Fibrinogen Function Research Articles

Fibrinogen dysfunction and fibrinolysis state in patients with hepatitis B-related cirrhosis

ABSTRACT Objective To assess the fibrinogen function in patients with hepatitis B-related cirrhosis and explore the relationship between dysfibrinogenemia and bleeding and thrombotic events. Methods Medical records and laboratory data of the patients with hepatitis B-related cirrhosis were collected. Patients were categorized into three groups based on the Child-Pugh score. Fibrinogen activity and antigen, fibrinogen-bound sialic acid (FSA), fibrinogen polymerization and fibrinolysis kinetic analysis, thrombin-antithrombin complex (TAT) and plasmin-α2-antiplasmin complex (PAP) were detected. Results Eighty patients with seventeen, thirty-eight and twenty-five in Child-Pugh A, B and C, respectively, were included. Seventeen patients experienced bleeding events and eight patients had thrombotic events. Fibrinogen activity and antigen levels were reduced with the severity of cirrhosis. Twenty-two patients exhibited dysfibrinogenemia. The FSA levels in patients with non-dysfibrinogenemia and those with dysfibrinogenemia were increased to 1.25 and 1.37 times of healthy controls, negatively correlated with fibrinogen activity (ρ = −0.393, p = 0.006). Compared to healthy controls, the amount of clot formation was reduced (p < 0.001), the polymerization was delayed (p < 0.001) and the rate of fibrinolysis was reduced (p < 0.001). The TAT levels were significantly increased in the Child-Pugh C patients compared to the Child-Pugh B patients (p = 0.032) while the PAP levels were comparable among 3 groups (p = 0.361). Conclusion Sialylation of fibrinogen is one of the main causes of modifications of fibrinogen in patients with hepatitis B-related cirrhosis. The polymerization and fibrinolysis functions of fibrinogen are impaired. The degree of impaired fibrinolysis function is more severe than that of polymerization function, and may be partly related to the occurrence of thrombotic events.

Rotational Thromboelastometric Profile in Early Sepsis: A Prospective Cohort Study.

Coagulation abnormalities are common in sepsis patients and are associated with increased mortality. This study aimed to assess the hemostatic profile of sepsis patients using rotational thromboelastometry (ROTEM) and to find the ROTEM parameters best predicting short-term mortality. We conducted a prospective analysis of consecutive sepsis patients hospitalized in the intensive care unit. The inclusion criteria were diagnosis of sepsis or septic shock and pro-calcitonin concentration >0.5 ng mL-1. Clinical, standard laboratory, and ROTEM analyses were performed. The study group comprised 38 (49%) males and 40 (51%) females. Median Sequential Organ Failure Assessment (SOFA) score was 8 (interquartile range IQR 5-11) points. The most common primary sites of infection were pneumonia (n = 27/35%), intra-abdominal (n = 27/35%), urinary tract infection (n=20/26%), and others (n = 4/6%). The following parameters evaluating fibrinogen function were outside the reference range: clotting time (CT), clot amplitude (A) at 10 and 20 min, and maximal clot firmness (MCF). Out of 78 patients, 28 (36%) died in the intensive care unit. Significant differences between survivors and non-survivors of sepsis were present for the ROTEM parameters assessing fibrinolytic activity. ROTEM in the early phase of sepsis reveals increased coagulation mediated through the function of fibrinogen. Non-survivors showed slightly lower fibrinolytic activity than survivors; however, it was still within test reference values. The highest predicting value was obtained by a model incorporating, among others, extrinsic coagulation pathway fibrinolytic parameters.

The Effect of Maternal Blood Glucose on Umbilical Cord Blood Fibrinogen in Women With Gestational Diabetes.

Gestational diabetes mellitus (GDM) is delineated by the presence of glucose intolerance at any level that manifests or is initially identified during pregnancy. Factor I fibrinogen is among the most essential blood coagulation proteins. The concentration of fibrinogen influences platelet aggregation and blood viscosity. This study aimed to determine the correlation between fetal cord blood fibrinogen and plasma fibrinogen in pregnant women with GDM and between fetal cord blood fibrinogen and maternal blood sugar. A cross-sectional study was executed at Al-Elwiya Maternity Teaching Hospital in the obstetrics and gynecology department. The sample included 90 term pregnant women: 45 were confirmed to have GDM, and 45 healthy pregnant women served as control. Estimation of prelabor maternal fasting and random plasma glucose and plasma fibrinogen was performed. During delivery, blood was drawn from the umbilical cord to estimate neonatal plasma glucose and fibrinogen levels. The mean maternal plasma fibrinogen level exhibited a notable increase in women with GDM compared to the control (330.11 ± 56.92 mg/dl versus 254.89 ± 41.01 mg/dl). The infants of diabetic mothers had significantly lower mean cord plasma glucose levels (65.71 ± 14.63 mg/dl versus 77.80 ± 7.81 mg/dl) and higher mean cord plasma fibrinogen levels (269.42 ± 25.91 mg/dl versus 229.69 ± 21.29 mg/dl). Umbilical cord plasma fibrinogen was correlated positively with maternal plasma sugar and fibrinogen. A positive correlation between maternal and fetal cord fibrinogen levels was determined in women with GDM. Monitoring plasma fibrinogen levels in neonates of mothers with GDM could be facilitated by longitudinal, large-scale validation studies enabled by artificial intelligence as a new, evolving technique that contributes to more valuable outcomes. This would shed additional light on the course and function of plasma fibrinogen for a more comprehensive analysis of the fetal clotting system.

Comparative studies between humans and golden Syrian hamsters via thromboelastography.

Thromboelastography (TEG) is a widely utilized clinical testing method for real-time monitoring of platelet function and the thrombosis process. Lipid metabolism disorders are crucial risk factors for thrombosis. The lipid metabolism characteristics of hamsters resemble those of humans more closely than mice and rats, and their relatively large blood volume makes them suitable for studying the mechanisms of thrombosis related to plasma lipid mechanisms. Whole blood samples from golden Syrian hamsters and healthy humans were obtained following standard clinical procedures. TEG was employed to evaluate coagulation factor function, fibrinogen (Fib) function, platelet function, and the fibrinolytic system. The whole blood from hamster or healthy human was isolated following the clinical procedure, and TEG was employed to evaluate the coagulation factor function, Fib function, platelet function, and fibrinolytic system. Coagulation analysis used ACLTOP750 automatic coagulation analysis pipeline. Blood routine testing used XN-2000 automatic blood analyzer. TEG parameters revealed that hamsters exhibited stronger coagulation factor function than humans (reaction time [R], p = 0.0117), with stronger Fib function (alpha angle, p < 0.0001; K-time [K], p < 0.0001). Platelet function did not differ significantly (maximum amplitude [MA], p = 0.077). Hamsters displayed higher coagulation status than humans (coagulation index [CI], p = 0.0023), and the rate of blood clot dissolution in hamsters differed from that in humans (percentage lysis 30 min after MA, p = 0.02). Coagulation analysis parameters indicated that prothrombin time (PT) and activated partial thromboplastin time (APTT) were faster in hamsters than in humans (PT, p = 0.0014; APTT, p = 0.03), whereas the Fib content was significantly lower in hamsters than in humans (p < 0.0001). No significant difference was observed in thrombin time (p = 0.1949). In summary, TEG could be used to evaluate thrombosis and bleeding parameters in whole blood samples from hamsters. The platelet function of hamsters closely resembled that of humans, whereas their coagulation function was significantly stronger.

Association of altered fibrinogen indexes levels as a potential biomarker in determining the possible onset of diabetic retinopathy

Research suggests that fibrinogen was related to diabetic retinopathy (DR). Then, the relationship between functional indices of fibrinogen and detailed staging of DR has not been explored. Type 2 diabetic and healthy control subjects (n = 960) were recruited in a cross-sectional study. Participants with type 2 diabetes mellitus were categorized into five stages according to their fundus lesions, and fibrinogen (Fib) and its functional indices (angle α and k value) were measured. The angle α levels increased in diabetic subjects with retinopathy compared with those without, and it was significantly elevated early in retinopathy. In contrast, the k value levels slightly decreased. Despite observing an increase in angle α levels and a decrease in k value levels during the later stages of retinopathy compared to the earlier stages, there was no statistically significant difference in the later stages. The association of the angle α and k value with DR was independent of the hyperglycaemic state and other potential confounders (OR = 1.672, 95% CI 1.489–1.876, P < 0.01; OR = 0.013, 95% CI 0.004–0.041, P < 0.01). The angle α levels and k value levels were closely correlated with retinopathy (r = 0.593, P < 0.00; r = − 0.646, P < 0.01). The ROC curve indicated that the diagnostic value of angle α and k value were (AUC = 0.897, P < 0.001; AUC = 0.859, P < 0.001). Fibrinogen function indexes, such as angle α and k value, may be valuable for the early diagnosis of DR but do not directly assess the severity of DR.

Investigation of acquired dysfibrinogenaemia in adult patients with sepsis using fibrinogen function vs. concentration ratios: a cross-sectional study.

Inherited or acquired molecular abnormalities form a clinically heterogeneous group of fibrinogen disorders called dysfibrinogenaemia. Apart from a pediatric case report and in contrast to other clinical conditions, acquired dysfibrinogenaemia has not been previously reported in septic patients. In an observational cohort study, 79 adult septic patients were investigated for the presence of acquired dysfibrinogenaemia at the time of their admission to the intensive care unit (ICU) of the University Hospital Frankfurt. Following established recommendations, fibrinogen clotting activity vs. antigen ratios were analyzed using Clauss fibrinogen, prothrombin-derived fibrinogen, and radial immunodiffusion (RID) fibrinogen concentration. Prothrombin-derived fibrinogen levels were highest (527 ± 182 mg/dL) followed by Clauss fibrinogen (492 ± 209 mg/dL) and radial immunodiffusion fibrinogen (426 ± 159 mg/dL). Very few cases demonstrated hypofibrinogenaemia making overt disseminated intravascular coagulation (DIC) unlikely in the cohort investigated. Clauss/RID fibrinogen ratios were lower (1.17 ± 0.19) compared to prothrombin time-derived/RID ratios (1.35 ± 0.33). Using the Clauss/RID dataset, 21% of patients (16/76 patients) demonstrated values below a threshold ratio for suspected acquired dysfibrinogenaemia arbitrarily set at 1.0. In contrast, prothrombin-derived ratios were below the threshold in only 7% (4/58 patients). The results point to the presence of acquired dysfibrinogenaemia in part of adult septic patients. If confirmed in further studies, this may form part of a specific laboratory signature of a sepsis-associated coagulation phenotype.

International council for standardisation in haematology recommendations on fibrinogen assays, thrombin clotting time and related tests in the investigation of bleeding disorders.

This guidance was prepared on behalf of the International Council for Standardisation in Haematology (ICSH) by an international working group of clinicians and scientists. The document focuses on tests and assays used for the assessment of fibrinogen function, particularly in the scenario of bleeding disorders. Thrombin clotting time (TT) is used as a screening test in some laboratories and also has some utility when direct anticoagulants are in use. The Clauss fibrinogen assay remains the method of choice for the assessment of fibrinogen function, but there are some situations where the results may be misleading. Prothrombin time derived fibrinogen assays are frequently used, but should be interpreted with caution; the results are not interchangeable between different methods and fibrinogen can be overestimated in certain clinical scenarios. Viscoelastic point of care methods may be helpful in emergency situations, while Reptilase time (and similar tests) are useful combined with TT in distinguishing heparin contamination of samples (i.e., if an incorrect blood draw is suspected) and the presence of direct thrombin inhibitors. Fibrinogen antigen assays should be used in the investigation of functional fibrinogen abnormalities; fibrinogen antigen and genetic testing are recommended in the confirmation of congenital fibrinogen disorders. The following recommendations for fibrinogen function assessment are based on published literature and expert opinion and should supplement local regulations and standards.

Clot Retraction and Its Correlation with the Function of Platelet Integrin αIIbβ3.

Clot retraction results from retractions of platelet filopodia and fibrin fibers and requires the functional platelet αIIbβ3 integrin. This assay is widely used to test the functions of platelets and fibrinogen as well as the efficacy of fibrinolysis. Changes in clot retraction have been found in a variety of hemostatic abnormalities and, more recently, in arterial thrombosis. Despite its broad clinical use and low cost, many aspects of clot retraction are poorly understood. In the present study, we performed two clinical standard clot retraction assays using whole-blood and platelet-rich plasma (PRP) samples to determine how clot retraction correlates with platelet counts and mean volume, the density of αIIbβ3 integrin and PLA genotypes, and plasma fibrinogen levels. We found that clot retraction was affected by platelet counts, but not mean platelet volume. It correlated with the surface density of the integrin αIibβ3, but not PLA genotypes. These results indicate that clot retraction measures a unique aspect of platelet function and can serve as an additional means to detect functional changes in platelets.

Cellular mechanisms of fibrin (ogen): insight from neurodegenerative diseases.

Neurodegenerative diseases are prevalent and currently incurable conditions that progressively impair cognitive, behavioral, and psychiatric functions of the central or peripheral nervous system. Fibrinogen, a macromolecular glycoprotein, plays a crucial role in the inflammatory response and tissue repair in the human body and interacts with various nervous system cells due to its unique molecular structure. Accumulating evidence suggests that fibrinogen deposits in the brains of patients with neurodegenerative diseases. By regulating pathophysiological mechanisms and signaling pathways, fibrinogen can exacerbate the neuro-pathological features of neurodegenerative diseases, while depletion of fibrinogen contributes to the amelioration of cognitive function impairment in patients. This review comprehensively summarizes the molecular mechanisms and biological functions of fibrinogen in central nervous system cells and neurodegenerative diseases, including Alzheimer's disease, Multiple Sclerosis, Parkinson's disease, Vascular dementia, Huntington's disease, and Amyotrophic Lateral Sclerosis. Additionally, we discuss the potential of fibrinogen-related treatments in the management of neurodegenerative disorders.

Administration of Robusta Coffee (Coffea canephora) Decreased Erythrocyte Sedimentation Rate on Hyperlipidemia Rats

Background: Hyperlipidemia is one of the factors that can trigger atherosclerosis which is characterized by abnormalities in lipid metabolism in the blood, especially increased LDL levels above normal. The increase in level of LDL stimulates the production of several cytokines that can affect the increase in acute phase proteins, especially fibrinogen. The presence of fibrinogen functions in increasing the Erytrocyte Sedimentation Rate (ESR) through its positive charge to neutralize the surface of erythrocytes. Prevention efforts to reduce ESR use herbal plants that do not have side effects, namely robusta coffee. Anti-inflammatory and antioxidant activity in robusta coffee is thought to be effective in reducing ESR through inhibition of cytokine production in the inflammatory response. Objective: This study aimed to determine differences in ESR values ​​after administration of robusta coffee to hyperlipidemia rats. Methods: Fiveteen male Wistar rats were randomly divided into 3 research groups including the control group (K), the hyperlipidemia group (H), and the hyperlipidemia + coffee group (C). Induction of hyperlipidemia by feeding duck egg yolk and pork oil. The calculation of the ESR level uses the Westegreen method in mm/hour. Results and Conclusions: Robusta coffee can affect the decrease in ESR values ​​in hyperlipidemia rats

Evaluation of fibrinogen function by CFF-A10 in cardiac surgery

Fibrinogen function is evaluated as the maximum amplitude (MA) of the citrated functional fibrinogen (CFF) assay in TEG6s®, however, CFF-MA requires a long time to obtain results. CFF-A10 (10-minute value), allowing more rapid decisions, however, no studies have evaluated the correlation between CFF-A10 levels and fibrinogen concentration. This study aimed to assess the correlation between CFF-A10 and blood fibrinogen levels measured using the dry hematology method after cardiopulmonary bypass (CPB). This retrospective study was conducted in a single university hospital and enrolled 192 patients of all ages who underwent cardiovascular surgery with CPB between 01 March 2020, and 05 November 2021. CFF-A10 and CFF-MA levels were measured using the TEG6s® global hemostasis assay, and blood fibrinogen levels were measured using the Fibcare® DRIHEMATO Fib-HSII after CPB. Simple linear regression analysis was used to evaluate the relationship between TEG6s® parameters and fibrinogen concentration. Furthermore, the patients were classified into four groups based on the cut-off values of fibrinogen at 150 mg/dL and CFF-A10, and the background factors for each group were analyzed. CFF-A10 and blood fibrinogen levels were correlated by linear regression (p &lt; 0.0001, R2 = 0.37), similar to CFF-MA and fibrinogen levels (p &lt; 0.0001, R2 = 0.40). The optimal cut-off value, which maximizes the sensitivity and specificity, of CFF-A10 for predicting low fibrinogen levels below 150 mg/dL, was 8.4 mm, with a sensitivity of 80.7% and specificity of 67.9%; that of CFF-MA was 9.2 mm, with a sensitivity of 76.3% and specificity of 69.8%. Despite sufficient blood fibrinogen levels, patients with low CFF-A10 levels experienced more postoperative bleeding. CFF-A10 predicted fibrinogen loss faster and with the same accuracy as CFF-MA did. Low CFF-A10 levels, despite sufficient fibrinogen levels, may be associated with increased blood loss following CPB.

Fibrinogen function indexes are potential biomarkers for evaluating the occurrence and severity of diabetic foot

Background and objectivesResearch suggests that fibrinogen (Fib) concentrations are used to assess the occurrence and severity of diabetic foot (DF) and to monitor the progression of diabetic foot in patients. However, its correlation with Fib function has not been reported. Here, angle α and k value, reflecting the Fib function, were used to analyse its correlation with DF, and their potential as biological indicators for evaluating the occurrence and severity of DF was explored.Subjects and methodsThis clinical study enrolled 163 type 2 diabetes mellitus (T2DM) patients, who were divided into the diabetes with DF (84 cases) group, diabetes with no DF (79 cases) group. Meanwhile, 90 healthy unrelated subjects were enrolled as controls.ResultsAngle α and fibrinogen levels increased greatly in subjects with DF compared with those without. The k value levels greatly decreased in subjects with DF compared with those without (P < 0.01). Spearman correlation analysis showed that angle α and fibrinogen were positively correlated with DF grading (r = 0.635, P < 0.01; r = 0.616, P < 0.01), k value was negatively correlated with DF (r= − 0.589, P < 0.01). ROC curve analysis showed that the optimal cut-off point for angle α to distinguish patients with DF from those without was 62.85 deg, with a sensitivity of 78.6% and specificity of 78.7%. The optimal cut-off point for k value was 1.75 min, with a sensitivity of 82.1% and specificity of 65.8%. The optimal cut-off point for fibrinogen was 3.85 g/l, with a sensitivity of 63.1% and specificity of 98.2%. The optimal cut-off point for angle α to evaluate the risk of diabetic foot progression was 70.20 deg, with a sensitivity of 73.2% and specificity of 90.7%. The optimal cut-off point for k value was 1.25 min, with a sensitivity of 67.9% and specificity of 90.8%. The optimal cut-off point for fibrinogen was 4.12 g/l, with a sensitivity of 85.7% and specificity of 93.5%.ConclusionAngle α, k-value and fibrinogen have clinical significance on the risk of occurrence and development of diabetic foot, which can contribute to early diagnosis and early clinical intervention in DF.

Impact of Genetic and Post-Translational Modifications on Structure and Function of Fibrinogen

Introduction: Fibrinogen is a highly heterogeneous protein that is a result of several types of alteration, including genetic polymorphisms, alternative mRNA processing, posttranslational modifications, proteolytic cleavage and environmental factors. The different combinations of these alternations cause a formation of abnormal variants of fibrinogen that may affect the molecule. Fibrinogen is more vulnerable to oxidative stress than other plasmatic proteins. The oxidative post-translational modifications can be caused by different reactive oxygen species (ROS) and change the spatial structure, thus, impaired protein function. Here, we characterized 48 patients, belonging to 30 unrelated families, with fibrinogen mutation. This study aims to understand the behavior of these alternated fibrinogens in blood coagulation. Methods: We investigated these fibrinogens using a wide range of biochemical procedures, including fibrin polymerization, fibrinolysis, fibrinopeptides (Fps) release measurement, tandem mass spectrometry, thromboelastography, protein modeling, and scanning electron microscopy (SEM). Results: Dysfibrinogenemia was diagnosed in 35 cases, mostly in exon 2 of FGA gene, around thrombin cleavage site in N-termini of Aα chain. Hypofibrinogenemia was found in 13 remaining cases. Novel mutations were identified in 7 cases - heterozygous missense BβY416C and BβA68S, homozygous nonsense BβY345*, heterozygous nonsense BβW403*, heterozygous missense FGG c.8G>A, heterozygous missense γT34A, and heterozygous missense γG284E mutations. All patients had decreased levels of functional and/or plasmatic fibrinogen. Functional tests showed abnormal fibrin development in all patients with lower maximal absorbance. Moreover, fibrinopeptide cleavage measurements revealed differences between the release of Fps in patients with mutation in position close or in the binding site od thrombin. The results obtained from SEM were significantly different in fiber thicknesses or average number of fibers per 1µm2. Homology modeling showed the impaired protein structure of BβA68S and γG284E. Mass spectrometry detected several post-translational oxidations of fibrinogen. Conclusion: The results indicate that detected post-translational modifications, induced very likely by ROS, may affect the overall clottability of fibrinogen and clot morphology. Consequently, our study demonstrates that the identification, characterization, and modeling of novel fibrinogen variants brings new knowledge to fibrinogen domain structures and interactions that influence the assembly, secretion and function of this molecule. This work was supported by the project of the Ministry of Health, Czech Republic (00023736).

Altered Cortical Palmitoylation Induces Widespread Molecular Disturbances in Parkinson's Disease.

The relationship between Parkinson's disease (PD), the second-most common neurodegenerative disease after Alzheimer's disease, and palmitoylation, a post-translational lipid modification, is not well understood. In this study, to better understand the role of protein palmitoylation in PD and the pathways altered in this disease, we analyzed the differential palmitoyl proteome (palmitome) in the cerebral cortex of PD patients compared to controls (n = 4 per group). Data-mining of the cortical palmitome from PD patients and controls allowed us to: (i) detect a set of 150 proteins with altered palmitoylation in PD subjects in comparison with controls; (ii) describe the biological pathways and targets predicted to be altered by these palmitoylation changes; and (iii) depict the overlap between the differential palmitome identified in our study with protein interactomes of the PD-linked proteins α-synuclein, LRRK2, DJ-1, PINK1, GBA and UCHL1. In summary, we partially characterized the altered palmitome in the cortex of PD patients, which is predicted to impact cytoskeleton, mitochondrial and fibrinogen functions, as well as cell survival. Our study suggests that protein palmitoylation could have a role in the pathophysiology of PD, and that comprehensive palmitoyl-proteomics offers a powerful approach for elucidating novel cellular pathways modulated in this neurodegenerative disease.

Space-time-regulated imaging analyzer for smart coagulation diagnosis

SummaryThe development of intelligent blood coagulation diagnoses is awaited to meet the current need for large clinical time-sensitive caseloads due to its efficient and automated diagnoses. Herein, a method is reported and validated to realize it through artificial intelligence (AI)-assisted optical clotting biophysics (OCB) properties identification. The image differential calculation is used for precise acquisition of OCB properties with elimination of initial differences, and the strategy of space-time regulation allows on-demand space time OCB properties identification and enables diverse blood function diagnoses. The integrated applications of smartphones and cloud computing offer a user-friendly automated analysis for accurate and convenient diagnoses. The prospective assays of clinical cases (n = 41) show that the system realizes 97.6%, 95.1%, and 100% accuracy for coagulation factors, fibrinogen function, and comprehensive blood coagulation diagnoses, respectively. This method should enable more low-cost and convenient diagnoses and provide a path for potential diagnostic-markers finding.

Establishment of normal reference range for thromboelastography based on 17,708 cases in Beijing, China.

BackgroundThromboelastography (TEG) can dynamically evaluate the interaction between platelets and coagulation cascade and the effects of other cellular components on the activities of plasma factors, to comprehensively analyze the whole process of blood coagulation and dissolution. Due to differences in both the incidence rates and the coagulation state of related diseases, many studies have highlighted the necessity of establishing the normal reference ranges for TEG for local regions. The aim of the present study was to determine the local normal reference ranges according to the TEG results of 17,708 volunteers in Beijing, to explore the coagulation characteristics related to the age and sex of the study population.MethodsReference ranges of reaction time (R), coagulation time (K), coagulation angle (α-angle), and maximum thrombus consistency (MA) for TEG in healthy adults in Beijing were determined in the physical examination of 17,708 Beijing volunteers (5,319 women and 12,389 men). The volunteers were divided into the elderly group (≥60 years old) and young and middle-aged group (20–59 years old), and the reference ranges of each group were calculated according to sex.ResultsBased on the TEG results of the 17,708 volunteers who underwent physical examination, the 95% reference ranges of R, K, α-angle, and MA for TEG in Beijing were 5.1–10 min, 1.3–3.8 min, 44.9–70.2°, and 50.4–71 min, respectively. The results of R, K, α-angle, and MA for TEG between the young and middle-aged group and the elderly group, as well as between women and men were significantly different (P<0.001). Finally, reference ranges for TEG in the young and middle-aged group and the elderly group were obtained.ConclusionsCompared with the reference standards provided by previous reagent manufacturers, the coagulation factor and fibrinogen function of TEG tend to be hypocoagulable in Beijing population. We found that the young and middle-aged group had lower coagulation activity than the elderly group, and women had higher coagulation activity than men in the same group.

The influence of circulating fibrinogen level on postoperative blood loss and blood transfusion in pediatric cardiac surgery: a retrospective observational study.

Pediatric patients are at high risk of massive bleeding after cardiac surgery under cardiopulmonary bypass (CPB). Fibrinogen is essential for coagulation; however, pediatric patients with congenital heart disease (CHD) present abnormal fibrinogen function. The pre- and post-operative fibrinogen level may affect the bleeding and transfusion amount in patients undergoing cardiac surgery. However, the relationship between plasma fibrinogen levels and the bleeding and transfusion amount in pediatric cardiac surgery remains unclear. This study aimed to assess the association of pre-CPB fibrinogen levels (PreFib) and post-CPB fibrinogen levels (PostFib) with postoperative bleeding and transfusion volume in pediatric cardiac surgery. We reviewed the medical records of 375 newborns and infants who underwent cardiac surgery under CPB for CHD. The primary endpoint was the correlation of the PreFib and PostFib values, as well as their difference (FibGap), with the bleeding and transfusion amount within 24 postoperative hours. There was no correlation of the PreFib, PostFib, and FibGap values with the bleeding and transfusion amounts at postoperative 24 hours. However, patients with PreFib and PostFib values of <150 and <100 mg/dL, respectively, showed a significantly higher frequency of postoperative platelet (PLT) transfusion. In patients with complex CHD, PreFib showed a weak negative correlation with the bleeding amount at postoperative 24 hours and the number of PLT-transfused patients. Our findings suggest that in pediatric patients with CHD who cannot undergo point-of-care (POC) tests, those presenting PreFib and PostFib values of <150 and <100 mg/dL, respectively, have a significantly higher frequency of postoperative PLT transfusion.

Effects of regional citrate anticoagulation on thrombin generation, fibrinolysis and platelet function in critically ill patients receiving continuous renal replacement therapy for acute kidney injury: a prospective study

BackgroundRegional citrate anticoagulation (RCA) is recommended for continuous renal replacement therapy (CRRT). However, filter life varies and premature filter clotting can occur. The aims of this explorative prospective study were to investigate the effects of RCA on thrombin generation, fibrinolysis and platelet function in critically ill patients receiving CRRT, to compare clotting parameters between systemic and intra-circuit blood samples, and to screen participants for coagulation disorders. We recruited critically ill adult patients admitted to a 30-bedded Intensive care unit in a tertiary care hospital who required CRRT with RCA for acute kidney injury (AKI). Patients with pre-existing thrombotic, bleeding tendencies or a CRRT duration less than 48 h were excluded. We measured coagulation and thrombophilia parameters at baseline. Thrombin generation, D-dimer and platelet function were measured pre-CRRT and at 12, 24, 36, 48 and 72 h after commencing CRRT using blood samples taken from the arterial line and the circuit.ResultsAt baseline, all eleven patients (mean age 62.4 years, 82% male) had Factor VIII and von Willebrand Factor concentrations above reference range and significantly increased peak thrombin generation. During CRRT, there were no significant changes in systemic maximum peak thrombin generation, time to peak thrombin generation, fibrinogen, D-dimer and platelet function analysis. We observed no significant difference between paired samples taken from the patient's arterial line and the circuit.ConclusionsCritically ill patients with AKI requiring CRRT are hypercoagulable. Citrate used for anticoagulation during CRRT does not affect thrombin generation, D-dimer or platelet function. Systemic clotting parameters reflect intra-circuit results.Trial registration: ClinicalTrials.gov Identifier: NCT02486614.Registered 01 July 2015—Registered after recruitment of first patient. https://clinicaltrials.gov/ct2/show/NCT02486614

Plasma D-dimer value corrected by inflammatory markers in patients with SARS-CoV-2 infection: Its prognostic value in the diagnosis of venous thromboembolism

IntroductionD-dimer levels are elevated in COVID 19 and they correlate to the levels of other inflammatory markers such us ferritin, fibrinogen and C-reactive protein. It may be possible to correct D-dimer value in function of inflammatory markers, thus identifying patients at higher risk of venous thromboembolism (VTE). Our objectives are estimating a corrected value of plasma D-dimer as a linear function of ferritin, C-reactive protein and fibrinogen and stablishing a cut-off point of high probability of VTE. Patients and methodsAge and sex matched case-control study of all patients diagnosed with COVID 19 and VTE between March and May 2020 in a tertiary hospital in Madrid (Spain). Using linear regression, the best predictive model will be estimated and residual D-dimer values will be obtained and analyzed using ROC curves to determine its discriminative performance. ResultsThirty-eight cases and seventy-six controls were included. There was 63.2% of men and mean age was 68.2. D-dimer was best predicted by a linear model including fibrinogen, ferritin and C-reactive protein. Using residual values, the optimal cutoff point was 2165ng/mL, with a sensitivity of 57.9% and specificity of 98.7%. ConclusionIt is possible to estimate a D-dimer corrected value in function of ferritin, C-reactive protein and fibrinogen. Using the observed and estimated value we can obtain a residual value that performs well as a screening method to detect patients who would benefit for further VTE diagnostic testing.

Leukocyte activation primes fibrinogen for proteolysis by mitochondrial oxidative stress

Critical illness leads to rapid fibrinogen consumption, hyperfibrinolysis, and coagulopathy that exacerbates bleeding and increases mortality. Immune cell activation and inflammation are associated with coagulopathy after injury but play an undetermined role. We performed high dimensional immunophenotyping and single-cell imaging flow cytometry to investigate for a pathophysiological mechanism governing the effects of leukocyte-associated inflammation on fibrinogen function. Fibrinogen was oxidized early, followed by its degradation after 3 hours of lipopolysaccharides (LPS)-induced sterile inflammation in a rat model in vivo. Fibrinogen incubated with human leukocytes activated by TNFα was similarly oxidized, and later proteolyzed after 3 hours in vitro. TNFα induced mitochondrial superoxide generation from neutrophils and monocytes, myeloperoxidase (MPO)-derived reactive oxygen species (ROS) from neutrophils, and nitric oxide from lymphocytes and monocytes. Inhibition of mitochondrial superoxide prevented oxidative modification and proteolysis of fibrinogen, whereas inhibition of MPO attenuated only fibrinogen proteolysis. Quenching of both mitochondrial superoxide and MPO-derived ROS prevented coagulopathy better than tranexamic acid. Collectively, these findings indicate that neutrophil and monocyte mitochondrial superoxide generation can rapidly oxidize fibrinogen as a priming step for fibrinogen proteolysis and coagulopathy during inflammation.