• metabolic dysfunction-associated steatotic liver disease
• platelets
• type 2 diabetes mellitus

• Humans
• Male
• Female
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/physiopathology
• Middle Aged
• Platelet Count/methods
• Aged
• Blood Platelets/metabolism
• Insulin Resistance
• Fatty Liver/blood
• Fatty Liver/complications
• Fatty Liver/physiopathology
• Adult
• Biomarkers/blood

• Research Grant number 10126/5/17.12.2020 George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș

• ST-segment elevation myocardial infarction
• fibrosis-5 index
• major adverse cardiovascular events
• predictor

• early warning
• fib-4
• fibrosis score
• liver stiffness measurements
• nafld

• Humans
• Non-alcoholic Fatty Liver Disease/diagnostic imaging
• Cross-Sectional Studies
• Elasticity Imaging Techniques
• Uric Acid
• Liver Cirrhosis/diagnostic imaging
• Metabolic Syndrome

• bleeding symptoms
• hepatitis B
• liver cirrhosis
• rhTPO
• thrombocytopenia

Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-β1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis. Here, we analyzed the effect of a decrease in TGF-β1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-β1 antibody (anti-TGF-β1; 1 mg/mL). Next, we correlated it with a thrombocytopenia-induced TGF-β1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-β1 decrease on blood–brain barrier functionality. The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins’ decrease in analyzed fractions occurred in anti-TGF-β1 mice. In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-β mice, was observed. The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-β1 model. The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-β1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice.

• GI
• Liver
• paracetamol

• Japan
• algorithm
• blood transfusion
• chronic liver disease
• thrombocytopenia
• thrombopoietin receptor agonist

• Exviera
• Harvoni
• Viekirax
• direct-acting antiviral therapy
• hematological disorders
• hepatitis C

• Antiviral Agents/therapeutic use
• Drug Therapy, Combination
• Genotype
• Hepatitis C
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Humans
• Romania
• Treatment Outcome

Liver cirrhosis is a significant source of morbidity and mortality worldwide. The disease is usually indolent and asymptomatic early in its course while many cirrhotic patients are diagnosed late when severe complications occur. A major challenge is to diagnose advanced fibrosis as early as possible, using simple and non-invasive diagnostics tools. Thrombocytopenia represents advanced fibrosis and portal hypertension (HTN) and most non-invasive scores that predict liver fibrosis incorporate platelets as a strong risk factor. However, little is known about the association between longitudinal changes in platelet counts (PTC), when still within the normal range, and the risk of cirrhosis.

To explore whether platelet counts trajectories over time, can predict advanced liver fibrosis across the different etiologies of liver diseases.

A nested case-control study utilizing a large computerized database. Cirrhosis cases (n = 5258) were compared to controls (n = 15744) matched for age and sex at a ratio of 1:3. All participants had multiple laboratory measurements prior to enrollment. We calculated the trends of PTC, liver enzymes, bilirubin, international normalized ratio, albumin and fibrosis scores (fibrosis-4 and aspartate transaminase-to-platelet ratio index) throughout the preceding 20 years prior to cirrhosis diagnosis compared to healthy controls. The association between PTC, cirrhosis complications and fibrosis scores prior to cirrhosis diagnosis was investigated.

The mean age in both groups was 56 (SD 15.8). Cirrhotic patients were more likely to be smokers, diabetic with chronic kidney disease and had a higher prevalence of HTN. The leading cirrhosis etiologies were viral, alcoholic and fatty liver disease. The mean PTC decreased from 240000/μL to 190000/μL up to 15 years prior to cirrhosis diagnosis compared to controls who’s PTC remained stable around the values of 240000/μL. This trend was consistent regardless of sex, cirrhosis etiology and was more pronounced in patients who developed varices and ascites. Compared to controls whose values remained in the normal range, in the cirrhosis group aspartate aminotransferase and alanine aminotransferase, increased from 40 U/L to 75 U/L and FIB-4 increased gradually from 1.3 to 3 prior to cirrhosis diagnosis. In multivariable regression analysis, a decrease of 50 units in PTC was associated with 1.3 times odds of cirrhosis (95%CI 1.25-1.35).

In the preceding years before the diagnosis of cirrhosis, there is a progressive decline in PTC, within the normal range, matched to a gradual increase in fibrosis scores.

• Cirrhosis
• Platelets
• Count
• Trend
• Prediction
• Range

• Adult
• Aged
• Alanine Transaminase
• Aspartate Aminotransferases
• Biomarkers
• Case-Control Studies
• Humans
• Liver/pathology
• Liver Cirrhosis/epidemiology
• Liver Cirrhosis/pathology
• Middle Aged
• Platelet Count
• Retrospective Studies

• liver cancer
• liver fibrosis scores
• mortality

• Alanine aminotransferase
• Aspartate aminotransferase
• Metabolic syndrome
• Transferrin saturation
• γ-glutamyl transpeptidase

• Thrombocytopenia
• hospital acquired
• pathophysiology
• thrombopoiesis
• thrombopoietin

• chronic liver disease
• cirrhosis
• thrombocytopenia
• thrombopoietin

• Hepatitis C infection
• bone marrow
• cytopenia
• hypersplenism
• liver transplantation

• Diabetes
• Liver Fibrosis
• NAFLD
• Saudi Arabia
• Stiffness Measurements

Thrombocytopenia is one of the most frequently observed secondary complications in many pathological conditions including liver diseases, where hyperbilirubinemia is very common. The present study sought to find the cause of thrombocytopenia in unconjugated hyperbilirubinemic conditions. Unconjugated bilirubin (UCB), an end-product of heme catabolism, is known to have pro-oxidative and cytotoxic effects at high serum concentration. We investigated the molecular mechanism underlying the pro-apoptotic effect of UCB on human platelets in vitro, and followed it up with studies in phenylhydrazine-induced hyperbilirubinemic rat model and hyperbilirubinemic human subjects. UCB is indeed found to significantly induce platelet apoptotic events including elevated endogenous reactive oxygen species generation, mitochondrial membrane depolarization, increased intracellular calcium levels, cardiolipin peroxidation and phosphatidylserine externalization (p < 0.001) as evident by FACS analysis. The immunoblots show the elevated levels of cytosolic cytochrome c and caspase activation in UCB-treated platelets. Further, UCB is found to induce mitochondrial ROS generation leading to p38 activation, followed by downstream activation of p53, ultimately resulting in altered expression of Bcl-2 and Bax proteins as evident from immunoblotting. All these parameters conclude that elevated unconjugated bilirubin causes thrombocytopenia by stimulating platelet apoptosis via mitochondrial ROS-induced p38 and p53 activation.