CLIF Consortium Acute Decompensation (CLIF-C AD), and Child-Pugh score in Cox regression models.

Ninety-three patients requiring paracentesis were included. Median ascites MFAP4 was 29.7 U/L [22.3–41.3], and MELD-Na was 19 [16–23]. A low MELD-Na score (<20) was observed in 49 patients (53%). During follow-up, 20 patients died (22%), and 6 received LTx (6%). High ascites MFAP4 (>29.7 U/L) was associated with 1-year transplant-free survival (p = 0.002). In Cox regression, ascites MFAP4 and MELD-Na independently predicted 1-year transplant-free survival (hazard ratio [HR] = 0.97, p = 0.03, and HR = 1.08, p = 0.01, respectively). Ascites MFAP4 and CLIF-C AD also predicted survival independently (HR = 0.96, p = 0.02, and HR = 1.05, p = 0.03, respectively), whereas only ascites MFAP4 did, controlling for the Child-Pugh score (HR = 0.97, p = 0.03, and HR = 1.18, p = 0.16, respectively). For patients with MELD-Na <20, ascites MFAP4 but not ascites protein predicted 1-year transplant-free survival (HR 0.91, p = 0.02, and HR = 0.94, p = 0.17, respectively).

Ascites MFAP4 predicts 1-year transplant-free survival in patients with cirrhosis and ascites. In patients with low MELD-Na scores, ascites MFAP4, but not total ascites protein, significantly predicted 1-year transplant-free survival.

Patients with cirrhosis who have fluid in the abdomen, ascites, are at an increased risk of death and in need for liver transplantation. Our study identified patients with ascites and a poor prognosis by measuring microfibrillar associated protein 4 (MFAP4), a protein present in the abdominal fluid. Patients with low levels of the MFAP4 protein are at particularly increased risk of death or liver transplantation, suggesting that clinical care should be intensified in this group of patients.

•

MFAP4 is a protein linked to liver fibrosis that can be found in the ascitic fluid in patients with cirrhosis.

• Biomarker
• CLIF-C AD, CLIF Consortium Acute Decompensation
• CPS, Child-Pugh score
• CRP, C-reactive protein
• CT, computed tomography
• Decompensated
• ECM, extracellular matrix
• Fibrosis
• GFR, glomerular filtration rate
• HR, hazard ratio
• INR, internationalised normal ratio
• LTx, liver transplantation
• Liver disease
• MELD-Na, model for end-stage liver disease
• MFAP4, microfibrillar associated protein 4
• Mortality
• NASH, non-alcoholic steatohepatitis
• Prognosis
• SBP, spontaneous bacterial peritonitis
• eGFR, estimated GFR

• Ascites
• Clot formation/lysis
• Coagulopathy
• Fibrinolysis
• Liver cirrhosis

• Aged
• Ascites/blood
• Ascites/complications
• Biomarkers/blood
• Blood Coagulation/physiology
• Blood Coagulation Tests
• Female
• Fibrinolysis/physiology
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/complications
• Male
• Prognosis

• Cirrhosis
• Fibrinolysis
• Loculated ascites

• Ascites
• Dialysis
• Hepatocellular carcinoma
• Tehran Liver Transplant Center

Dogs with intracavitary effusion have coagulative abnormalities indicative of primary fibrinolysis/hyperfibrinolysis. The aim of this case control study was to investigate by rotational thromboelastometry (ROTEM) and standard coagulation tests (fibrin-fibrinogen degradation products, D-dimer and fibrinogen) fibrinolysis in dogs with intracavitary effusions. Thirty-two dogs with intracavitary effusion and 32 control sick dogs without effusion were studied. Frequency of fibrinolysis grade of severity (i.e., hypofibrinolysis/basal fibrinolysis vs increased fibrinolysis vs hyperfibrinolysis) by ROTEM and standard coagulation tests were compared between groups. Pattern of fibrinolysis by ROTEM (i.e., late vs intermediate vs fulminant) and type of fibrinolysis by standard coagulation tests (i.e., hypofibrinolysis/basal fibrinolysis vs primary fibrinolysis vs secondary fibrinolysis vs primary hyperfibrinolysis vs secondary hyperfibrinolysis) were also compared between groups. Dogs with intracavitary effusion had a lesser degree of hypofibrinolysis and basal fibrinolysis and a higher degree of increased fibrinolysis and hyperfibrinolysis compared to controls, both by ROTEM and by standard coagulation tests (P = 0.042 and P = 0.017, respectively). Nevertheless, there was a poor agreement between the two classification schemes (34.4%, K = 0.06, 95% CI = -0.14 ‒ +0.26). Dogs with intracavitary effusion showed, by ROTEM, a lesser degree of hypofibrinolysis and basal fibrinolysis and a higher degree of late, intermediate, and fulminant fibrinolysis compared to controls (P = 0.044). Finally, dogs with intracavitary effusion had, by standard coagulation tests, a higher frequency of primary fibrinolysis and primary hyperfibrinolysis and a lower frequency of secondary fibrinolysis compared to controls. Dogs with intracavitary effusion showed an increased frequency and a different and more severe pattern of fibrinolysis compared to controls.

• Animals
• Blood Coagulation Disorders/blood
• Blood Coagulation Disorders/diagnosis
• Blood Coagulation Disorders/veterinary
• Blood Coagulation Tests
• Dogs
• Female
• Fibrin Fibrinogen Degradation Products/analysis
• Fibrinogen/analysis
• Fibrinolysis
• Male
• Thrombelastography

• Acute-on-chronic liver failure
• Coagulation
• D-dimer
• Fibrinolysis

• Acute-On-Chronic Liver Failure/blood
• Acute-On-Chronic Liver Failure/mortality
• Adult
• Biomarkers/blood
• China/epidemiology
• Female
• Fibrin Fibrinogen Degradation Products/metabolism
• Humans
• Male
• Middle Aged
• Prognosis
• Retrospective Studies

• 2018ZX10723203 National Science and Technology Major Project
• 81270533 National Natural Science Foundation of China
• 81470038 National Natural Science Foundation of China
• 2017YFC0908100 National Key Research and Development Program of China
• 20124433120016 the Specialized Research Fund for the Doctoral Program of Higher Education of China
• 863 program, 2012AA022605 National High Technology Research and Development Program
• 201508020262 Key Scientific and Technological Program of Guangzhou City
• 2014B020228003 Department of Science and Technology of Guangdong Province
• 2015B020226004 Department of Science and Technology of Guangdong Province
• 2017C047 President Foundation of Nanfang Hospital, Southern Medical University
• National Science and Technology Major Project
• President Foundation of Nanfang Hospital, Southern Medical University

• Animals
• Biomedical Research/methods
• Blood Coagulation Tests
• Hemorrhage/blood
• Hemorrhage/diagnosis
• Hemorrhage/epidemiology
• Hemorrhage/therapy
• Hemostasis
• Humans
• Liver/metabolism
• Liver Diseases/blood
• Liver Diseases/diagnosis
• Liver Diseases/epidemiology
• Liver Diseases/therapy
• Prognosis
• Risk Factors
• Thrombosis/blood
• Thrombosis/diagnosis
• Thrombosis/epidemiology
• Thrombosis/therapy

• anidulafungin
• candidemia
• caspofungin
• micafungin

The primary objective of this study was to determine if activation of coagulation and fibrinolysis occurs in canine pleural effusions. Thirty-three dogs with pleural effusions of different origin were studied. Pleural effusion fibrinogen concentrations were significantly lower, while pleural fibrin-fibrinogen degradation products (FDPs) and D-dimer concentrations were significantly higher than those in plasma (P < 0.001 for all comparisons). These results show that, in canine pleural fluids, there is evidence of coagulation activation and fibrinolysis. The secondary aims of the current study were to determine if primary hyperfibrinolysis ([PHF] i.e., elevated plasma FDPs with a normal D-dimer concentrations), occurs in dogs with pleural effusion, and whether the presence of a concurrent inflammatory process may have activated the hemostatic cascade, with its intrinsically linked secondary hyperfibrinolysis, masking the concurrent PHF. The previously 33 selected dogs with pleural effusion (group 1) were compared to two control groups of 33 healthy (group 2) and 33 sick dogs without pleural effusion (group 3). Serum fibrinogen, FDPs, D-dimer, C-reactive protein (CRP), fibrinogen/CRP ratio, and frequency of PHF were determined. Fibrinogen, FDPs, D-dimer and CRP concentrations in group 1 were significantly increased compared to group 2 (P < 0.001 for all comparisons). FDPs and CRP concentrations in group 1 were also significantly increased compared to group 3 (P = 0.001 and P < 0.001, respectively). The fibrinogen/CRP ratio was significantly decreased in group 1 compared to groups 2 and 3 (P < 0.001 for both comparison). The frequency of PHF was significantly higher in group 1 compared to groups 2 (P = 0.004), but not compared to group 3. These results support the hypothesis that PHF occurs significantly more often in dogs with pleural effusion compared to healthy dogs. Nevertheless, the decrease in the fibrinogen/CRP ratio in group 1 compared to group 3, considering the higher FDPs and similar D-dimer concentrations, would suggest that PHF is also more frequent in dogs with pleural effusion compared to sick control dogs, and that this phenomenon is hidden due to concurrent secondary hyperfibrinolysis.

The presence of cirrhosis poses an increased risk of both thrombosis and bleeding in individuals with chronic liver disease. This duality is a result of a dynamic disequilibrium between procoagulant and anticoagulant states in individuals with cirrhosis. The mechanism of this imbalance in cirrhosis remains unclear. It is known that the progression of cirrhosis leads to decreased synthetic function and a concurrent lack of natural anticoagulants. Other proposed mechanisms contributing to this hemostatic imbalance include decreased platelet production, increased platelet destruction from hypersplenism, decreased synthesis of Vitamin K-dependent and independent clotting factors and anticoagulant factors, and alterations in purinergic signaling pathways.

Given the current state of flux in our understanding of bleeding and thrombophilia in cirrhosis, the recommendations for treatment of these conditions are still evolving.

We provide a current update on the proposed pathophysiology of altered hemostasis and thrombophilia in cirrhosis. We discuss recent studies in portal vein thrombosis (PVT) and venous thromboembolism (VTE), which are the common thrombotic consequences of cirrhosis, resulting in substantive morbidity and mortality. To address these, we discuss new prophylactic interventions and current treatment options to manage the heightened risk of thrombosis in cirrhosis, while limiting hemorrhagic complications.

• anticoagulation
• bleeding
• cirrhosis
• hemorrhage
• liver disease
• thrombosis

• Ascites
• Canine
• Fibrinogenolysis
• Fibrinolysis

• Animals
• Ascites/metabolism
• Ascites/veterinary
• Ascitic Fluid/metabolism
• Blood Coagulation Disorders/metabolism
• Blood Coagulation Disorders/veterinary
• Cross-Sectional Studies
• Dog Diseases/metabolism
• Dogs
• Female
• Fibrin Fibrinogen Degradation Products/metabolism
• Fibrinogen/metabolism
• Male
• Partial Thromboplastin Time

The objective of this study was to evaluate the elimination kinetics of hemostasis-related biomarkers including the prothrombin activation fragment F1+2, thrombin-antithrombin complex (TAT), plasmin-α₂-antiplasmin complex (PAP), and D-dimer in humans. Autologous serum was used as a biomarker source and infused into 15 healthy volunteers. Serum was prepared from whole blood in the presence of recombinant tissue-type plasminogen activator (final concentration 20 μg/mL) to induce plasmin generation required for PAP and D-dimer formation. Serum transfusions (50 mL/30 min) were well tolerated by all subjects. Endogenous thrombin formation was not induced by serum infusions as measured using a highly sensitive oligonucleotide-based enzyme capture assay. Median peak levels (x-fold increase over baseline) of F1+2, TAT, PAP, and D-dimer of 3.7 nmol/L (28.9), 393 ng/mL (189.6), 3,829 ng/mL (7.0), and 13.4 mg/L (34.2) were achieved at the end of serum infusions. During a 48 h lasting follow-up period all biomarkers showed elimination kinetics of a two-compartment model. Median (interquartile range) terminal half-lives were 1.9 (1.3–3.6) h for F1+2, 0.7 (0.7–2.6) h for TAT, and 10.8 (8.8–11.4) h for PAP. With 15.8 (13.1–23.1) h the D-dimer half-life was about twice as long as previously estimated from radiolabeling studies in animals and small numbers of human subjects. The serum approach presented here allows label-free and simultaneous analysis of the elimination kinetics of various hemostasis-related biomarkers. Based on these data changes in biomarker levels could more precisely used to estimate the activity level of the hemostatic system.

• Adult
• Biomarkers/blood
• Blood Transfusion, Autologous
• Female
• Fibrin Fibrinogen Degradation Products/analysis
• Fibrinolysis/drug effects
• Half-Life
• Healthy Volunteers
• Humans
• Kinetics
• Male
• Middle Aged
• Prospective Studies
• Thrombin/analysis
• Tissue Plasminogen Activator/pharmacology
• Young Adult

This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.

• Inflammation
• Macrophages
• Cirrhosis
• Alcohol
• Hepatitis C virus
• Cytokines
• Liver

• Bacterial Infections/immunology
• Bacterial Infections/microbiology
• Bacterial Translocation
• Diagnosis, Differential
• Hepacivirus/immunology
• Hepacivirus/pathogenicity
• Hepatitis C/complications
• Hepatitis C/diagnosis
• Hepatitis C/immunology
• Hepatitis C/metabolism
• Host-Pathogen Interactions
• Humans
• Inflammation Mediators/immunology
• Inflammation Mediators/metabolism
• Liver/immunology
• Liver/metabolism
• Liver/pathology
• Liver/virology
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/immunology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/virology
• Liver Cirrhosis, Alcoholic/diagnosis
• Liver Cirrhosis, Alcoholic/immunology
• Liver Cirrhosis, Alcoholic/metabolism
• Predictive Value of Tests
• Prognosis
• Risk Factors
• Signal Transduction

Several studies have investigated the effect of intraoperative blood loss (IBL) on recurrence of tumors. However, the independent effect of IBL on oncological outcome after liver transplantation (LT) for hepatocellular carcinoma (HCC) is unclear.

A total of 479 patients who underwent LT for HCC from January 2001 to December 2012 at our institution were enrolled in this retrospective study. Kaplan–Meier and Cox regression methods were used to assess the recurrence rate, as well as its risk factors. Stratified analysis was performed to further examine the effect of IBL on HCC recurrence according to different characteristics of tumors. We also investigated the independent risk factors for excessive IBL using logistic regression analysis.

The median follow-up was 28 months (range, 1–131 months). Kaplan–Meier analysis with the log-rank test according to IBL at per liter intervals showed that IBL > 4 L was significantly associated with a higher recurrence rate (P < 0.001). Multivariate analysis identified that IBL > 4 L (P < 0.001; hazard ratio [HR] = 2.32, 95 % confidence interval [CI] = 1.60–3.36) was an independent risk factor for post-LT HCC recurrence, as well as age < 60 years, exceeding Milan criteria, α-fetoprotein levels > 400 ng/mL, and micro- and macrovascular invasion. IBL > 4 L (P < 0.001; HR = 2.45, 95 % CI = 1.64–3.66) was also independently associated with early (within 1 year) recurrence after LT. Furthermore, a significant correlation between IBL > 4 L and vascular invasion (P = 0.019) was found. IBL > 4 L was independently associated with HCC recurrence for patients with vascular invasion, but not for patients without vascular invasion. Finally, we found that the presence of ascites, model for end-stage liver disease score, and operation time were independent risk factors for IBL > 4 L.

Excessive IBL is an independent predictor of HCC recurrence after LT, especially in patients with vascular invasion.

• Acute Disease
• Amino Acids/therapeutic use
• Antifibrinolytic Agents/therapeutic use
• Blood Coagulation Disorders/etiology
• Blood Coagulation Disorders/therapy
• Chronic Disease
• Gastrointestinal Hemorrhage/therapy
• Humans
• Liver Diseases/complications

• ADAM Proteins/metabolism
• ADAMTS13 Protein
• Antifibrinolytic Agents/therapeutic use
• Blood Coagulation
• Blood Coagulation Disorders/complications
• Blood Coagulation Factors/therapeutic use
• Deamino Arginine Vasopressin/metabolism
• Factor VIIa/therapeutic use
• Fibrinolysis
• Hemorrhage
• Hemostasis/drug effects
• Humans
• International Normalized Ratio
• Liver Diseases/complications
• Plasma
• Prothrombin Time
• Receptors, Thrombopoietin/agonists
• Recombinant Proteins/therapeutic use
• Risk Factors
• Thrombelastography
• Thrombin/chemistry
• Vitamin K/metabolism

• Blood Coagulation/physiology
• Blood Coagulation Factors/analysis
• Blood Coagulation Factors/metabolism
• Case-Control Studies
• Child
• Chronic Disease
• Female
• Fibrinolysis/physiology
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/diagnosis
• Liver Diseases/blood
• Liver Diseases/diagnosis
• Liver Function Tests/methods
• Male
• Prospective Studies

• Amino Acids/therapeutic use
• Antifibrinolytic Agents/therapeutic use
• Blood Coagulation Disorders/etiology
• Blood Coagulation Disorders/therapy
• Humans
• Liver Diseases/complications

Refractory ascites can occur in patients with various conditions. Although several procedures based on the reinfusion of ascitic fluid have been reported after the failure of bed rest, salt and water restriction, diuretics, intravenous administration of albumin, and repeated paracentesis, these procedures are performed for ascitic fluid removal without dialytic effect. In this study, a flow control reinfusion of ascites during hemodialysis (HD) was performed to demonstrate the efficacy of this method in a lupus patient with massive refractory ascites and respiratory and acute renal failure (ARF). The alleviation of ascites and ARF attests to the success of the flow control reinfusion of ascites during HD. This procedure can control the rate of ascites and body fluid removal simultaneously during HD using the roller pump. In conclusion, with a normal coagulation profile, the procedure of flow control reinfusion of ascites during HD is an effective alternative treatment for the alleviation of refractory ascites with renal failure.

• ascites
• lupus
• reinfusion
• renal failure