Antifibrinolytic and Adjunct Hemostatic Agents: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding antifibrinolytic and adjunct hemostatic agents in neonates and children supported with extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE consensus conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Use of antifibrinolytics (epsilon-aminocaproic acid [EACA] or tranexamic acid), recombinant factor VII activated (rFVIIa), or topical hemostatic agents (THAs). DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Eleven references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. MEASUREMENTS AND MAIN RESULTS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One weak recommendation and three consensus statements are presented. CONCLUSIONS: Evidence supporting recommendations for administration of antifibrinolytics (EACA or tranexamic acid), rFVIIa, and THAs were sparse and inconclusive. Much work remains to determine effective and safe usage strategies.

Metabolic engineering combined with site-directed saturated mutations of α-keto acid decarboxylase for efficient production of 6-aminocaproic acid and 1,6-hexamethylenediamine.

6-Aminocaproic acid (6ACA) and 1,6-hexamethylenediamine (HMDA) are key precursors for nylon synthesis, and both are produced using petroleum-based chemical processes. However, the utilization of bio-based raw materials for biological production of monomers is crucial for nylon industry. In this study, we demonstrated that metabolic engineering of Escherichia coli and selected mutations of α-keto acid decarboxylase successfully synthesized 6ACA and HMDA. An artificial iterative cycle from l-lysine to chain-extended α-ketoacids was introduced into Escherichia coli BL21 (DE3). Then, the extended α-ketoacids were decarboxylated and oxidized for 6ACA production. Overexpression of catalase (KatE) combined with the site-directed mutations of α-isopropylmalate synthase (LeuA) contributed synergistic enhancement effect on synthesis of 6ACA, resulting in a 1.3-fold increase in 6ACA titer. Selected mutations in α-keto acid decarboxylase (KivD) improved its specificity and 170.00 ± 5.57 mg/L of 6ACA with a yield of 0.13 mol/mol (6ACA/l-lysine hydrochloride) was achieved by shake flask cultivation of the engineered strain with the KivD# (F381Y/V461I). Meanwhile, the engineered E. coli could accumulate 84.67 ± 4.04 mg/L of HMDA with a yield of 0.08 mol/mol (HMDA/l-lysine hydrochloride) by replacing aldehyde dehydrogenase with bi-aminotransferases. This achievement marks a significant advancement in the biological synthesis of 6-carbon compounds, since the biosynthetic pathways of HMDA are rarely identified.

Enhancing Selective Antimicrobial and Antibiofilm Activities of Melittin through 6-Aminohexanoic Acid Substitution.

Leucine residues are commonly found in the hydrophobic face of antimicrobial peptides (AMPs) and are crucial for membrane permeabilization, leading to the cell death of invading pathogens. Melittin, which contains four leucine residues, demonstrates broad-spectrum antimicrobial properties but also significant cytotoxicity against mammalian cells. To enhance the cell selectivity of melittin, this study synthesized five analogs by replacing leucine with its structural isomer, 6-aminohexanoic acid. Among these analogs, Mel-LX3 exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Importantly, Mel-LX3 displayed significantly reduced hemolytic and cytotoxic effects compared to melittin. Mechanistic studies, including membrane depolarization, SYTOX green uptake, FACScan analysis, and inner/outer membrane permeation assays, demonstrated that Mel-LX3 effectively permeabilized bacterial membranes similar to melittin. Notably, Mel-LX3 showed robust antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Furthermore, Mel-LX3 effectively inhibited biofilm formation and eradicated existing biofilms of MDRPA. With its improved selective antimicrobial and antibiofilm activities, Mel-LX3 emerges as a promising candidate for the development of novel antimicrobial agents. We propose that the substitution of leucine with 6-aminohexanoic acid in AMPs represents a significant strategy for combating resistant bacteria.

Bleeding Reversal With Antifibrinolytics or Cryoprecipitate Following Thrombolysis for Acute Ischemic Stroke: A Case Series.

Patients who develop an intracerebral hemorrhage (ICH) following thrombolysis in acute ischemic stroke (AIS) have a mortality rate as high as 50%. Treatment options include blood products, such as cryoprecipitate, or antifibrinolytics, such as tranexamic acid (TXA) or ε-aminocaproic acid (EACA). Current guidelines recommend cryoprecipitate first-line despite limited data to support one agent over another. In addition, compared to antifibrinolytics, cryoprecipitate is higher in cost and requires thawing before use. This case series seeks to characterize the management of thrombolytic reversal at a single institution as well as provide additional evidence for antifibrinolytics in this setting. Patients were included for a retrospective review if they met the following criteria: presented between January 2011-January 2017, were >18 years of age, were admitted for AIS, received a thrombolytic, and received TXA EACA, or cryoprecipitate. Twelve patients met the inclusion criteria. Ten (83.3%) developed an ICH, one (8.3%) experienced gastrointestinal bleeding, and one (8.3%) had bleeding at the site of knee arthroscopy. Eleven patients received cryoprecipitate (median dose: 10 units), three received TXA (median dose: 1,000 mg), and one patient received EACA (13 g). TXA was administered faster than the first blood product at a mean time of 19 min and 137 min, respectively. Hemorrhagic expansion (N = 8, 66.67%) and inhospital mortality (N = 7, 58.3%) were high. While limited by its small sample size, this case series demonstrates significant variability in reversal strategies for thrombolysis-associated bleeding. It also provides additional evidence for the role of antifibrinolytics in this setting.

Pharmacological interventions for the prevention of bleeding in people undergoing elective hip or knee surgery: a systematic review and network meta-analysis.

BACKGROUND: Hip and knee replacement surgery is a well-established means of improving quality of life, but is associated with a significant risk of bleeding. One-third of people are estimated to be anaemic before hip or knee replacement surgery; coupled with the blood lost during surgery, up to 90% of individuals are anaemic postoperatively. As a result, people undergoing orthopaedic surgery receive 3.9% of all packed red blood cell transfusions in the UK. Bleeding and the need for allogeneic blood transfusions has been shown to increase the risk of surgical site infection and mortality, and is associated with an increased duration of hospital stay and costs associated with surgery. Reducing blood loss during surgery may reduce the risk of allogeneic blood transfusion, reduce costs and improve outcomes following surgery. Several pharmacological interventions are available and currently employed as part of routine clinical care. OBJECTIVES: To determine the relative efficacy of pharmacological interventions for preventing blood loss in elective primary or revision hip or knee replacement, and to identify optimal administration of interventions regarding timing, dose and route, using network meta-analysis (NMA) methodology. SEARCH METHODS: We searched the following databases for randomised controlled trials (RCTs) and systematic reviews, from inception to 18 October 2022: CENTRAL (the Cochrane Library), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Transfusion Evidence Library (Evidentia), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: We included RCTs of people undergoing elective hip or knee surgery only. We excluded non-elective or emergency procedures, and studies published since 2010 that had not been prospectively registered (Cochrane Injuries policy). There were no restrictions on gender, ethnicity or age (adults only). We excluded studies that used standard of care as the comparator. Eligible interventions included: antifibrinolytics (tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid (EACA)), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants and non-fibrin sealants. DATA COLLECTION AND ANALYSIS: We performed the review according to standard Cochrane methodology. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using CINeMA. We presented direct (pairwise) results using RevMan Web and performed the NMA using BUGSnet. We were interested in the following primary outcomes: need for allogenic blood transfusion (up to 30 days) and all-cause mortality (deaths occurring up to 30 days after the operation), and the following secondary outcomes: mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), length of hospital stay and adverse events related to the intervention received. MAIN RESULTS: We included a total of 102 studies. Twelve studies did not report the number of included participants; the other 90 studies included 8418 participants. Trials included more women (64%) than men (36%). In the NMA for allogeneic blood transfusion, we included 47 studies (4398 participants). Most studies examined TXA (58 arms, 56%). We found that TXA, given intra-articularly and orally at a total dose of greater than 3 g pre-incision, intraoperatively and postoperatively, ranked the highest, with an anticipated absolute effect of 147 fewer blood transfusions per 1000 people (150 fewer to 104 fewer) (53% chance of ranking 1st) within the NMA (risk ratio (RR) 0.02, 95% credible interval (CrI) 0 to 0.31; moderate-certainty evidence). This was followed by TXA given orally at a total dose of 3 g pre-incision and postoperatively (RR 0.06, 95% CrI 0.00 to 1.34; low-certainty evidence) and TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively (RR 0.10, 95% CrI 0.02 to 0.55; low-certainty evidence). Aprotinin (RR 0.59, 95% CrI 0.36 to 0.96; low-certainty evidence), topical fibrin (RR 0.86, CrI 0.25 to 2.93; very low-certainty evidence) and EACA (RR 0.60, 95% CrI 0.29 to 1.27; very low-certainty evidence) were not shown to be as effective compared with TXA at reducing the risk of blood transfusion. We were unable to perform an NMA for our primary outcome all-cause mortality within 30 days of surgery due to the large number of studies with zero events, or because the outcome was not reported. In the NMA for deep vein thrombosis (DVT), we included 19 studies (2395 participants). Most studies examined TXA (27 arms, 64%). No studies assessed desmopressin, EACA or topical fibrin. We found that TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively ranked the highest, with an anticipated absolute effect of 67 fewer DVTs per 1000 people (67 fewer to 34 more) (26% chance of ranking first) within the NMA (RR 0.16, 95% CrI 0.02 to 1.43; low-certainty evidence). This was followed by TXA given intravenously and intra-articularly at a total dose of 2 g pre-incision and intraoperatively (RR 0.21, 95% CrI 0.00 to 9.12; low-certainty evidence) and TXA given intravenously and intra-articularly, total dose greater than 3 g pre-incision, intraoperatively and postoperatively (RR 0.13, 95% CrI 0.01 to 3.11; low-certainty evidence). Aprotinin was not shown to be as effective compared with TXA (RR 0.67, 95% CrI 0.28 to 1.62; very low-certainty evidence). We were unable to perform an NMA for our secondary outcomes pulmonary embolism, myocardial infarction and CVA (stroke) within 30 days, mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), or length of hospital stay, due to the large number of studies with zero events, or because the outcome was not reported by enough studies to build a network. There are 30 ongoing trials planning to recruit 3776 participants, the majority examining TXA (26 trials). AUTHORS' CONCLUSIONS: We found that of all the interventions studied, TXA is probably the most effective intervention for preventing bleeding in people undergoing hip or knee replacement surgery. Aprotinin and EACA may not be as effective as TXA at preventing the need for allogeneic blood transfusion. We were not able to draw strong conclusions on the optimal dose, route and timing of administration of TXA. We found that TXA given at higher doses tended to rank higher in the treatment hierarchy, and we also found that it may be more beneficial to use a mixed route of administration (oral and intra-articular, oral and intravenous, or intravenous and intra-articular). Oral administration may be as effective as intravenous administration of TXA. We found little to no evidence of harm associated with higher doses of tranexamic acid in the risk of DVT. However, we are not able to definitively draw these conclusions based on the trials included within this review.

The effect of ε-aminocaproic acid on blood product requirement, outcome and thromboelastography parameters in severely thrombocytopenic dogs.

BACKGROUND: No treatment other than platelet administration is known to protect against spontaneous hemorrhage in thrombocytopenic dogs. OBJECTIVES: Primary: determine if treatment with ε-aminocaproic acid (EACA) decreases the requirement for blood transfusions and improves outcome in dogs with severe thrombocytopenia. Secondary: find evidence of hyperfibrinolysis and determine the effect EACA administration on rapid (rTEG) and tissue plasminogen activator-spiked (tPA-rTEG) thromboelastography parameters. ANIMALS: Twenty-seven dogs with severe thrombocytopenia were treated with EACA, and data from an additional 33 were obtained from the hospital database as historical control (HC) cohort. METHODS: Single arm clinical trial with HCs. The EACA group dogs received EACA (100 mg/kg IV followed by a constant-rate infusion [CRI] of 400 mg/kg/24 hours). Thromboelastography before and during EACA infusion, hospitalization days, number of transfusions, and mortality were compared. RESULTS: No difference was found in number of transfusions per dog (median, interquartile range; 1, 0-2.5 vs 0.9, 0-2; P = .5) and hospitalization days (4, 4-6 vs 4.5, 3.75-6; P = .83) between HC and EACA groups, respectively, and no difference in survival was identified by log-rank analysis (P = .15). Maximum amplitude on both rTEG and tPA-rTEG increased after EACA administration (rTEG baseline: 23.6, 9.6-38.9; post-EACA: 27.3, 19.8-43.2; P < .001; tPA-rTEG baseline: 23, 10.9-37.2; post-EACA: 24.7, 16.7-44.8; P < .002). CONCLUSIONS AND CLINICAL IMPORTANCE: Although EACA increased clot strength, there was no effect on outcome. Treatment with EACA at this dosage cannot be recommended as a routine treatment but may be considered for dogs with severe ongoing hemorrhage.

Consensus of the Brazilian association of hematology, hemotherapy and cellular therapy on patient blood management: Antifibrinolytics

Abstract The use of strategies to reduce blood loss and transfusions is essential in the treatment of surgical patients, including in complex cardiac surgeries and those that use cardiopulmonary bypass. Antifibrinolytics, such as epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA), are widely used in these procedures, as well as in other types of surgeries. These medicines are included in the World Health Organization (WHO) list of 'essential medicines'. Scientific evidence demonstrates the effectiveness of EACA in reducing bleeding and the need for transfusions in heart surgery. EACA is highly recommended for use in heart surgery by the American Society of Anesthesiology Task Force on Perioperative Blood Management. Regarding the safety of EACA, there is no robust evidence of any significant thrombotic potential. TXA has also been shown to be effective in reducing the use of blood transfusions in cardiac and non-cardiac surgeries and is considered safer than other antifibrinolytic agents. There is no evidence of any increased risk of thromboembolic events with TXA, but doses greater than 2 g per day have been associated with an increased risk of seizures. It is also important to adjust the dose in patients with renal impairment. In conclusion, antifibrinolytics, such as EACA and TXA, are effective in reducing blood loss and transfusion use in cardiac and non-cardiac surgeries, without causing serious adverse effects.

Comparison of efficacy between tranexamic acid and epsilon-aminocaproic acid for total knee arthroplasty: A meta-analysis of randomized controlled trials.

BACKGROUND: Tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) have been demonstrated to reduce blood loss following total knee arthroplasty (TKA). This meta-analysis aimed to compare the efficacy and safety of TXA and EACA in reducing blood loss in primary TKA patients. METHODS: A search of the PubMed, Embase, and Cochrane Library databases identified all relevant studies published until December 2022. Randomized controlled trials (RCTs) reporting a comparison of TXA and EACA for TKA patients were selected. The main outcomes were total blood loss (TBL), hemoglobin (Hb) drop on postoperative day 3, intraoperative blood loss, operation time and the transfusion rate were evaluated. The weighted mean differences (WMD) and risk ratio (RR) with 95% confidence intervals (CI) were calculated using a fixed-effects or random-effects model. Stata 12.0 software was used for meta-analysis. RESULTS: Six studies involving 739 (TXA:372; EACA:367) patients were included in this meta-analysis. There was no significant difference in terms of intraoperative blood loss, Hb drop on postoperative day 3, operation time, tourniquet time (TT), transfusion rate and the occurrence of deep venous thrombosis (DVT) between the 2 treatments groups. However, compared with EACA, TXA significant reduced TBL (WMD, 174.60; 95% CI, -244.09 to -105.11). CONCLUSION: Our research did not demonstrate TXA to be superior to EACA in reducing need for transfusion and Hb drop. TXA was superior than EACA in reducing TBL in TKA patients. More RCTs with identical inclusion criteria and dose and duration of treatment, are required to confirm these findings.

Comprehensive Regulation of Liquid-Liquid Phase Separation of Polypeptides.

The elucidation of the molecular driving forces responsible for Liquid-liquid Phase Separation (LLPS) of proteins and nucleic acids within living cells is crucial for understanding its biological functions and its role in related diseases. In the present study, we investigated the regulation of LLPS in a series of polypeptides with repetitive proline and arginine (PR) sequences by modifying their length and the salt concentration in the solution. Our findings indicate that higher salt concentrations are necessary for LLPS of repetitive PR peptides longer than eight PRs, which emerges as a threshold value. To pinpoint the molecular forces driving the LLPS in peptides, we sequentially introduced various concentrations of hydrophobic disruptors, such as 1,6-hexanediol, and electrostatic regulators, such as ethyl alcohol and 6-Aminocaproic acid. We further modulated the electrostatic interaction by introducing ethyl alcohol and 6-Aminocaproic acid to alter the dielectric constant of the solution. The inclusion of ethyl alcohol intensified the electrostatic interaction between arginine molecules, facilitating LLPS of PR15, while 6-Aminocaproic acid yielded the reverse effect. We deduced that the phase separation in peptide systems is conjointly driven by hydrophobicity and electrostatic interactions. These insights can guide the regulation of LLPS in other peptide and protein systems, and could be pivotal in addressing abnormal aggregations of proteins and nucleic acids.

The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis.

BACKGROUND: The prognosis of esophageal adenocarcinoma (EAC) and gastric adenocarcinoma (GAC) remains poor, and new therapeutic approaches are urgently needed. Claudin 6 (CLDN6) is an oncofetal antigen that is largely absent in healthy tissues and upregulated in several cancers, making it a promising therapeutical target. In this study, the expression of CLDN6 was assessed in an large Caucasian EAC and GAC cohort. METHODS: RNA-Seq data from 89 EACs and 371 GACs were obtained from The Cancer Genome Atlas project and EAC/GAC cases were stratified by CLDN6 mRNA expression based on a survival-associated cutoff. For groups with CLDN6 expression above or below this cutoff, differential gene expression analyses were performed using DESeq, and dysregulated biological pathways were identified using the Enrichr tool. Additionally, CLDN6 protein expression was assessed in more than 800 EACs and almost 600 GACs using a CLDN6-specific immunohistochemical antibody (clone 58-4B-2) that is currently used in Phase I/II trials to identify patients with CLDN6-positive tumors (NCT05262530; NCT04503278). The expression of CLDN6 was also correlated with histopathological parameters and overall survival (OS). RESULTS: EACs and GACs with high CLDN6 mRNA levels displayed an overexpression of pathways regulating the cell cycle, DNA replication, and receptor / extracellular matrix interactions. CLDN6 protein expression was associated with shorter OS in EAC and GAC, both in treatment-naïve subgroups and cohorts receiving neoadjuvant therapy. In multivariate analysis, CLDN6 protein expression was an independent adverse prognostic factor in EAC associated with a shorter OS (HR: 1.75; p = 0.01) and GAC (HR: 2.74; p = 0.028). CONCLUSIONS: High expression of CLDN6 mRNA is associated with the dysregulation of distinct biological pathways regulating cell growth, proliferation, and cell-matrix interactions. Clinically, the expression of CLDN6 protein is a valuable adverse prognostic marker in EAC and GAC.

Anti-Toxoplasma gondii Effects of Lipopeptide Derivatives of Lycosin-I.

Toxoplasmosis, caused by Toxoplasma gondii (T. gondii), is a serious zoonotic parasitic disease. We previously found that Lycosin-I exhibited anti-T. gondii activity, but its serum stability was not good enough. In this study, we aimed to improve the stability and activity of Lycosin-I through fatty acid chain modification, so as to find a better anti-T. gondii drug candidate. The α/ε-amino residues of different lysine residues of Lycosin-I were covalently coupled with lauric acid to obtain eight lipopeptides, namely L-C12, L-C12-1, L-C12-2, L-C12-3, L-C12-4, L-C12-5, L-C12-6, and L-C12-7. Among these eight lipopeptides, L-C12 showed the best activity against T. gondii in vitro in a trypan blue assay. We then conjugated a shorter length fatty chain, aminocaproic acid, at the same modification site of L-C12, namely L-an. The anti-T. gondii effects of Lycosin-I, L-C12 and L-an were evaluated via an invasion assay, proliferation assay and plaque assay in vitro. A mouse model acutely infected with T. gondii tachyzoites was established to evaluate their efficacy in vivo. The serum stability of L-C12 and L-an was improved, and they showed comparable or even better activity than Lycosin-I did in inhibiting the invasion and proliferation of tachyzoites. L-an effectively prolonged the survival time of mice acutely infected with T. gondii. These results suggest that appropriate fatty acid chain modification can improve serum stability and enhance anti-T. gondii effect of Lycosin-I. The lipopeptide derivatives of Lycosin-I have potential as a novel anti-T. gondii drug candidate.

Evaluation of Therapeutic Use of Antifibrinolytics in Cats.

Limited data are available regarding the use of the antifibrinolytic drugs tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) in cats. This study aimed to evaluate the indications for the use of TXA and EACA in cats and to describe dosing regimens used, occurrence of adverse events, and patient outcomes. This was a retrospective multicenter study. Medical databases were searched for feline patients billed for TXA or EACA between 2015 and 2021. Thirty-five cats met the inclusion criteria; 86% received TXA and 14% received EACA. The most common indication was nontraumatic hemorrhage (54%), followed by traumatic hemorrhage (17%) and elective surgery (11%). The median dose was 10 mg/kg for TXA and 50 mg/kg for EACA. Overall, 52% of cats survived to discharge. Potential adverse events were noted in 7/35 (20%) patients. Of these, 29% survived to discharge. No standardized dosing regimen was identified; rather, dose, dosing interval, and duration of administration varied markedly between patients. Administration was potentially associated with severe adverse events, although the retrospective design makes it difficult to establish a causal association with antifibrinolytic use. This study provides a base for future prospective studies by giving an insight into the use of antifibrinolytic drugs in cats.

Efficacy and safety of using aminocaproic acid and tranexamic acid during the perioperative period for treating trochanteric fractures in elderly femurs.

BACKGROUND: Tranexamic acid (TXA) has long been the antifibrinolytic hemostatic drug of choice for orthopedic surgery. In recent years, the hemostatic effect of epsilon aminocaproic acid (EACA) has gradually been recognized by orthopedic surgeons and has begun to be used in hip and knee arthroplasty with little mention of the comparison of these two drugs; Therefore, this study compared the efficacy and safety of EACA and TXA in the perioperative period of elderly patients with trochanteric fractures to verify whether EAC could be a "qualified alternative" to TXA and to provide theoretical support for the clinical application of TXA. METHODS: Two hundred and forty-three patients who received proximal femoral nail antirotation (PFNA) for trochanteric fractures from January 2021 to March 2022 at our institution were included and divided into the EACA group (n = 146) and the TXA group. (n = 97) determined by the drugs used in the perioperative period The main observations were blood loss and blood transfusion.The second second outcome was blood routine, coagulation, Hospital complications and complications after discharge. RESULTS: The perioperative EACA patients had significantly lower significant blood loss (DBL) than the TXA group (p < 0.0001) and statistically significant lower C-reactive protein in the EACA group than in the TXA group on postoperative day 1 (p = 0.022). Patients on perioperative TXA had better postoperative day one (p = 0.002) and postoperative day five erythrocyte width than the EACA group (p = 0.004). However, there was no statistically significant difference between the two groups in the remaining indicators in both drugs: blood items, coagulation indicators, blood loss, blood transfusion, length of hospital(LOH), total hospital expense, and postoperative complications (p > 0.05). CONCLUSION: The hemostatic effects and safety of EACA and TXA in the perioperative application of trochanteric fractures in the elderly are essentially similar, and EACA can be considered for use as an alternative to TXA, increasing the flexibility of physicians to use it in the clinical setting. However, the limited sample size included necessitated a high-quality, large sample of clinical studies and long-term follow-up.

An aminocaproic acid-grafted chitosan derivative with superior antibacterial and hemostatic properties for the prevention of secondary bleeding.

Uncontrolled bleeding is one of the leading causes of human mortality. Existing hemostatic materials or techniques cannot meet the clinical requirements for safe and effective hemostasis. The development of novel hemostatic materials has always been of great interest. Chitosan hydrochloride (CSH), a derivative of chitin, is extensively used on wounds as an antibacterial and hemostatic agent. However, the formation of intra- or intermolecular hydrogen bonds between hydroxyl and amino groups limits its water solubility and dissolution rate and affects its effectiveness in promoting coagulation. Herein, we covalently grafted aminocaproic acid (AA) to the hydroxyl and amino groups of CSH via ester and amide bonds, respectively. The solubility of CSH in water (25 °C) was 11.39 ± 0.98 % (w/v), whereas the AA-grafted CSH (CSH-AA) reached 32.34 ± 1.23 % (w/v). Moreover, the dissolution rate of CSH-AA in water was 6.46 times higher than that of CSH. Subsequent studies proved that CSH-AA is non-toxic, biodegradable, and has superior antibacterial and hemostatic properties to CSH. Additionally, anti-plasmin activity can be exerted by the dissociated AA from the CSH-AA backbone, which can help to lessen secondary bleeding.

Virtual screening of carboxylic acid reductases for biocatalytic synthesis of 6-aminocaproic acid and 1,6-hexamethylenediamine.

The key precursors for nylon synthesis, that is, 6-aminocaproic acid (6-ACA) and 1,6-hexamethylenediamine (HMD), are produced from petroleum-based feedstocks. A sustainable biocatalytic alternative method from bio-based adipic acid has been demonstrated recently. However, the low efficiency and specificity of carboxylic acid reductases (CARs) used in the process hampers its further application. Herein, we describe a highly accurate protein structure prediction-based virtual screening method for the discovery of new CARs, which relies on near attack conformation frequency and the Rosetta Energy Score. Through virtual screening and functional detection, five new CARs were selected, each with a broad substrate scope and the highest activities toward various di- and ω-aminated carboxylic acids. Compared with the reported CARs, KiCAR was highly specific with regard to adipic acid without detectable activity to 6-ACA, indicating a potential for 6-ACA biosynthesis. In addition, MabCAR3 had a lower Km with regard to 6-ACA than the previously validated CAR MAB4714, resulting in twice conversion in the enzymatic cascade synthesis of HMD. The present work highlights the use of structure-based virtual screening for the rapid discovery of pertinent new biocatalysts.

Epsilon aminocaproic acid is associated with acute kidney injury after life-threatening hemorrhage in children.

BACKGROUND: Antifibrinolytic medications have been associated with reduced mortality in pediatric hemorrhage but may contribute to adverse events such as acute kidney injury (AKI). STUDY DESIGN AND METHODS: We conducted a secondary analysis of the MAssive Transfusion in Children (MATIC), a prospectively collected database of children with life-threatening hemorrhage (LTH), and evaluated for risk of adverse events with either antifibrinolytic treatment, epsilon aminocaproic acid (EACA) or tranexamic acid (TXA). The primary outcome was AKI and secondary outcomes were acute respiratory distress syndrome (ARDS) and sepsis. RESULTS: Of 448 children included, median (interquartile range) age was 7 (2-15) years, 55% were male, and LTH etiology was 46% trauma, 34% operative, and 20% medical. Three hundred and ninety-three patients did not receive an antifibrinolytic (88%); 37 (8%) received TXA and 18 (4%) received EACA. Sixty-seven (17.1%) patients in the no antifibrinolytic group developed AKI, 6 (16.2%) patients in the TXA group, and 9 (50%) patients in the EACA group (p = .002). After adjusting for cardiothoracic surgery, cyanotic heart disease, preexisting renal disease, lowest hemoglobin pre-LTH, and total weight-adjusted transfusion volume during the LTH, the EACA group had increased risk of AKI (adjusted odds ratio 3.3 [95% CI: 1.0-10.3]) compared to no antifibrinolytic. TXA was not associated with AKI. Neither antifibrinolytic treatment was associated with ARDS or sepsis. CONCLUSION: Administration of EACA during LTH may increase the risk of AKI. Additional studies are needed to compare the risk of AKI between EACA and TXA in pediatric patients.

An interlaboratory capillary zone electrophoresis-UV study of various monoclonal antibodies, instruments, and ε-aminocaproic acid lots.

Capillary zone electrophoresis ultraviolet (CZE-UV) has become increasingly popular for the charge heterogeneity determination of mAbs and vaccines. The ε-aminocaproic acid (eACA) CZE-UV method has been used as a rapid platform method. However, in the last years, several issues have been observed, for example, loss in electrophoretic resolution or baseline drifts. Evaluating the role of eACA on the reported issues, various laboratories were requested to provide their routinely used eACA CZE-UV methods, and background electrolyte compositions. Although every laboratory claimed to use the He et al. eACA CZE-UV method, most methods actually deviate from He's. Subsequently, a detailed interlaboratory study was designed wherein two commercially available mAbs (Waters' Mass Check Standard mAb [pI 7] and NISTmAb [pI 9]) were provided to each laboratory, along with two detailed eACA CZE-UV protocols for a short-end, high-speed, and a long-end, high-resolution method. Ten laboratories participated each using their own instruments, and commodities, showing excellence method performance (relative standard deviations [RSDs] of percent time-corrected main peak areas from 0.2% to 1.9%, and RSDs of migration times from 0.7% to 1.8% [n = 50 per laboratory], analysis times in some cases as short as 2.5 min). This study clarified that eACA is not the main reason for the abovementioned variations.

Comparative efficacy and safety of different hemostatic medications during spinal surgery: A network meta-analysis.

BACKGROUND: Significant blood loss is still one of the most frequent issues in spinal surgery. There were different hemostatic methods to prevent blood loss during spinal surgery. However, the optimal hemostatic therapy for spinal surgery is controversial. The purpose of this study was to assess the efficacy and safety of different hemostatic therapies in spinal surgery. METHODS: Two independent reviewers conducted electronic literature searches in 3 electronic databases (PubMed, Embase, and Cochrane library database) as well as a manual search to identify eligible clinical studies from inception to Nov 2022. Studies that including different hemostatic therapy (tranexamic acid [TXA], epsilon-acetyl aminocaproic acid [EACA], and aprotinin [AP]) for spinal surgery were included. The Bayesian network meta-analysis was performed with a random effects model. The surface under the cumulative ranking curve (SUCRA) analysis was performed to determine the ranking order. All analyses were performed by R software and Stata software. P value less than .05 was identified as statistically significant. RESULTS: Finally, a total of 34 randomized controlled trials met the inclusion criteria and finally included in this network meta-analysis. The SUCRA shows that TXA ranked first (SUCRA, 88.4%), AP ranked second (SUCRA, 71.6%), EACA ranked third (SUCRA, 39.9%), and placebo ranked the last (SUCRA, 0.3%) as for total blood loss. The SUCRA shows that TXA ranked first (SUCRA, 97.7%), AP ranked second (SUCRA, 55.8%), EACA ranked third (SUCRA, 46.2%), and placebo ranked the last (SUCRA, 0.2%) for need for transfusion. CONCLUSIONS: TXA appears optimal in the reduction of perioperative bleeding and blood transfusion during spinal surgery. However, considering the limitations in this study, more large-scale, well-designed randomized controlled trials are needed to confirm these findings.