Prothrombin Activation Research Articles

Relationship of immunonutritional factor with changes in liver volume after portal vein embolization

BackgroundTo identify predictors of changes in hepatic volumes after portal vein embolization, we examined the relationship with preoperative nutritional and immunological parameters. Patients and MethodsNinety-three patients who underwent portal vein embolization were included. The control group comprised 13 patients who underwent right hepatectomy without portal vein embolization. Computed tomographic volumetric parameter was measured for changes in embolized and nonembolized liver. Correlation with various candidates of immunonutritional parameters was examined. ResultsDifference in increased liver ratio was 9.1%. C-reactive protein levels significantly increased after portal vein embolization (P < .01), whereas albumin and total cholesterol levels significantly decreased, respectively (P < .01). The C-reactive protein/albumin ratio, prognostic nutritional index, Controlling Nutritional Status score, and modified Glasgow Prognostic Score were significantly different, respectively (P < .01). Prothrombin activity and total cholesterol level significantly correlated with the increased change in nonembolized liver (P < .05). The C-reactive protein and C-reactive protein/albumin ratio after portal vein embolization negatively correlated with hypertrophic ratio (P < .05). By comparing posthepatectomy outcomes between 64 patients undergoing portal vein embolization and 13 who did not, the prevalence of severe complications and mortality in the portal vein embolization group was not different from that in the non–portal vein embolization group. Liver activity at 15 minutes > 0.92 and increased liver volume ≥ 10% tended to correlate with lower prevalence of severe complications. Only increased intraoperative blood loss ≥1,500 mL was significantly associated with morbidity and mortality (P < .05). ConclusionContrary to our hypothesis, immunonutritional parameters, except C-reactive protein and C-reactive protein/albumin ratio, did not reflect hypertrophy after portal vein embolization. Although it is difficult to predict the hypertrophic degree, the strategy of scheduled hepatectomy should be switched in case of impaired inflammatory status after portal vein embolization.

Analysis of the diagnostic efficiency of combining multiple laboratory hematological indicators in alpha-fetoprotein-negative hepatocellular carcinoma

Objective: To establish a diagnostic model for alpha-fetoprotein-negative hepatocellular carcinoma (AFP-NHCC) by combining multiple laboratory hematological indicators and explore its clinical diagnostic efficiency. Methods: A total of 124 inpatients, including 110 males and 14 females, aged 57 (51, 66) years, who were first diagnosed with AFP-NHCC in the PLA General Hospital were included from December 2011 to June 2017. Meanwhile, 331 cases of non-HCC were enrolled as the control group, including 279 males and 52 females, aged 58 (51, 63) years old, with 47 cases of hepatitis B virus (HBV) infection, 40 cases of liver cirrhosis, 64 cases of hepatic hemangioma or cysts, 7 cases of liver nodules, 8 cases of fatty liver, 146 cases of non-liver disease and 19 health controls. Subjects in the AFP-NHCC group and the control group were divided into a training group and a validation group. A total of 196 subjects were involved in the training group, including 103 AFP-NHCC patients and 93 non-HCC patients (19 healthy controls, 25 patients with HBV infection, 22 patients with liver cirrhosis, 23 patients with hepatic hemangioma or cyst, and 4 patients with liver nodules). The differences in laboratory parameters were analyzed, and a diagnostic model of AFP-NHCC under different AFP levels was established. Likewise, 259 subjects, including 113 patients with liver disease, were involved in the validation group to verify the diagnostic efficiency of the model for AFP-NHCC. The receiver operating characteristic (ROC) curve was used to analyze the sensitivity and specificity of different models, and the area under the curve (AUC) was calculated to evaluate the diagnostic performance of different models. Results: In the training group, the indicators of AFP-NHCC diagnostic model included platelet (PLT), prothrombin activity (PTA), serum albumin (ALB), prothrombin time (PT) and carbohydrate antigen 19-9 (CA19-9), and the AUC of the model was 0.848 (95%CI: 0.786-0.911) when AFP≤5 μg/L. Similarly, the indicators of AFP-NHCC diagnostic model included PLT, PTA, ALB, PT and hematocrit (HCT), and the AUC of the model was 0.839 (95%CI: 0.780-0.897) when AFP≤10 μg/L. When AFP≤20 μg/L, the indicators of AFP-NHCC diagnostic model contained PLT, PTA, ALB, PT, HCT and AFP, and the AUC of the model was 0.866 (95%CI: 0.815-0.917). The AUC values of these three models were higher than those of AFP and CA19-9 alone for the diagnosis of AFP-NHCC [0.634 (95%CI: 0.560-0.709), 0.691 (95%CI:0.620-0.761), all P<0.05]. The indicators screened by these three models were combined to establish the final diagnostic model, and the AUC of the model was 0.873 (95%CI: 0.824-0.923), with the sensitivity of 78.6% (81/103) and the specificity of 81.7% (76/93). In the validation group, the predictive AUC of the final model in liver disease patients was 0.892 (95%CI: 0.832-0.951), with the sensitivity of 100% (21/21) and the specificity of 71.7% (66/92), while in the total validation population, the predictive AUC was 0.931 (95%CI: 0.890-0.972), with the sensitivity of 100.0% (21/21) and the specificity of 75.6% (180/238). Conclusion: The final diagnostic model includes PLT, PTA, ALB, PT, HCT, CA19-9 and AFP, which has higher sensitivity and specificity, and has good diagnostic efficiency for the clinical diagnosis of AFP-NHCC.

Germline rare variants of lectin pathway genes predispose to asymptomatic SARS-CoV-2 infection in elderly individuals

PurposeEmerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants — referred as qualifying variants (QVs) — of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease. MethodsExploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19. ResultsWe found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue. ConclusionThis study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/

Multi‐Omics Integration and the Development of Gestational High Altitude Induced Pulmonary Arterial Hypertension

High altitude (&gt; 2500 meters) during pregnancy reduces oxygen delivery to the fetus (i.e., gestational hypoxia), causing abnormal fetal lung development. The pulmonary arteries become thicker and less functional, increasing the risk of pulmonary hypertension, which is a multiorgan disease that promotes right heart failure and under five‐years mortality rate. Our previous work showed endoplasmic reticulum stress and metabolomic alterations in fetal sheep pulmonary arteries indicative of an unregulated inflammatory response after gestational hypoxia. To understand the relationships between inflammation, vascular remodeling, and pulmonary arterial hypertension development, we examined the omic links between the pulmonary arteries and plasma exosomes in fetal sheep exposed to high altitude (3801 meters) for the majority of the pregnancy (110+ days out of 138‐141 days of pregnancy). Specifically, metabolomics and proteomic analyses from the pulmonary arteries and transcriptomic analysis of plasma exosomes were integrated from fetal sheep to understand the mechanisms driving this multiorgan disease. Sixteen miRNAs and 75 proteins were differentially expressed between normoxic and hypoxic samples. Gestational hypoxia resulted in significant changes in 90 metabolites in fetal pulmonary arteries. These results show exosomal microRNA are linked with pulmonary artery proteins and metabolites important to cell membrane composition which might explain their role in the facilitation of changes in vascular remodeling, inflammation, and cell signaling. Top canonical pathways noted in omics data integration were acute phase response signaling, atherosclerosis signaling, FXR/RXR activation, intrinsic prothrombin activation pathway, and LXR/RXR activation. This multi‐omics study illustrates the intricacy of complex adaptations that occur in the fetal sheep lung in response to gestational hypoxia.

Клинический случай: «острая-на-хроническую» печеночная недостаточность (ACLF)

Acute-on-chronic liver failure (AcLF) is an acute liver disorder manifested as jaundice (serum bilirubin levels ≥5 mg/dL) and coagulopathy (Inr ≥1.5 or prothrombin activity &lt; 40%), complicated by ascites and/or encephalopathy within 4 weeks, that is found in patients with the previously diagnosed or undiagnosed chronic liver disease. AcLF is a serious medical issue worldwide. The AcLF pathogenesis is based on the pronounced systemic inflammatory response to pathogenic antigens and biological structures produced during the liver cell death, with subsequent immune paralysis and multiple organ failure. Acute-on-chronic liver failure (AcLF) may develop at any stage, from compensated to decompensated cir- rhosis; the disorder may involve both hepatic and extrahepatic precipitating events. drug treatment of AcLF includes early detection and treat-ment of the precipitating factor and maintenance therapy. It has been proven that treatment of the trigger at an early stage reduces mortality,however, the management of AcLF is focused mostly on the maintenance therapy. AcLF belongs to the syndromes seldom diagnosed in clinical practice, that is why the AcLF case study is of special interest. The paper reports a confirmed case of AcLF.

Clinical Characteristics of Diabetes Complicated by Bacterial Liver Abscess and Nondiabetes-Associated Liver Abscess.

Background Bacterial liver abscess (BLA) is a secondary infectious disease caused by hepatic parenchymal inflammation and bacterial necrosis. Studies have shown that diabetic patients with BLA have higher rates of related adverse events than patients without diabetes. Aim To explore the clinical characteristics of BLA complicated with diabetes and nondiabetes-related BLA. Methods From January 2019 to June 2020, 61 diabetic patients with BLA were included as the study group, and 61 BLA patients without diabetes were included as the control group. Clinical manifestations, laboratory examination index (prothrombin activity (PTA), albumin (propagated), white blood cell count (WBC), red blood cell count (RBC), plasma fibrinogen (FIB), C-reactive protein (CRP), neutrophil percentage (NEUT), and prealbumin (PA)) levels, blood cultivation, and fester situation in the two groups were analyzed. Results No differences of Fever, right upper abdominal pain, jaundice, vomiting and nausea, liver tenderness, and liver pain upon percussion were observed between the study and control groups. However, chill, cough and expectoration, and liver pain upon percussion were higher in the study group, while abdominal distension was lower. WBC, RBC, PA, PTA, FIB, and CRP were higher than the control group. NEUT was higher in the study group than in the control group and Alb was lower than that in the control group. There was no significant difference between the positivity of blood bacterial culture in the study and control groups. The positivity rate of Klebsiella pneumoniae in Gram-negative aerobic bacteria in the study group was higher than that in the control group. There was no significant difference between the positivity of fester culture of the two groups. The positivity of K. pneumoniae in Gram-negative aerobic bacteria in the study group was higher than that in the control group. The positivity of E. coli was lower in the study group than in the control group. Conclusion Clinical manifestations and laboratory results of BLA patients with and without diabetes mellitus were significantly different. The symptoms of diabetics with BLA were serious.

Effects of primary preventive treatment under endoscope for esophageal and gastric varices on bleeding rate and its relevant factors

Objective: To investigate the effects of primary preventive treatment under endoscope for esophageal and gastric varices on bleeding rate and its relevant factors. Methods: 127 cases with liver cirrhosis accompanied with esophageal and gastric varices without bleeding history were included in the endoscopic and non-endoscopic treatment group, respectively. Informed consent was obtained from both groups. Gastric varices (Lgf) and esophageal varices (Leg) were diagnosed according to LDRf classification criteria, and the corresponding treatment scheme was selected according to the recommended principle of this method.The incidence rate of bleeding from ruptured esophageal varices were observed at 3, 6 months, and 1, and 2 years in the treated and the untreated group, and the patients with different Child-Pugh scores were followed-up for 2 years. Gender, age, etiology, varicose degree, Child-Pugh grade, platelet count, prothrombin activity, portal vein thrombosis, collateral circulation, portal vein width and other factors affecting the bleeding rate were assessed. Measurement data were described as mean ± standard deviation (x¯±s), and qualitative data of categorical variables were expressed as percentage (%), and χ2 test was used. Results: 127 cases were followed up for 2 years. There were 55 cases in the endoscopic treatment group (18 cases underwent band ligation, 2 cases underwent band ligation combined with tissue adhesive embolization, 28 cases underwent sclerotherapy, and 7 cases underwent sclerotherapy combined with tissue adhesive embolization). Recurrent bleeding and hemorrhage was occurred in 5 (9.1%) and 28 cases (38.9%), respectively (P<0.05). In addition, there were 72 cases in the untreated group (P<0.05). Severe varicose veins proportions in treated and untreated group were 91.1% and 85.1%, respectively (P>0.05). There was no statistically significant difference in liver cirrhosis-related medication and β-blocker therapy between the treated and untreated group (P>0.05). There was no statistically significant difference in the bleeding rate between the different treated groups (P>0.05). The bleeding rates at 3, 6 months, 1, and 2 years in endoscopic treated and untreated group were 2.00% vs. 2.59% (P>0.05), 2.30% vs. 5.88% (P>0.05), 3.10% vs. 7.55% (P>0.05) and 4.00% vs. 21.62% (P<0.05), respectively. All patients with Child-Pugh grade A, B and C in the treated and the untreated group were followed-up for 2 years, and the bleeding rates were 1.8% vs. 8.1% (P<0.05), 1.1% vs. 9.4% (P<0.05) and 9.1% vs. 10.1% (P>0.05), respectively. There were statistically significant differences in the rupture and bleeding of esophageal and gastric varices, varices degree, Child-Pugh grade and presence or absence of thrombosis formation in portal vein (P<0.05); however, no statistically significant differences in gender, age, etiology, platelet count, prothrombin activity, collateral circulation and portal vein width (P>0.05). There was no intraoperative bleeding and postoperative related serious complications in the treated group. Conclusion: The risk of initial episodes of bleeding from esophageal and gastric varices is significantly correlated with the varices degree, Child-Pugh grade, and portal vein thrombosis. Primary preventive treatment under endoscope is safe and effective for reducing the long-term variceal bleeding risk from esophageal and gastric varices.

Cryo-EM structure of the prothrombin-prothrombinase complex

AbstractThe intrinsic and extrinsic pathways of the coagulation cascade converge to a common step where the prothrombinase complex, comprising the enzyme factor Xa (fXa), the cofactor fVa, Ca2+ and phospholipids, activates the zymogen prothrombin to the protease thrombin. The reaction entails cleavage at 2 sites, R271 and R320, generating the intermediates prethrombin 2 and meizothrombin, respectively. The molecular basis of these interactions that are central to hemostasis remains elusive. We solved 2 cryogenic electron microscopy (cryo-EM) structures of the fVa-fXa complex, 1 free on nanodiscs at 5.3-Å resolution and the other bound to prothrombin at near atomic 4.1-Å resolution. In the prothrombin-fVa–fXa complex, the Gla domains of fXa and prothrombin align on a plane with the C1 and C2 domains of fVa for interaction with membranes. Prothrombin and fXa emerge from this plane in curved conformations that bring their protease domains in contact with each other against the A2 domain of fVa. The 672ESTVMATRKMHDRLEPEDEE691 segment of the A2 domain closes on the protease domain of fXa like a lid to fix orientation of the active site. The 696YDYQNRL702 segment binds to prothrombin and establishes the pathway of activation by sequestering R271 against D697 and directing R320 toward the active site of fXa. The cryo-EM structure provides a molecular view of prothrombin activation along the meizothrombin pathway and suggests a mechanism for cleavage at the alternative R271 site. The findings advance our basic knowledge of a key step of coagulation and bear broad relevance to other interactions in the blood.

КЛИНИЧЕСКИЕ И ГЕМОСТАЗИОЛОГИЧЕСКИЕ ОСОБЕННОСТИ ЦИРРОЗА ПЕЧЕНИ АУТОИММУННОЙ ЭТИОЛОГИИ У ДЕТЕЙ

Objective of the study: to determine clinical, hemostasiological features and evaluate the relationship of autoantibodies with hemostasiological disorders in children with liver cirrhosis (LC) class A according to Child–Pugh score in the outcome of autoimmune hepatitis (AIH). Materials and methods of research: a single-center, retrospective, controlled, non-randomized study. From 2017 to 2021, 31 children aged 13 (10; 15.5) years old [15 girls (48%) and 16 boys (52%)] with LC class A according to Child–Pugh classification in the outcome of AIH and 15 children aged 13 (10; 15.5) years [8 girls (53%) and 7 boys (47%)], belonging to health groups I–II. All participants were examined according to the medical standard for specialized medical care for children with LC in accordance with the «Autoimmune hepatitis in children” of the Federal clinical guidelines (Moscow, 2016) and the medical standard for specialized medical care for children with AIH. The parameters of the hemostatic system were determined on the ACL-TOP 500 hemocoagulation analyzer (Instrumentation Laboratory Company, USA) using standard kits: activated partial thromboplastin time (aPTT), Prothrombin time (PT) calculated as % of prothrombin activity according to Quick, thrombin time, fibrinogen content, activity of antithrombin III (ATIII), protein C, plasminogen, alpha2-antiplasmin (α2-AP). To determine the factor XII-dependent fibrinolysis activity (XIIa-DF) and the content of Soluble fibrin monomer complexes (SFMCs), reagent kits from the Tekhnologiya-Standard company (Russia) were used. The platelet count was determined using a Cell-Dyn 610 hematology analyzer (Abbott Diagnostics, USA). The study of platelet aggregation activity was carried out on a platelet aggregation analyzer using adenosine diphosphate (ADP) at a concentration of 1.25 mg/ml and collagen at a concentration of 2.0 microns/ml as an aggregation inducer. Measurement of plasma endothelin-1 was carried out by using Endothelin 1-21 ELISA Assay kit. Homocysteine concentration and VWF activity were determined on an ACL-TOP 500 hemocoagulation analyzer (Instrumentation Laboratory Company, USA) using standard kits. Results: the clinical picture was characterized by asthenoneurotic (100%), abdominal pain (45%), hemorrhagic [ecchymosis (55%), epistaxis (30%), bleeding gums (16%)] syndromes, hepatomegaly (90%), splenomegaly ( 65%). Hemostasiological disorders were characterized by a decrease in the content of platelets (p=0.001), an increase in the degree (ADP inducer, p=0.001; collagen inducer, p=0.023) and speed (ADP inducer, p=0.003; collagen inducer, p=0.032) of their aggregation, inhibition coagulation (p=0.001) and anticoagulant (p=0.002) components of hemostasis in comparison with a group of healthy children. Positive autoantibodies were diagnosed in 97% of patients, in 49% of cases, which is typical for Type 2 AIH. Indicators of vascular-platelet hemostasis can be used to assess autoimmune activity in children with Child–Pugh class A cirrhosis: VWF activity 200.0% is associated with an increase in antinuclear antibodies (ANA) in the blood (sensitivity – 83%, specificity – 69% ). Conclusion: indicators of vascular-platelet hemostasis can be used to assess autoimmune activity in children with class A cirrhosis according to Child–Pugh in the outcome of AIH.

Hepatitis B core-related antigen serum levels are associated with significant liver fibrosis in treatment-naive chronic HBV infection patients.

Several hepatitis B virus (HBV) serum markers have been identified as risk factors for liver fibrosis in patients with chronic HBV infection, and several noninvasive fibrosis tests based on serum indexes are now used to identify the severity of liver fibrosis. We aimed to identify the relationship between hepatitis B core-related antigen (HBcrAg) serum levels and liver fibrosis in treatment-naive chronic HBV infection patients. A total of 246 treatment-naive chronic HBV infection patients were enrolled in this study. All of the patients underwent liver biopsies at baseline. Using the METAVIR fibrosis stages, there were 15, 140, 50, 26 and 15 patients in the F0, F1, F2, F3 and F4stages (METAVIR scoring system), respectively. The biochemical, serological and virological parameters were measured using standard laboratory procedures. The HBcrAg serum levels of the patients were examined via ELISA. HBcrAg serum levels of F2, F3 and F4stage patients were significantly higher than those of nonsignificant liver fibrosis patients (METAVIR F0-F1), but there were no significant differences among F2, F3 and F4stage patients. Serum HBcrAg (OR, 2.18; 95% confidence interval [CI], 1.51-3.16), albumin (ALB) (OR, 0.60; 95% CI, 0.41-0.87), prothrombin activity (PTA) (OR, 0.58; 95% CI, 0.40-0.83) and platelet (PLT) counts (OR, 0.38; 95% CI, 0.25-0.57) were associated with significant liver fibrosis (METAVIR F2-F4). The serum HBcrAg value enabled the correct identification of patients with significant fibrosis, with an area under the receiver operating characteristic curve of 0.81 (95% CI, 0.75-0.88). The APRI, FIB-4 index and ALBI score can identify significant liver fibrosis with an area under the ROC curve of 0.74 (95% CI, 0.66-0.81), 0.73 (95% CI, 0.65-0.80) and 0.63 (95% CI, 0.55-0.72), respectively. Compared with these three indexes, the accuracy rate of diagnosis of significant fibrosis based on HBcrAg was higher than that of the FIB-4 index (p=0.0479) and ALBI score (p=0.0030). HBcrAg, ALB, PTA serum levels and PLT counts were associated with significant liver fibrosis in treatment-naive chronic HBV infection patients. HBcrAg serum levels enabled the correct identification of patients with significant fibrosis (METAVIR F2-F4), and HBcrAg was moreeffective than the FIB-4 index and ALBI score.

NLRP3 inflammasome contributes to endotoxin-induced coagulation

IntroductionExcessive activation of the coagulation cascades leads to life-threatening disseminated intravascular coagulation (DIC) in sepsis. Two recent studies by our group and others have both demonstrated the noncanonical inflammasome is pivotal for the endotoxin or gram-negative bacterial-induced coagulation. Based on this, we further evaluated the function of the NLRP3 inflammasome, the most studied inflammasome, in endotoxin-induced coagulation. Materials and methodsWe established an endotoxin-induced coagulation model by intraperitoneal injection of sublethal doses of LPS in mice. Mice were sacrificed 8 h after injection and blood was collected for thrombin-antithrombin (TAT), plasminogen activator inhibitor-1 (PAI-1), prothrombin time (PT), D-dimer, IL-1β and tissue factor (TF) measurements by commercial ELISA. Lungs and livers were examined via HE staining images to determine injury scores and immunohistochemistry for TF expression and fibrin deposits. The role of NLRP3 activation was evaluated in wild-type (WT), Nlrp3−/−, Asc−/− (apoptosis-associated speck-like protein containing a CARD), Caspase-11−/− mice and 30 min after treatment with MCC950, a potent inhibitor of NLRP3. Western blotting and Q-PCR were performed to assess TF expression in the lungs and livers. To uncover the different effects of NLRP3 and Caspase-11, we also compared the time-dependent IL-1β release in LPS-treated Nlrp3−/− and Caspase-11−/− mice. Correlation analysis of TAT, PAI-1 were estimated the relationship of coagulation and release of IL-1β, as well as IL-1β and TF. ResultsInhibition of NLRP3 by MCC950 as well as NLRP3 or ASC deficiency decreased TAT, PAI-1, PT, D-dimer, and TF levels in blood and impaired the thrombus formation and fibrin deposition, as well as declined expression of TF in the liver and lung in endotoxin-induced coagulation but not caspase-11 deficiency. Impressively, IL-1β release is increased in LPS-treated Caspase-11−/− mice, but not in Nlrp3−/− mice. Moreover, the correlation analysis is indicated that downstream of the NLRP3 inflammasome, IL-1β expression, is positively correlated with TAT, PAI-1 and TF in blood circulation. ConclusionsThe NLRP3 inflammasome contributes to endotoxin-induced coagulation by promoting TF expression at least in part through the induction of IL-1β release. These findings broadened our understanding of the mechanism of coagulation and implicated a possible therapeutic strategy for preventing coagulation in sepsis.

The Clinical Efficacy of Double Plasma Molecular Absorption System Combined with Plasma Exchange in the Treatment of Acute-on-Chronic Liver Failure: A Systematic Review and Meta-Analysis.

Objective This study aims to investigate the clinical efficacy of plasma exchange in treating acute-on-chronic liver failure (ACLF) through meta-analysis. Method PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched using a computer for all relevant Chinese and English literature from 2000 to 2021 in each database. At the same time, a large number of related papers and materials were manually consulted. Randomized controlled trials of plasma exchange (PE, control group) and combined double plasma molecular absorption system (DPMAS + PE, observation group) for the treatment of ACLF were collected. Meta-analysis was performed with Stata16.0 software. Result A total of 474 articles were retrieved, and 11 papers were finally included for research after screening. Meta-analysis results showed that the effective rate of treatment in the experimental group was significantly higher than that in the control group. At the same time, the observation group's prothrombin activity (PTA) level was better than that of the control group after treatment. After treatment, there was no significant difference in prothrombin time (PT) and international normalized ratio (INR) between the two groups. In addition, after treatment, the alanine aminotransferase (ALT) level of the observation group was significantly lower than that of the control group. However, TBIL levels and albumin (ALB) levels did not change significantly between the two groups. Regarding blood routine indexes, there were no significant changes in creatinine (Cr) levels and platelet counts (PLT) in the two groups after treatment, but hemoglobin (HGB) levels in the observation group were significantly lower than those in the control group. Conclusion DPMAS combined with plasma exchange therapy can improve liver function, coagulation function, and blood routine level of ACLF patients and increase the effective rate of treatment. It is an effective treatment for acute-on-chronic liver failure.

Transcriptomics of Wet Skin Biopsies Predict Early Radiation-Induced Hematological Damage in a Mouse Model.

The lack of an easy and fast radiation-exposure testing method with a dosimetric ability complicates triage and treatment in response to a nuclear detonation, radioactive material release, or clandestine exposure. The potential of transcriptomics in radiation diagnosis and prognosis were assessed here using wet skin (blood/skin) biopsies obtained at hour 2 and days 4, 7, 21, and 28 from a mouse radiation model. Analysis of significantly differentially transcribed genes (SDTG; p ≤ 0.05 and FC ≥ 2) during the first post-exposure week identified the glycoprotein 6 (GP-VI) signaling, the dendritic cell maturation, and the intrinsic prothrombin activation pathways as the top modulated pathways with stable inactivation after lethal exposures (20 Gy) and intermittent activation after sublethal (1, 3, 6 Gy) exposure time points (TPs). Interestingly, these pathways were inactivated in the late TPs after sublethal exposure in concordance with a delayed deleterious effect. Modulated transcription of a variety of collagen types, laminin, and peptidase genes underlay the modulated functions of these hematologically important pathways. Several other SDTGs related to platelet and leukocyte development and functions were identified. These results outlined genetic determinants that were crucial to clinically documented radiation-induced hematological and skin damage with potential countermeasure applications.

Long-Term Efficacy and Safety of Rifaximin in Japanese Patients with Hepatic Encephalopathy: A Multicenter Retrospective Study.

Background: Rifaximin is commonly used for hepatic encephalopathy (HE). However, the effects of long-term treatment for Japanese people are limited. Therefore, this study aimed to investigate the effects and safety of long-term treatment with rifaximin on HE. Methods: A total of 215 patients with cirrhosis administered with rifaximin developed overt or covert HE, which was diagnosed by an attending physician for >12 months. Laboratory data were extracted at pretreatment and 3, 6, and 12 months after rifaximin administration. The long-term effect of rifaximin was evaluated, and the incidence of overt HE during 12 months and adverse events was extracted. Results: Ammonia levels were significantly improved after 3 months of rifaximin administration and were continued until 12 months. There were no serious adverse events after rifaximin administration. The number of overt HE incidents was 9, 14, and 27 patients within 3, 6, and 12 months, respectively. Liver enzymes, renal function, and electrolytes did not change after rifaximin administration. Prothrombin activity is a significant risk factor for the occurrence of overt HE. The serum albumin, prothrombin activity, and albumin–bilirubin (ALBI) scores were statistically improved after 3 and 6 months of rifaximin administration. Moreover, the same results were obtained in patients with Child–Pugh C. Conclusions: The long-term rifaximin treatment was effective and safe for patients with HE, including Child–Pugh C.

Clinical correlation between coagulation disorders and sepsis in patients with liver failure.

This study aimed to explore the clinical detection and prognosis of coagulation function in patients with liver failure and sepsis. The plasma fibrinogen (FIB), factor II, factor VII, factor V, factor IV, antithrombin III (ATIII), platelet (PLT), mean PLT volume (MPV), D-dimer, prothrombin activity (PTA), and fibrin degradation product (FDP) levels and thromboelastogram values were detected in patients with liver failure complicated with sepsis and compared with those in the liver failure and liver cirrhosis groups. The patients with liver failure complicated with sepsis were analyzed by univariate and multivariate logistic regression, and the regression equation was established. The levels of FIB, factor II, factor VII, factor V, ATIII, PLT, MPV, D-dimer, and FDP in the patients with liver failure complicated with sepsis were compared with those in the control group patients, and the differences were statistically significant (p < 0.05). Among the thromboelastography parameters in the patients with liver failure and sepsis, the differences in the K-value, R-value, angle, maximum amplitude, and coagulation index values compared with those of the control group were statistically significant (p < 0.05). The logistic regression model obtained was as follows: p = 1/(1 + e [-0.128×X1-0.058×X2 + 0.211×X3 + 0.2×X4 + 0.25]). The specificity, sensitivity, and accuracy values of the regression equation in determining the prognosis were 92%, 93.9%, and 92.8%, respectively. Among the 11 factors, factor VII, PLT, FDP, and D-dimer were included in the regression equation. Coagulation disorder is exacerbated in patients with liver failure and sepsis. Among the 11 coagulation-related factors, factor VII, PLT, FDP, and D-dimer may be the independent factors influencing the prognosis of patients with acute liver failure and sepsis.

The functional role of the autolysis loop in the regulation of factor X upon hemostatic response

BackgroundThe regulation of factor X (FX) is critical to maintain the balance between blood coagulation and fluidity. ObjectivesTo functionally characterize the role of the FX autolysis loop in the regulation of the zymogen and active form of FX. MethodsWe introduced novel N‐linked glycosylations on the surface‐exposed loop spanning residues 143–150 (chymotrypsin numbering) of FX. The activity and inhibition of recombinant FX variants was quantified in pure component assays. The in vitro thrombin generation potential of the FX variants was evaluated in FX‐depleted plasma. ResultsThe factor VIIa (FVIIa)‐mediated activation and prothrombin activation was reduced, presumably through steric hinderance. Prothrombin activation was, however, recovered in presence of cofactor factor Va (FVa) despite a reduced prothrombinase assembly. The introduced N‐glycans exhibited position‐specific effects on the interaction with two FXa inhibitors: tissue factor pathway inhibitor (TFPI) and antithrombin (ATIII). Ki for the inhibition by full‐length TFPI of these FXa variants was increased by 7‐ to 1150‐fold, whereas ATIII inhibition in the presence of the heparin‐analog Fondaparinux was modestly increased by 2‐ to 15‐fold compared with wild‐type. When supplemented in zymogen form, the FX variants exhibited reduced thrombin generation activity relative to wild‐type FX, whereas enhanced procoagulant activity was measured for activated FXa variants. ConclusionThe autolysis loop participates in all aspects of FX regulation. In plasma‐based assays, a modest decrease in FX activation rate appeared to knock down the procoagulant response even when down regulation of FXa activity by inhibitors was reduced.

The medusa of Aurelia coerulea is similar to its polyp in molecular composition and different from the medusa of Stomolophus meleagris in toxicity

BackgroundThe incidents of Aurelia sp. stinging have recently increased because of a bloom in offshore area. However, their symptoms are much milder than those from another scyphozoan jellyfish, Stomolophus meleagris. MethodsThe molecular composition of the medusa and polyp of Aurelia coerulea was analyzed by sequencing the transcriptome and proteome. The toxicity of tentacle extract from A. coerulea medusa (A-TE) and S. meleagris medusa (S-TE) was measured by the survival rates of mice, their blood indexes, and integrity of red blood cells. ResultsThe medusa and polyp of A. coerulea are similar in molecular composition, while their gene expressions are significantly different at both transcriptome and proteome levels. A-TE displayed no in vitro hemolysis and caused mild damage to the liver, heart and kidney instead of lethality. In contrast, S-TE showed strong hemolytic toxicity, and lethal effect with serious damage to the liver, heart and kidney. The toxin screening in the medusae showed that there were similar toxin categories though the number of toxin species in A. coerulea was larger than that in S. meleagris. Among them, lactotransferrin and venom prothrombin activator were the two predominant protein toxins in the medusae of A. coerulea and S. meleagris, respectively. ConclusionsA. coerulea medusa and polyp have similar molecular compositions, though there are observable morphological differences. The toxicity of A. coerulea medusa is significantly weaker than that of S. meleagris medusa of which the variation in toxin expressions is feasibly an important reason.

Hypomethylation of thymosin β4 promoter is associated with glucocorticoid therapy in patients with acute-on-chronic hepatitis B-induced liver failure.

We aimed to determine whether the methylation status of thymosin β4 (Tβ4) promoter reflects the severity of acute-on-chronic hepatitis B liver failure (ACHBLF) and whether glucocorticoids affect this status. Fifty-six patients with ACHBLF, 45 with chronic hepatitis B (CHB) and 32 healthy controls (HCs), were retrospectively enrolled. Methylation-specific PCR and real-time PCR were used to detect Tβ4 methylation frequency and mRNA level. The expression of Tβ4 was measured before and after glucocorticoid treatment in patients with ACHBLF. Clinical and laboratory parameters were obtained. Tβ4 mRNA expression of patients with ACHBLF was lower than in patients with CHB or HCs, but the methylation frequency was higher. Tβ4 promoter methylation frequency was correlated with serum total bilirubin, prothrombin activity and model for end-stage liver disease score. Moreover, Tβ4 promoter methylation frequency decreased and demethylation occurred during glucocorticoid therapy. After glucocorticoid therapy, Tβ4 mRNA expression and liver function were better in patients with low levels of methylation than in those with higher levels. After 90 d, the survival of patients with low levels of methylation was significantly higher than those with high levels. Patients with ACHBLF who have low levels of Tβ4 methylation may show a more favorable response to glucocorticoid treatment.

Binding modes of prothrombin cleavage site sequences to the factor Xa catalytic triad: Insights from atomistic simulations

Prothrombin is a key zymogen of the coagulation process and can be converted to thrombin by the prothrombinase complex, which consists of factor Xa (FXa), cofactor Va (FVa), and phospholipids. Prothrombin can be activated at two cleavage sites, R271 and R320, which generates two intermediates: prethrombin-2 via the initial cleavage at R271, and meizothrombin via the first cleavage at R320. Several mechanisms have been proposed to explain this activation preference, but the role of cleavage site sequences in prothrombin activation has not been thoroughly investigated. Here, we used an advanced sampling technique, parallel tempering metadynamics with a well-tempered ensemble (PTMetaD-WTE), to study the binding modes of prothrombin cleavage site sequences R266AIEGRTATSEY277 (denoted as Pep271) and S315YIDGRIVEGSD326 (denoted as Pep320) to the FXa catalytic triad. Our study indicates that there exist three binding modes for Pep271 to the FXa catalytic triad but only one binding mode for Pep320 to the FXa catalytic triad. Further molecular dynamics simulations revealed that due to the strong electrostatic interactions, especially the H-bond interactions and salt bridges formed between Pep320 and FXa, the binding mode in the Pep320-FXa system is more stable than the binding modes in the Pep271-FXa system. In view of experimental observations and our results that there exists only one binding mode for Pep320 to the FXa catalytic triad and especially R320 in Pep320 can stably bind to the FXa catalytic triad, we believe that the first cleavage at R320 is favored.

Relationship between Hepatic Venous Anatomy and Blood Loss: Proposal of Vena Cava Half-Clamp with Trendelenburg Posture to Control Hepatic Venous Bleeding during Hepatectomy

Introduction: Predicting increased blood loss based on anatomical intervascular relationships is essential in major hepatectomy to understand the mechanism of hepatic venous bleeding. Method: We assessed 63 consecutive patients undergoing anatomical hepatectomy exposing the hepatic vein (HV) trunk at two institutes. Correlations between anatomical alterations of the hepatic inferior vena cava (IVC), HV, hepatic IVC, or right atrium (RA) and the blood loss per standard weight (BLSW) or blood transfusion (n=18) were analyzed. The results of IVC partial clamping (PC) were additionally examined. Result: The BLSW in type V-up anatomical morphology was significantly higher than that in straight type (p<0.05). The parameters associated with an increased BLSW (>13.5 mL/kg) were tumour size (>4 cm), prothrombin activity (<87%), CVP (>7 mmHg), area of suprahepatic IVC (<360 mm2), IVC-RA gap (>28 mm), longitudinal angle of IVC (<160°), and axial angle of the MHV (<55°). Multivariate analysis revealed that a high IVC-RA gap was a significant independent risk factor (odds ratio; 4.3, p<0.05). Among 25 patients undergoing IVC-PC, only three showed a remarkable decrease in hepatic venous bleeding. Although IVC-PC led to a decrease in systolic arterial pressure and difficult to control systemic circulation in many cases, the combined Trenderenburg posture could solve this problem. Conclusions: The IVC-RA gap might be a promising novel predictive parameter reflecting increased blood loss leading to blood transfusion in anatomical hepatectomy. Further, in the case of increased IVC gap and hepatic venous bleeding is difficult, our proposal combined procedure is feasible、easy, safe and useful.