Fabrication of heart tubes from iPSC derived cardiomyocytes and human fibrinogen by rotating mold technology.

Due to its structural and functional complexity the heart imposes immense physical, physiological and electromechanical challenges on the engineering of a biological replacement. Therefore, to come closer to clinical translation, the development of a simpler biological assist device is requested. Here, we demonstrate the fabrication of tubular cardiac constructs with substantial dimensions of 6 cm in length and 11 mm in diameter by combining human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and human foreskin fibroblast (hFFs) in human fibrin employing a rotating mold technology. By centrifugal forces employed in the process a cell-dense layer was generated enabling a timely functional coupling of iPSC-CMs demonstrated by a transgenic calcium sensor, rhythmic tissue contractions, and responsiveness to electrical pacing. Adjusting the degree of remodeling as a function of hFF-content and inhibition of fibrinolysis resulted in stable tissue integrity for up to 5 weeks. The rotating mold device developed in frame of this work enabled the production of tubes with clinically relevant dimensions of up to 10 cm in length and 22 mm in diameter which-in combination with advanced bioreactor technology for controlled production of functional iPSC-derivatives-paves the way towards the clinical translation of a biological cardiac assist device.

The Relationship between the Level of Coagulative Function Hypertensive Disorder Complicating Pregnancy.

BACKGROUND AND AIM: Preeclampsia, a pregnancy complication associated with significant maternal and perinatal mortality and morbidity, has been found to be closely linked to dysfunction in the blood coagulation-fibrinolysis system. However, the relationship between hematologic data and severity and onset time of preeclampsia remains unclear. This study aimed to identify specific hematologic parameters in both preeclamptic and normotensive pregnant women and determine their potential significance in the pathogenesis of preeclampsia. MATERIALS AND METHODS: A total of 112 patients with gestational hypertension disease were divided into two groups: early-onset preeclampsia (32 cases) and late-onset preeclampsia (80 cases). A control group of 82 normotensive pregnant women matched for age and parity was also selected. Blood samples were collected from all participants to test for specific hematologic parameters. RESULTS: Mild and severe preeclampsia were associated with lower hemoglobin level (P = 0.01 and P = 0.03, respectively), higher mean platelet volume (P = 0.01 and P = 0.01, respectively) and fibrinogen (P = 0.01 and P = 0.01, respectively), and shorter prothrombin time (P = 0.02 and P = 0.01, respectively) and activated partial thromboplastin time (P = 0.01 and P = 0.02, respectively). CONCLUSION: These findings have provided evidence on the hematologic coagulative actors in the pathogenesis and severity of preeclampsia.

Fibrinogen to albumin ratio's prognostic value in ischemic stroke patients who underwent mechanical thrombectomy.

Background and purpose:

Fibrinogen to albumin ratio (FAR) is thought to have a predictive effect in diseases such as cancer and myocardial infarction. We aimed to elucidate the prognostic value of FAR in ischemic stroke patients who underwent mechanical thrombectomy.

A total of 103 patients hospita­lized for acute stroke who underwent me­cha­nical thrombectomy within 6 hours of symp­toms’ outset have been analyzed retro­spectively. Stroke severity was interpreted via the National Institutes of Health Stroke Scale (NIHSS) score during the neurological examination. Recanalization success after mechanical thrombectomy was evaluated with the TICI score (Thrombolysis in Cerebral Infarction scale), and 2b – 3 patients were recorded as those with recanalization. The patients’ modified Rankin scale (mRS) at discharge and at the end of the third month were recorded. 

 Statistically significant differen­ces were observed in age, admission blood glucose, glomerular filtration rate and FAR according to the mRS scores of the patients in the third month (p<0.05). Significant va­riab­les in the risk factor analysis were re-evaluated in the multivariate model. The best model was determined using the backward Wald method in the multivariate model, and it was determined that differences in age, admission blood glucose, and FAR were significant.

FAR can be used as a novel, effective, economical, and practical biomarker in patient with acute ischemic stroke who underwent mechanical thrombectomy.

Fibrinogen-albumin ratio predicts treatment response in phospholipase A2 receptor-associated membranous nephropathy with nephrotic syndrome.

BACKGROUND: The M-type phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy (PMN) is an immune-related disease in adults with increasing morbidity and variable treatment response, in which inflammation may contribute to the multifactorial immunopathogenesis. The relationship between fibrinogen-albumin ratio (FAR), serving as a novel inflammatory biomarker, and PMN is still unclear. Therefore, this study aims to clarify the association between FAR and disease activity and therapy response of PMN. METHODS: 110 biopsy-proven phospholipase A2 receptor (PLA2R) -associated PMN participants with nephrotic syndrome from January 2017 to December 2021 were recruited in the First Affiliated Hospital of Nanjing Medical University. The independent risk factors of non-remission (NR) and the predictive ability of FAR were explored by Cox regression and receiver-operating characteristic (ROC) curve analysis. According to the optimal cutoff value, study patients were categorized into the low-FAR group (≤the cutoff value) and the high-FAR group (>the cutoff value). Spearman's correlations were used to examine the associations between FAR and baseline clinicopathological characteristics. Kaplan-Meier method was used to assess the effects of FAR on remission. RESULTS: In the entire study cohort, 78 (70.9%) patients reached complete or partial remission (CR or PR). The optimal cutoff value of FAR for predicting the remission outcome (CR + PR) was 0.233. The Kaplan-Meier survival analysis demonstrated that the high-FAR group (>0.233) had a significantly lower probability to achieve CR or PR compared to the low-FAR group (≤0.233) (Log Rank test, p = 0.021). Higher levels of FAR were identified as an independent risk factor for NR, and the high-FAR group was associated with a 2.27 times higher likelihood of NR than the low-FAR group (HR 2.27, 95% CI 1.01, 5.13, p = 0.048). These relationships remained robust with further analysis among calcineurin inhibitors (CNIs)-receivers. In the multivariate Cox regression model, the incidence of NR was 4.00 times higher in the high-FAR group than in the low-FAR group (HR 4.00, 95% CI 1.41, 11.31, p = 0.009). Moreover, ROC analysis revealed the predictive value of FAR for CR or PR with a 0.738 area under curve (AUC), and the AUC of anti-PLA2R Ab was 0.675. When combining FAR and anti-PLA2R Ab, the AUC was boosted to 0.766. CONCLUSIONS: FAR was significantly correlated with proteinuria and anti-PLA2R Ab in PMN. As an independent risk factor for NR, FAR might serve as a potential inflammation-based prognostic tool for identifying cases with poor treatment response, and the best predictive cutoff value for outcomes was 0.233.

[Predictive value of albumin-to-fibrinogen ratio for acute kidney injury in infants undergoing ventricular septal defect repair with cardiopulmonary bypass].

OBJECTIVE: To investigate the predictive value of albumin-to-fibrinogen ratio (AFR) for postoperative acute kidney injury (AKI) in infants with ventricular septal defect repair under cardiopulmonary bypass (CPB). METHODS: A retrospective analysis was conducted on infants diagnosed with ventricular septal defect in Anhui Children's Hospital from January 2019 to July 2023. The infants were divided into AKI group and non-AKI group according to whether AKI occurred in hospital after operation. Demographic data, preoperative data, intraoperative data, postoperative data and laboratory results during CPB were collected. Multivariate Logistic regression analysis was used to find the factors of AKI after ventricular septal defect repair with CPB. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of AFR for postoperative AKI after ventricular septal defect repair with CPB. RESULTS: A total of 215 children were collected, including 28 in AKI group and 187 in non-AKI group. There were no significant differences in age, gender, body weight, height, history of pneumonia and history of chronic heart failure between the two groups, but the left ventricular ejection fraction (LVEF) in the AKI group was significantly lower than that in the non-AKI group (0.526±0.028 vs. 0.538±0.030, P = 0.048). The duration of CPB (minutes: 74.1±12.1 vs. 65.8±11.3, P < 0.001), aortic cross-clamping (minutes: 41.7±9.7 vs. 37.2±9.4, P = 0.021) and hypothermic circulation arrest (21.4% vs. 8.6%, P = 0.047) in AKI group were significantly higher than those in non-AKI group, but there were no significant differences in the proportion of ultrafiltration and urine volume between the two groups. The length of intensive care unit (ICU) stay in AKI group was significantly longer than that in non-AKI group (days: 5.3±2.0 vs. 4.0±1.7, P < 0.001), but there were no significant differences in duration of mechanical ventilation and the proportion of postoperative hypotension between the two groups. During CPB, the levels of blood glucose (mmol/L: 9.4±1.3 vs. 8.8±0.8, P < 0.001), blood lactic acid (mmol/L: 2.2±0.3 vs. 2.0±0.3, P = 0.015) and serum creatinine (µmol/L: 79.7±11.5 vs. 74.4±10.9, P = 0.018) in AKI group were significantly higher than those in non-AKI group, while the AFR was significantly lower than that in non-AKI group (8.5±1.3 vs. 10.2±1.6, P < 0.001), but there were no significant differences in the levels of hemoglobin, blood urea nitrogen, alanine aminotransferase and aspartate aminotransferase between the two groups during CPB. Multivariate Logistic regression showed that AFR was a protective factor for AKI after ventricular septal defect repair with CPB [odds ratio (OR) = 0.439, 95% confidence interval (95%CI) was 0.288-0.669, P < 0.001]. Blood glucose (OR = 2.133, 95%CI was 1.239-3.672, P = 0.006) and blood lactic acid (OR = 5.568, 95%CI was 1.102-28.149, P = 0.038) were risk factors for AKI after ventricular septal defect repair with CPB. ROC curve analysis showed that the area under the curve (AUC) of AFR in predicting AKI after ventricular septal defect repair with CPB was 0.804 (95%CI was 0.712-0.897, P < 0.001). When the optimal cut-off value was less than 9.05, the corresponding sensitivity was 75.0% and the specificity was 72.7%. CONCLUSIONS: Low AFR (≤9.05) during CPB is an independent risk factor for AKI after ventricular septal defect repair with CPB. AFR during CPB has a high predictive value for postoperative AKI after ventricular septal defect repair with CPB.

Diaphragm reconstruction using a TachoSil patch as alternative to intrasellar packing for small focal diaphragm defects in pituitary surgery: a cohort study.

BACKGROUND: During pituitary surgery, CSF leaks are often treated by intrasellar packing, using muscle or fat grafts. However, this strategy may interfere with the interpretation of postoperative MRI and may impact the quality of resection in cases of second surgery, due to the existence of additional fibrous tissue. We present an alternative technique, using a diaphragm reconstruction with a heterologous sponge combining fibrinogen and thrombin (TachoSil), applied in selected patients with low-flow CSF leaks. This study investigates the surgical outcome of patients treated with this strategy. METHODS: From a cohort of 2231 patients treated from June 2011 to June 2023 by endoscopic endonasal approach for pituitary surgery, the surgical technique of diaphragm repair with TachoSil patch performed in 55 patients (2.6%) was detailed, and the rate of closure failure was analyzed at 6 months postoperatively. No intrasellar packing was used and sellar floor reconstruction was performed whenever possible. The rate of postoperative CSF leak was compared with that reported in three previous publications that also used the TachoSil patch technique. RESULTS: Patients were mostly women (F/M ratio: 1.2) with a median age of 53.6 years. Surgery was indicated for non-functioning adenomas, Cushing's disease, acromegaly, and Rathke's cleft cysts in 38/55 (69.1%), 6/55 (10.9%), 5/55 (9.1%) and 6/55 (10.9%) patients respectively. The rate of postoperative CSF leak was 1.8% (n = 1/55), which was not significantly different from that reported in the three cohorts from the literature (2.8%, p > 0.05). No postoperative meningitis was recorded. CONCLUSIONS: In highly selected patients with low-flow CSF leaks related to small focal diaphragm defects, diaphragm reconstruction using a TachoSil patch can be a safe and valuable alternative to intrasellar packing.

U-Shaped Relationship Between Fibrinogen Level and 10-year Mortality in Patients With Acute Coronary Syndrome: Prospective Cohort Study.

This study demonstrated that fibrinogen is an independent risk factor for 10-year mortality in patients with acute coronary syndrome (ACS), with a U-shaped nonlinear relationship observed between the two. These findings underscore the importance of monitoring fibrinogen levels and the consideration of long-term anti-inflammatory treatment in the clinical management of patients with ACS.

Analysis of coagulation factors in angioedema/urticaria: increased values of D-dimer and fibrinogen in isolated angioedema.

INTRODUCTION: Recent research has shown that blood coagulation and the extrinsic coagulation cascade are involved in the pathogenesis of chronic spontaneous urticaria (CSU), but little is known about the coagulation factors in angioedema. METHODS: This study included 58 participants: 29 patients with chronic angioedema (14 with isolated angioedema and 15 with angioedema with wheals) and 29 healthy controls (HCs). We compared the values of coagulation factors in patients with isolated angioedema to those with wheals. Plasma levels of D-dimer, fibrinogen, and factor VII were measured by enzyme-linked immunosorbent assay (ELISA) for all participants. RESULTS: Significantly higher D-dimer (p = 0.016; ε² = 0.381) and fibrinogen (p = 0.044; ε² = 0.331) levels were recorded in patients with angioedema (both groups) than in the HCs, with higher levels for angioedema with wheals. Factor VII and fibrinogen levels did not differ significantly between the groups with angioedema, but coagulation factors were more often elevated in both angioedema groups than in HCs. CONCLUSIONS: One characteristic of angioedema is an elevated blood coagulation potential, which may help produce fibrin and may be important in controlling angioedema attacks.

Significance of serum protein electrophoresis in the diagnosis of Tsukayama type IV periprosthetic joint infection.

Objectives: To investigate the efficacy of serum protein electrophoresis (SPE) in the diagnosis of periprosthetic joint infection (PJI) after hip and knee arthroplasty. Methods: The medical records of patients undergoing hip and knee arthroplasty at a class A tertiary hospital between August 2013 and January 2021 were retrospectively investigated. A total of 179 patients were included and divided into two groups: 66 patients in the PJI group and 113 patients in the aseptic loosening (AL) group. Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), D-dimer, Fibrinogen, Serum albumin and the proportion of serum protein in SPE were compared between the two groups. The diagnostic sensitivity and specificity were determined using the receiver operating characteristic (ROC) curve, and the diagnostic value was compared using the area under the ROC curve (AUC). Results: There was no significant difference in age, sex and body mass index (BMI) between PJI group and AL group (P>0.05), but there was significant difference in the ratio of hip to knee (X2 = 22.043, P<0.001). The CRP, ESR, D-dimer, Fibrinogen and the proportion of α1 globulin band in PJI group was 22.99(10.55,40.58) mg/L, 37.00(23.00,61.70) mm/h, 790.00(500.00,1500.00) ng/ml, 4.84(3.81,5.55) g/L and 5.80(5.00,7.73) % which was higher than that in AL group [1.89(0.50,4.12) mg/L, U=7.984, P<0.001; 10.10(7.00,16.90) mm/h, U=8.095, P<0.001; 570.00(372.50,780.00) ng/ml, U=3.448, P<0.001; 2.84(2.45,3.43) g/L, U=8.053, P<0.001 and 4.20(3.90,4.80) %, U=8.154, P<0.001]. The Serum albumin and the proportion of Albumin band in PJI group was 36.10(33.10,39.00) g/L and 49.00(44.95,52.20) % which was lower than that in AL group [38.10(34.00,41.10) g/L, U=-2.383, P=0.017 and 54.40(51.55,56.70) %, U=-6.162, P<0.001]. The proportion of In PJI group, the AUC of proportion of α1 globulin was 0.8654, which was equivalent to CRP (0.8698), ESR (0.8680) and outperformed that of fibrinogen (0.8025). Conclusions: Elevated proportion of α1 globulin in SPE presented with good diagnostic value for Tsukayama type IV PJI, and its accuracy was comparable to those of ESR and CRP. And α1 globulin can assist with CRP and ESR to determining the timing of second-stage revision.

Infection Is Not Associated With Plasma or Cryoprecipitate Transfusion Volumes in Trauma: A Retrospective Study Using the National Trauma Data Bank.

Background: Packed red blood cell (PRBC) transfusion has been shown to increase nosocomial infection risk in the injured population; however, the post-traumatic infectious risk profiles of non-PRBC blood products are less clear. We hypothesized that plasma (fresh frozen plasma [FFP]), platelet (PLT), and cryoprecipitate administration would not be associated with increased rates of nosocomial infections. Patients and Methods: We performed a retrospective, matched, case-control study utilizing the American College of Surgeons National Trauma Data Bank data for 2019. We included all patients who received any volume of PRBC within four hours of presentation. Our outcome of interest was any infection. Controls were matched to cases using individual matching with a desired 1:3 case:control ratio. Bivariable analysis according to infection status, and multivariable logistic regression modeling the development of infection were then performed upon the matched data. Results: A total of 1,563 infectious cases were matched to 3,920 non-infectious controls. First four-hour transfusion volumes for FFP, PLT, and cryoprecipitate in the infection group exceeded those in the control group. The first four-hour FFP transfusion volume (per unit odds ratio [OR], 1.02; 95% confidence interval [CI], 0.99-1.04; p = 0.28) and cryoprecipitate transfusion volume (per unit OR, 1.01; 95% CI, 0.99-1.02; p = 0.43) were similar in cases and controls whereas PLT transfusion volume (per unit OR, 0.92; 95% CI, 0.86-0.98; p = 0.01) was lower in cases of infection than in controls. Conclusions: Fresh frozen plasma, PLT, and cryoprecipitate transfusion volumes were not independent risk factors for the development of nosocomial infection in a trauma population. PLT transfusion volume was associated with less infection.

[Value of serum levels in predicting lower extremity deep vein thrombosis after hip joint surgery in the elderly].

OBJECTIVE: To explore the value of serum D-dimer (D-D), fibrinogen (FIB), platelet (PLT), C-reactive protein (CRP) and tissue plasminogen activator inhibitor (PAI)-1 levels in predicting lower extremity deep vein thrombosis (DVT) after hip joint surgery in the elderly. METHODS: A retrospective analysis was performed on 165 elderly patients with hip joint surgery admitted from February 2020 to May 2022, including 89 males and 76 females, aged from 60 to 75 years old with an average of (66.43±5.48) years, and there were 102 cases of femoral neck fracture and 63 cases of femoral head necrosis. Serum levels of D-D, FIB, PLT, CRP and PAI-1 tests were performed in all patients within 24 hours after admission, and the patients were divided into DVT group and non-DVT group according to whether they developed DVT. RESULTS: The levels of D-D, FIB, PLT, CRP, and PAI-1 in the DVT group were higher than those in the non-DVT group (P<0.001). Spearman analysis showed that DVT was positively correlated with PLT, CRP, D-D, FIB, and PAI-1 levels (r=0.382, 0.213, 0.410, 0.310, 0.353, all P<0.001). The results of binary Logistic regression analysis showed that D-D and PLT were independent factors affecting the occurrence of DVT (OR=0.038, 0.960, P=0.032, 0.011). The area under curve (AUC) of D-D, FIB, PLT, CRP, PAI-1, and the five combined predictions for DVT were 0.843, 0.692, 0.871, 0.780, 0.819, and 0.960, respectively. The AUC of the five combined predictions was higher than that of the single prediction (P<0.05). CONCLUSION: D-D, FIB, PLT, CRP and PAI-1 are effective in predicting DVT after hip surgery in the elderly, and the combined prediction of the five factors has higher efficacy.

Nonlinear association of fibrinogen levels with functional prognosis in patients with acute ischemic stroke: a prospective cohort study.

OBJECTIVE: Fibrinogen, essential in primary hemostasis, platelet aggregation, and leukocyte-endothelial interactions, is also associated with a heightened risk of acute ischemic stroke (AIS). However, its influence on AIS patient outcomes is unclear. This study examines the correlation between fibrinogen levels and the risk of unfavorable outcomes three months post-AIS. METHODS: This is a secondary analysis of a prospective cohort study conducted in Korea. The sample consisted of 1851 AIS patients who received treatment at a Korean hospital between January 2010 and December 2016. Statistical models were established to understand the relationship between fibrinogen levels(mg/dL) and unfavorable outcomes(mRs ≥ 3), including logistic regression models, Generalized Additive Models (GAM), and smooth curve fitting (penalized splines). The log-likelihood ratio test has been utilized to evaluate the best fit. To ensure the robustness of the results, sensitivity analyses were conducted by reanalyzing the relationship after excluding participants with TG > 200 mg/dl and BMI > 25 kg/m2. Subgroup analyses were also performed to assess whether influencing factors modify the association between fibrinogen levels and unfavorable outcomes. RESULTS: After adjusting for multiple covariates including age, BMI, sex, LDL-c, TG, HGB, HDL-c, BUN, FPG, ALB, PLT, AF, hypertension, smoking, DM, mRs score at admission, the binary logistic regression model demonstrated revealed a significant positive association between fibrinogen levels and the risk of unfavorable outcomes in AIS patients (OR = 1.215, 95% CI: 1.032-1.429, p = 0.019). Sensitivity analyses supported these findings, with similar ORs observed in subsets of patients with TG < 200 mg/dL (OR = 1.221, 95% CI: 1.036-1.440) and BMI < 25 kg/m2 (OR = 1.259, 95% CI: 1.051-1.509). Additionally, the relationship between fibrinogen levels and outcomes was nonlinear, with a critical threshold of 2.74 g/L. Below the inflection point, the OR for unfavorable outcomes was 0.666 ((95% CI: 0.360, 1.233, p = 0.196), whereas above it, the OR increased to 1.374 (95% CI: 1.138, 1.659). CONCLUSIONS: This study has provided evidence of a positive and nonlinear correlation between fibrinogen levels and 3-month poor functional outcomes in patients with AIS. When fibrinogen levels exceeded 2.74 g/L, a significant and positive association was observed with the risk of poor outcomes. This study provides a further reference for optimizing rehabilitation exercises and facilitating clinical counseling in patients with acute ischemic stroke.

U-shaped relationship found between fibrinogen-to-albumin ratio and systemic inflammation response index in osteoporotic fracture patients.

The relationship between the Systemic Inflammatory Response Index (SIRI) and the Fibrinogen-to-albumin ratio (FAR) has not been extensively investigated. The objective of this study was to determine the independent relationship between FAR and SIRI in people with osteoporotic fractures (OPF). A cross-sectional study was conducted using retrospective data from 3431 hospitalized OPF patients. The exposure variable in this study was the baseline FAR, while the outcome variable was the SIRI. Covariates, including age, gender, BMI, and other clinical and laboratory factors, were adjusted. Cross-correlation analysis and linear regression models were applied. The generalized additive model (GAM) investigated non-linear relationships. Adjusted analysis revealed an independent negative association between FAR and SIRI in OPF patients (ß = - 0.114, p = 0.00064, 95% CI - 0.180, - 0.049). A substantial U-shaped association between FAR and SIRI was shown using GAM analysis (p < 0.001). FAR and SIRI indicated a negative association for FAR below 6.344% and a positive correlation for FAR over 6.344%. The results of our study revealed a U-shaped relationship between SIRI and FAR. The lowest conceivable FAR for a bone-loose inflammatory disease might be 6.344%, suggesting that this has particular significance for the medical diagnosis and therapy of persons with OPF. Consequently, the term "inflammatory trough" is proposed. These results offer fresh perspectives on controlling inflammation in individuals with OPF and preventing inflammatory osteoporosis.

Predictors of bleeding complications during catHeter-dirEcted thrombolysis for peripheral arterial occlusions (POCHET).

INTRODUCTION: The risk of major bleeding complications in catheter directed thrombolysis (CDT) for acute limb ischemia (ALI) remains high, with reported major bleeding complication rates in up to 1 in every 10 treated patients. Fibrinogen was the only predictive marker used for bleeding complications in CDT, despite the lack of high quality evidence to support this. Therefore, recent international guidelines recommend against the use of fibrinogen during CDT. However, no alternative biomarkers exist to effectively predict CDT-related bleeding complications. The aim of the POCHET biobank is to prospectively assess the rate and etiology of bleeding complications during CDT and to provide a biobank of blood samples to investigate potential novel biomarkers to predict bleeding complications during CDT. METHODS: The POCHET biobank is a multicentre prospective biobank. After informed consent, all consecutive patients with lower extremity ALI eligible for CDT are included. All patients are treated according to a predefined standard operating procedure which is aligned in all participating centres. Baseline and follow-up data are collected. Prior to CDT and subsequently every six hours, venous blood samples are obtained and stored in the biobank for future analyses. The primary outcome is the occurrence of non-access related major bleeding complications, which is assessed by an independent adjudication committee. Secondary outcomes are non-major bleeding complications and other CDT related complications. Proposed biomarkers to be investigated include fibrinogen, to end the debate on its usefulness, anti-plasmin and D-Dimer. DISCUSSION AND CONCLUSION: The POCHET biobank provides contemporary data and outcomes of patients during CDT for ALI, coupled with their blood samples taken prior and during CDT. Thereby, the POCHET biobank is a real world monitor on biomarkers during CDT, supporting a broad spectrum of future research for the identification of patients at high risk for bleeding complications during CDT and to identify new biomarkers to enhance safety in CDT treatment.

Rapid Separation and Display of Active Fibrinogenolytic Agents in Sipunculus nudus through Fibrinogen-Polyacrylamide Gel Electrophoresis.

Fibrinogenolytic agents that can dissolve fibrinogen directly have been widely used in anti-coagulation treatment. Generally, identifying new fibrinogenolytic agents requires the separation of each component first and then checking their fibrinogenolytic activities. Currently, polyacrylamide gel electrophoresis (PAGE) and chromatography are mostly used in the separating stage. Meanwhile, the fibrinogen plate assay and reaction products based PAGE are usually adopted to display their fibrinogenolytic activities. However, because of the spatiotemporal separation of those two stages, it is impossible to separate and display the active fibrinogenolytic agents with the same gel. To simplify the separating and displaying processes of fibrinogenolytic agent identification, we constructed a new fibrinogen-PAGE method to rapidly separate and display the fibrinogenolytic agents of peanut worms (Sipunculus nudus) in this study. This method includes fibrinogen-PAGE preparation, electrophoresis, renaturation, incubation, staining, and decolorization. The fibrinogenolytic activity and molecular weight of the protein can be detected simultaneously. According to this method, we successfully detected more than one active fibrinogenolytic agent of peanut wormhomogenate within 6 h. Moreover, this fibrinogen-PAGE method is time and cost-friendly. Furthermore, this method could be used to study the fibrinogenolytic agents of the other organisms.

Glycine by enteral route does not improve major clinical outcomes in severe COVID-19: a randomized clinical pilot trial.

There is a worrying scarcity of drug options for patients with severe COVID-19. Glycine possesses anti-inflammatory, cytoprotective, endothelium-protective, and platelet-antiaggregant properties, so its use in these patients seems promising. In this open label, controlled clinical trial, inpatients with severe COVID-19 requiring mechanical ventilation randomly received usual care (control group) or usual care plus 0.5 g/kg/day glycine by the enteral route (experimental group). Major outcomes included mortality, time to weaning from mechanical ventilation, total time on mechanical ventilation, and time from study recruitment to death. Secondary outcomes included laboratory tests and serum cytokines. Patients from experimental (n = 33) and control groups (n = 23) did not differ in basal characteristics. There were no differences in mortality (glycine group, 63.6% vs control group, 52.2%, p = 0.60) nor in any other major outcome. Glycine intake was associated with lower fibrinogen levels, either evaluated per week of follow-up (p < 0.05 at weeks 1, 2, and 4) or as weighted mean during the whole hospitalization (608.7 ± 17.7 mg/dl vs control 712.2 ± 25.0 mg/dl, p = 0.001), but did not modify any other laboratory test or cytokine concentration. In summary, in severe COVID-19 glycine was unable to modify major clinical outcomes, serum cytokines or most laboratory tests, but was associated with lower serum fibrinogen concentration.Registration: ClinicalTrials.gov NCT04443673, 23/06/2020.

Extreme γ' fibrinogen levels in COVID-19 patients.

COVID-19 disease progression can be accompanied by a "cytokine storm" that leads to secondary sequelae such as acute respiratory distress syndrome. Several inflammatory cytokines have been associated with COVID-19 disease progression, but have high daily intra-individual variability. In contrast, we have shown that the inflammatory biomarker γ' fibrinogen (GPF) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP. The aims of the study were to measure GPF in serial blood samples from COVID-19 patients at a tertiary care medical center in order to investigate its association with clinical measures of disease progression. COVID-19 patients were retrospectively enrolled between 3/16/2020 and 8/1/2020. GPF was measured using a commercial ELISA. We found that COVID-19 patients can develop extraordinarily high levels of GPF. Our results showed that ten out of the eighteen patients with COVID-19 had the highest levels of GPF ever recorded. The previous highest GPF level of 80.3 mg/dL was found in a study of 10,601 participants in the ARIC study. GPF levels were significantly associated with the need for ECMO and mortality. These findings have potential implications regarding prophylactic anticoagulation of COVID-19 patients.

Apigenin Provides Structural Protection to Human Fibrinogen against Nitrosative Stress: Biochemical and Molecular Insights.

BACKGROUND: Peroxynitrite (ONOO-) is an oxidant linked with several human pathologies. Apigenin, a natural flavonoid known for its health benefits, remains unexplored in relation to ONOO- effects. This study investigated the potential of apigenin to structurally protect fibrinogen, an essential blood clotting factor, from ONOO--induced damage. METHODS: Multi-approach analyses were carried out where fibrinogen was exposed to ONOO- generation while testing the efficacy of apigenin. The role of apigenin against ONOO--induced modifications in fibrinogen was investigated using UV spectroscopy, tryptophan or tyrosine fluorescence, protein hydrophobicity, carbonylation, and electrophoretic analyses. RESULTS: The findings demonstrate that apigenin significantly inhibits ONOO--induced oxidative damage in fibrinogen. ONOO- caused reduced UV absorption, which was reversed by apigenin treatment. Moreover, ONOO- diminished tryptophan and tyrosine fluorescence, which was effectively restored by apigenin treatment. Apigenin also reduced the hydrophobicity of ONOO--damaged fibrinogen. Moreover, apigenin exhibited protective effects against ONOO--induced protein carbonylation. SDS-PAGE analyses revealed that ONOO-treatment eliminated bands corresponding to fibrinogen polypeptide chains Aα and γ, while apigenin preserved these changes. CONCLUSIONS: This study highlights, for the first time, the role of apigenin in structural protection of human fibrinogen against peroxynitrite-induced nitrosative damage. Our data indicate that apigenin offers structural protection to all three polypeptide chains (Aα, Bß, and γ) of human fibrinogen. Specifically, apigenin prevents the dislocation or breakdown of the amino acids tryptophan, tyrosine, lysine, arginine, proline, and threonine and also prevents the exposure of hydrophobic sites in fibrinogen induced by ONOO-.

Effect of electrospun poly (L-lactide-co-caprolactone) and formulated porcine fibrinogen for diabetic foot ulcers.

Diabetic foot ulcers were a significant complication of diabetes and were accompanied by delayed wound healing. To compare the effect of topical application electrospun poly (L-lactide-co-caprolactone) and formulated porcine fibrinogen (PLCL/Fg) dressing with alginate dressing when treating diabetic foot ulcers (DFUs). A single-center, prospective, randomized, patient-blinded clinical trial was conducted from July 1, 2023, to December 26, 2023. The clinical trial registration was completed on August 28, 2023 (ClinicalTrials.gov Identifier: NCT06014437). The eligible patients with DFUs of 1-20 cm2 present for at least 1 month and with Wagner grade 1 or 2. They were randomized 1:1 to receive PLCL/Fg or alginate dressing. Participants received PLCL/Fg dressing 1-3 times per week or alginate dressing 3 times per week for 12 weeks. A total of 52 patients (33 men [63.5 %]; mean [SD] age, 63.1 [11.9] years; mean [SD] diabetes time, 8.3 [4.6] years) with DFUs were assessed for this study. The DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 3.8 [3.2] cm2) were randomized to receive either the PLCL/Fg dressing (n = 26) or the alginate dressing (n = 26) for as long as 12 weeks. In this study, the incidence of complete healing included 22 patients (91.7 %) in the PLCL/Fg group and 14 (63.6 %) in the alginate group during the 12-week treatment period (P = 0.003). The treatment-related adverse events that occurred were 5 (20.8 %) in the PLCL/Fg group and 4 (18.1 %) in the comparator group. In this randomized clinical trial, PLCL/Fg dressing showed beneficial effects in DFUs treatment of wound surface reduction and regulating the wound microenvironment.

Long-Term Safety Analysis of a Fibrinogen Concentrate (RiaSTAP®/Haemocomplettan® P).

Fibrinogen concentrate treatment is recommended for acute bleeding episodes in adult and pediatric patients with congenital and acquired fibrinogen deficiency. Previous studies have reported a low risk of thromboembolic events (TEEs) with fibrinogen concentrate use; however, the post-treatment TEE risk remains a concern. A retrospective evaluation of RiaSTAP®/Haemocomplettan® P (CSL Behring, Marburg, Germany) post-marketing data was performed (January 1986-June 2022), complemented by a literature review of published studies. Approximately 7.45 million grams of fibrinogen concentrate was administered during the review period. Adverse drug reactions (ADRs) were reported in 337 patients, and 81 (24.0%) of these patients experienced possible TEEs, including 14/81 (17.3%) who experienced fatal outcomes. Risk factors and the administration of other coagulation products existed in most cases, providing alternative explanations. The literature review identified 52 high-ranking studies with fibrinogen concentrate across various clinical areas, including 26 randomized controlled trials. Overall, a higher number of comparative studies showed lower rates of ADRs and/or TEEs in the fibrinogen group versus the comparison group(s) compared with those that reported higher rates or no differences between groups. Post-marketing data and clinical studies demonstrate a low rate of ADRs, including TEEs, with fibrinogen concentrate treatment. These findings suggest a favorable safety profile of fibrinogen concentrate, placing it among the first-line treatments effective for managing intraoperative hemostatic bleeding.