Aminocaproic Acid Research Articles

Intraoperative transfusion management, antifibrinolytic therapy, coagulation monitoring and the impact on short-term outcomes after liver transplantation-A systematic review of the literature and expert panel recommendations.

Liver transplantation (LT) is frequently complicated by coagulopathy associated with end-stage liver disease (ESLD), that is, often multifactorial. The objective of this systematic review was to identify evidence based intraoperative transfusion and coagulation management strategies that improve immediate and short-term outcomes after LT. PRISMA-guidelines and GRADE-approach were followed. Three subquestions were formulated. (Q); Q1: transfusion management; Q2: antifibrinolytic therapy; and Q3: coagulation monitoring. Sixteen studies were included for Q1, six for Q2, and 10 for Q3. Q1: PRBC and platelet transfusions were associated with higher mortality. The use of prothrombin complex concentrate (PCC) and fibrinogen concentrate (FC) were not associated with reductions in intraoperative transfusion or increased thrombotic events. The use of cell salvage was not associated with hepatocellular carcinoma (HCC) recurrence or mortality. Cell salvage and transfusion education significantly decreased blood product transfusions. Q2: Epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) were not associated with decreased blood product transfusion, improvements in patient or graft survival, or increases in thrombotic events. Q3: Viscoelastic testing (VET) was associated with decreased allogeneic blood product transfusion compared to conventional coagulation tests (CCT) and is likely to be cost-effective. Coagulation management guided by VET may be associated with increases in FC and PCC use. Q1: A specific blood product transfusion practice is not recommended (QOE; low | Recommendation; weak). Cell salvage and educational interventions are recommended (QOE: low | Grade of Recommendation: moderate). Q2: The routine use of antifibrinolytics is not recommended (QOE; low | Recommendation; weak). Q3: The use of VET is recommended (QOE; low-moderate | Recommendation; strong).

Modulation of gut microbiota and their metabolites by functional mulberry juice non-thermally pasteurized using microfiltration

Background: Mulberry fruit is a source of phenolic compounds and has biological properties. This study aimed to assess the effects of isomaltooligosaccharide (IMO) added to mulberry juice on prebiotic activity and gut fermentation properties.Objectives: The study aimed to produce mulberry juice supplemented with IMO, which might generate short chain fatty acids (SCFA), and to examine the effects of a prebiotic activity after fecal fermentation.Materials and methods: Functional mulberry juices were prepared with three different levels of isomaltooligosaccharide (IMO), namely 0% (MBI0), 2% (MBI2), and 8% (MBI8). The study tested mulberry juices supplemented with IMO, which generated short-chain fatty acids (SCFA), phenolic metabolites, and favored beneficial gut bacteria, and examined the prebiotic activity after fecal fermentation by the colonic microbiota. A crossflow hollow fiber microfiltration system with a 0.22 μm pore size was employed to deliver permeates considered non-thermally pasteurized juices.Results: The results show that short chain fatty acids (SCFA) included large propionic acid and butyric acid concentrations at 48h. The percent of bifidobacteria significantly increased to 5.03% and 17.53% in 24 hours fermentation of MBI2 and MBI8, respectively. After fecal batch culture fermentation, some anthocyanin metabolites such as 3-(2-hydroxyphenyl) propionic acid, 3,4-dihydroxybenzaldehyde, L-phenylalanine, and aminocaproic acid, were detected. Therefore, IMO can serve as a potential prebiotic ingredient added in mulberry juice for promoting the growth of beneficial gut microbiota.Conclusion: The results show that IMO favored beneficial microorganisms in the gut and contributed to biologically active compounds such as metabolites of polyphenols and anthocyanins in the gut.Keywords: Mulberry, isomaltooligosaccharide, prebiotic, gut microbiota, metabolites

Prophylactic Use of Antifibrinolytics During Pediatric Cardiac Surgery With Cardiopulmonary Bypass on Postoperative Bleeding and Transfusion: A Systematic Review and Meta-Analysis.

To determine the effect of intraoperative antifibrinolytics, including tranexamic acid (TXA), aminocaproic acid (EACA), or aprotinin, on bleeding in children undergoing cardiac surgery with cardiopulmonary bypass (CPB). Relevant articles were systematically searched from Ovid MEDLINE, Ovid EMBASE, CINAHL, Cochrane Library, and Web of Science to November 15, 2021. Abstracts were screened, and full texts were reviewed using predetermined inclusion and exclusion criteria using the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. A standardized data extraction tool was used. Sixty-eight studies including 28,735 patients were analyzed. TXA compared with placebo resulted in a mean decrease in chest tube output of 9.1 mL/kg (95% CI, 6.0-12.3 mL/kg), I2 equals to 65.2%, p value of less than 0.001, platelet requirement of 2.9 mL/kg (95% CI, 0.1-5.8 mL/kg), I2 =72.5%, p value less than 0.001 and plasma requirement of 4.0 mL/kg (95% CI, 0.6-7.2 mL/kg), I2 equals to 94.5%, p value less than0.001. Aprotinin compared with placebo resulted in a mean decrease in chest tube output of 4.3 mL/kg (2.4-6.2 mL/kg), I2 equals to 66.3%, p value of less than 0.001, platelet transfusion of 4.6 mL/kg (95% CI, 0.6-8.6 mL/kg), I2 equals to 93.6%, p value of less than 0.001, and plasma transfusion of 7.7 mL/kg (95% CI, 2.1-13.2 mL/kg), I2 equals to 95.3%, p value of less than 0.001. EACA compared with placebo resulted in a mean decrease in chest tube output of 9.2 mL/kg (2.3-21.0 mL/kg), I2 equals to 96.4%, p value of less than 0.001, RBC transfusion of 7.2 mL/kg (95% CI, 2.4-12.1 mL/kg), I2 equals to 94.5%, p value equals to 0.002, and platelet transfusion of 10.7 mL/kg (95% CI, 2.9-18.5 mL/kg), I2 equals to 0%, p value of less than 0.001. No statistical difference was observed in chest tube output when TXA was compared with aprotinin. Subgroup analysis of cyanotic patients showed a significant decrease in chest tube output, platelet requirement, and plasma requirement for patients receiving aprotinin. Overall, the quality of evidence was moderate. Antifibrinolytics are effective at decreasing blood loss and blood product requirement in children undergoing cardiac surgery with CPB although the quality of evidence is only moderate.

Experience With Pre-procedural Hemostatic Medications versus Platelet Transfusion in Patients With Platelet Storage Pool Deficiency

Background Storage pool deficiency (SPD) is a rare bleeding disorder characterized by reduction in the number of delta granules within platelets, interfering with hemostasis. Current literature lacks well-designed studies from which to draw concrete conclusions regarding pre-procedural management of bleeding complications. Objective: The purpose of this study is to describe bleeding and safety outcomes of SPD patients receiving either pre-procedural platelet transfusions or platelet-sparing regimens. Methods: An exploratory retrospective cohort study was conducted among SPD patients, comparing major bleeding events between those who received platelet transfusion and those who received desmopressin, tranexamic acid, and/or aminocaproic acid within 24 hours prior to procedure. Results: Rates of major bleeding were not found to be higher among patients who received a platelet-sparing regimen [platelet-sparing: 2/25 (8%); platelet transfusion: 2/29 (6.9%); P = .99]. Incidence of non-major bleeding was higher in the platelet transfusion group, but this was not statistically significant [platelet-sparing: 0/25 (0%); platelet transfusion: 3/29 (10.3%); P = .24]. Treatment-related adverse effects were observed following 8 of 54 procedures (14.8%). Conclusion: Use of a platelet-sparing regimen was not associated with a significantly higher incidence of major or non-major bleeding events. Future prospective trials are recommended to compare outcomes between therapies.

Optimizing Blood Loss and Management in Craniosynostosis Surgery: A Systematic Review of Outcomes Over the Last 40 Years.

Surgical correction of craniosynostosis can involve significant blood loss. Rates of allogenic blood transfusion have been reported to approach 100%. Multiple interventions have been described to reduce blood loss and transfusion requirements. The aim of this study was to analyze various approaches over the last 4 decades to optimize blood loss and management during craniosynostosis surgery. PRISMA guidelines for systematic reviews were followed. PubMed and Cochrane database searches identified studies analyzing approaches to minimizing blood loss or transfusion rate in craniosynostosis surgery. Primary outcomes included rate or amount of allogenic or autologous blood transfusion, estimated blood loss (EBL), postoperative hemoglobin (Hg), or hematocrit (Hct) levels. Secondary outcomes were examined when reported. Fifty-two studies met inclusion criteria. There was marked heterogeneity regarding design, inclusion criteria, surgical intervention, and endpoints. The majority of the studies were nonrandomized and noncomparative. Four studies analyzed erythropoietin (EPO), 6 analyzed various cell-saver (CS) technologies, 18 analyzed antifibrinolytics (tranexamic acid [TXA], aminocaproic acid [ACA], and aprotinin [APO]), 8 analyzed various alternatives, and 16 analyzed multimodal pathways & protocols. Some studies analyzed multiple approaches. Although the majority of studies reviewed represent level III/IV evidence, several high-quality level I studies were identified and included. Level I evidence supported an improvement in blood outcomes by utilizing EPO, CS, and TXA, individually or in concert with one another. Thus, this review suggests that a multi-prong approach may be the most effective means to optimize blood loss and transfusion outcomes in craniosynostosis surgery.

Comparison of trauma-dosed tranexamic acid versus aminocaproic acid in cardiac surgery in the setting of drug shortage.

Antifibrinolytic agents, tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA), are often used during cardiac surgery to decrease the number of allogenic blood transfusions and to prevent perioperative bleeding. Weight-based TXA dosing regimens have been compared to fixed-dose regimens of EACA with variable outcomes in perioperative blood product transfusions and chest tube output. Serious adverse events, including seizures, have been reported with higher doses of TXA. Fixed-dose TXA regimens have been evaluated in trauma and orthopedic surgery but there is a paucity of evidence in the cardiac surgery population. To compare the safety and efficacy of fixed-dose TXA versus EACA in patients undergoing cardiac surgery. A single-center, retrospective chart review was conducted at a 793-bed tertiary care academic teaching hospital comparing cardiac surgery patients receiving either fixed-dose TXA 1000 mg followed by a 500-1000 mg infusion or EACA-7.5 gintravenousboluses followed by a 1-1.25 g/hinfusion for the duration of the surgery. The major endpoint included chest tube output at 12 h, 24 h, and 7 days postoperatively. Minor endpoints included quantity and incidence of blood product transfusions and reported safety events. There were 1544 patients included. Chest tube output was similar between groups and the TXA group required more intraoperative blood product transfusions (22.7% vs. 18.2%, p = .03). There were no differences in the median quantity of total blood products administered postoperatively at 24 h or at 7 days. Reported safety events were similar between groups. Both fixed-dose TXA and EACA may be considered safe and effective options for antifibrinolytic therapy in cardiac surgery patients.

Ultrasmall polymer-coated cerium oxide nanoparticles as a traumatic brain injury therapy

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.

The Efficacy of Mannitol Combined with 6-Aminocaproic Acid in the Treatment of Patients with Cerebral Hemorrhage and Its Impact on Immune Function.

Objective To determine the efficacy of Mannitol combined with 6-aminocaproic acid in the treatment of patients with cerebral hemorrhage, as well as its impact on the immune system. Methods The study subjects consisted of 122 patients with early intracerebral hemorrhage treated in our hospital from April 2019 to April 2022. Based on the different admission times, the participants were randomly divided into the control group and the study group in a ratio of 1:1. 6-Aminocaproic acid was used to treat patients in the control group, while Mannitol along with 6-aminocaproic acid was used to treat patients in the study group. Short form-36 health survey (SF-36) scores, hematoma volume changes, National Institutes of Health Stroke Scale (NIHSS), and Mini-Mental State Examination (MMSE) scores, clinical efficacy, and changes in the immune function in patients from the two groups were analyzed and compared. Results The total efficacy of treatment in the study group was significantly higher than that in the control group (x2 = 9,375, P < 0.001). Patients in the study group had significantly higher scores in social function, mental health, physical function, and physiological function compared to those in the control group (P < 0.05). After treatment, there was a significant reduction in NIHSS scores in patients from both groups, but a greater reduction was seen in patients from the study group (P < 0.05). After 2 weeks of treatment, the volume of cerebral edema was significantly smaller in patients from the study group than in those from the control group (P < 0.05). Before treatment, there was no significant difference in the number of CD4+ and CD8+ T lymphocytes between patients in the two groups. However, after treatment, patients in the study group had higher numbers of CD4+ T lymphocytes and lower numbers of CD8+ T lymphocytes compared to those in the control group (P < 0.05). Conclusions The combination of Mannitol and 6-aminocaproic acid appears to be very efficacious in the treatment of cerebral hemorrhage. It improves immune function, reduces neurological damage, and minimizes the volume of cerebral edema.

Biocatalytic Production of a Nylon 6 Precursor from Caprolactone in Continuous Flow.

6‐Aminocaproic acid (6ACA) is a key building block and an attractive precursor of caprolactam, which is used to synthesize nylon 6, one of the most common polymers manufactured nowadays. (Bio)‐production of platform chemicals from renewable feedstocks is instrumental to tackle climate change and decrease fossil fuel dependence. Here, the cell‐free biosynthesis of 6ACA from 6‐hydroxycaproic acid was achieved using a co‐immobilized multienzyme system based on horse liver alcohol dehydrogenase, Halomonas elongata transaminase, and Lactobacillus pentosus NADH oxidase for in‐situ cofactor recycling, with >90 % molar conversion (m.c.) The integration of a step to synthesize hydroxy‐acid from lactone by immobilized Candida antarctica lipase B resulted in >80 % m.c. of ϵ‐caprolactone to 6ACA, >20 % of δ‐valerolactone to 5‐aminovaleric acid, and 30 % of γ‐butyrolactone to γ‐aminobutyric acid in one‐pot batch reactions. Two serial packed‐bed reactors were set up using these biocatalysts and applied to the continuous‐flow synthesis of 6ACA from ϵ‐caprolactone, achieving a space‐time yield of up to 3.31 g6ACA h−1 L−1 with a segmented liquid/air flow for constant oxygen supply.

Epsilon Aminocaproic Acid's Safety and Efficacy in Pediatric Surgeries Including Craniosynostosis Repair: A Review of the Literature.

Craniosynostosis, the premature fusion of skull sutures in children, requires surgical correction. This procedure routinely requires allogeneic blood transfusions, which are associated with multiple risks of their own. Since 2008, antifibrinolytics tranexamic acid (TXA) and epsilon aminocaproic acid (EACA or Amicar) have been widely used. There is literature comparing the two agents in scoliosis and cardiothoracic surgery, but the literature comparing the two agents in pediatric craniofacial surgery (CF) is limited. Tranexamic acid use is more common in pediatric CF surgery and has been thoroughly studied; however, it costs about three times as much as EACA and has been associated with seizures. This study compiles the literature assessing the safety and efficacy of EACA in reducing blood loss and transfusion volumes in children and explores its potential use in pediatric CF surgery.Papers from 2000 to 2021 regarding the effectiveness and safety of EACA in Pediatric scoliosis, cardiothoracic, and craniosynostosis surgery were reviewed and compiled. Papers were found via searching PubMed and Cochrane databases with the key terms: Epsilon aminocaproic acid, EACA, Amicar, Tranexamic acid, TXA, craniosynostosis, scoliosis, cardiothoracic, and pediatric. Prospective studies, retrospective studies, and meta-analyses were included.Twenty-nine papers were identified as pertinent from the literature searched. Four were meta-analyses, 14 were retrospective, and 11 were prospective. Of these papers, seven were of cardiac surgery, 12 were of scoliosis, and nine were of craniosynostosis. During our search, EACA has been shown to consistently reduce blood transfusion volumes compared to control. However, it is not as effective when compared to TXA. EACA has a similar safety profile to TXA but has a reduced risk of seizures. There are not many studies of EACA in craniosynostosis repair, but the existing literature shows promising results for EACA's efficacy and safety, warranting more studies.

Cryoprecipitate for Alteplase-Related Hemorrhagic Conversion of Acute Ischemic Stroke.

Background: Evidence to support cryoprecipitate for reversal of alteplase-related hemorrhagic conversion of acute ischemic stroke is limited. Guidelines recommend cryoprecipitate as first line treatment, followed by aminocaproic acid as a conditional recommendation with very low-quality evidence. The purpose of this case series was to describe the use of cryoprecipitate for alteplase-related hemorrhagic conversion of acute ischemic stroke. Methods: This was an IRB-approved retrospective case series of adults who received cryoprecipitate for an alteplase-related hemorrhagic conversion of acute ischemic stroke at two comprehensive stroke centers within a large academic medical center. Thromboembolism at 14 days and hemostasis within 24 hours were collected. The outcomes of cryoprecipitate alone vs cryoprecipitate with aminocaproic acid (C + A) were also described. Results: A total of 19 patients were included. Thrombosis occurred in 1/19 (5%) and hemostasis occurred in 4/14 (29%) of evaluable patients. In-hospital mortality was seen in 9/19 (47%) patients. Seventy four percent (14/19) of patients received concomitant blood products other than cryoprecipitate and 63% received a concomitant reversal agent. Thirteen patients received cryoprecipitate alone and six received C + A. Thrombosis was seen in 1/13 (8%) vs 0/6 (0%) and hemostasis occurred in 2/11 (18%) and 2/3 (67%) evaluable cryoprecipitate vs C + A patients respectively. Conclusion: Cryoprecipitate was associated with a low rate of thrombosis and hemostasis for alteplase-associated hemorrhagic conversion of acute ischemic stroke. There was significant heterogeneity in treatment regimens, including the use of and dosing of adjunctive aminocaproic acid and monitoring of fibrinogen levels.

Urinary Metabolomic Study in a Healthy Children Population and Metabolic Biomarker Discovery of Attention-Deficit/Hyperactivity Disorder (ADHD).

ObjectivesKnowledge of the urinary metabolomic profiles of healthy children and adolescents plays a promising role in the field of pediatrics. Metabolomics has also been used to diagnose disease, discover novel biomarkers, and elucidate pathophysiological pathways. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in childhood. However, large-sample urinary metabolomic studies in children with ADHD are relatively rare. In this study, we aimed to identify specific biomarkers for ADHD diagnosis in children and adolescents by urinary metabolomic profiling.MethodsWe explored the urine metabolome in 363 healthy children aged 1–18 years and 76 patients with ADHD using high-resolution mass spectrometry.ResultsMetabolic pathways, such as arachidonic acid metabolism, steroid hormone biosynthesis, and catecholamine biosynthesis, were found to be related to sex and age in healthy children. The urinary metabolites displaying the largest differences between patients with ADHD and healthy controls belonged to the tyrosine, leucine, and fatty acid metabolic pathways. A metabolite panel consisting of FAPy-adenine, 3-methylazelaic acid, and phenylacetylglutamine was discovered to have good predictive ability for ADHD, with a receiver operating characteristic area under the curve (ROC–AUC) of 0.918. A panel of FAPy-adenine, N-acetylaspartylglutamic acid, dopamine 4-sulfate, aminocaproic acid, and asparaginyl-leucine was used to establish a robust model for ADHD comorbid tic disorders and controls with an AUC of 0.918.

Single-Cell Protein and Transcriptional Characterization of Epiretinal Membranes From Patients With Proliferative Vitreoretinopathy.

PurposeProliferative vitreoretinopathy (PVR) remains an unresolved clinical challenge and can lead to frequent revision surgery and blindness vision loss. The aim of this study was to characterize the microenvironment of epiretinal PVR tissue, in order to shed more light on the complex pathophysiology and to unravel new treatment options.MethodsA total of 44 tissue samples were analyzed in this study, including 19 epiretinal PVRs, 13 epiretinal membranes (ERMs) from patients with macular pucker, as well as 12 internal limiting membranes (ILMs). The cellular and molecular microenvironment was assessed by cell type deconvolution analysis (xCell), RNA sequencing data and single-cell imaging mass cytometry. Candidate drugs for PVR treatment were identified in silico via a transcriptome-based drug-repurposing approach.ResultsRNA sequencing of tissue samples demonstrated distinct transcriptional profiles of PVR, ERM, and ILM samples. Differential gene expression analysis revealed 3194 upregulated genes in PVR compared with ILM, including FN1 and SPARC, which contribute to biological processes, such as extracellular matrix (ECM) organization. The xCell and IMC analyses showed that PVR membranes were composed of macrophages, retinal pigment epithelium, and α-SMA-positive myofibroblasts, the latter predominantly characterized by the co-expression of immune cell signature markers. Finally, 13 drugs were identified as potential therapeutics for PVR, including aminocaproic acid and various topoisomerase-2A inhibitors.ConclusionsEpiretinal PVR membranes exhibit a unique and complex transcriptional and cellular profile dominated by immune cells and myofibroblasts, as well as a variety of ECM components. Our findings provide new insights into the pathophysiology of PVR and suggest potential targeted therapeutic options.

Low dose prophylaxis and antifibrinolytics: Options to consider with proven benefits for persons with haemophilia.

Prophylaxis has become standard of care for persons with severe phenotype haemophilia (PWsH). However, 'standard prophylaxis' with either factor or non-factor therapies (emicizumab) is prohibitively expensive for much of the world. We sought to evaluate whether haemophilia care can be provided at a lower cost yet achieve good results using Lower dose/Lower frequency prophylaxis (LDP) and with increasing use of antifibrinolytics (Tranexamic acid and Epsilon amino caproic acid). We identified 12 studies that collectively included 335 PWsH using LDP. Additionally, we undertook a literature search regarding the benefits of antifibrinolytics in haemophilia care. Identified studies show that LDP is far superior to no prophylaxis (On demand [OD] therapy) resulting in significant patient benefits. Patients on LDP showed (in comparison to patients OD) on average: 72% less total bleeds; 75% less joint bleeds; 91% less days lost from school; 77% less hospital admission days; and improved quality of life measures. These benefits come at similar or only slightly higher (<2-fold greater) costs than OD therapy. Antifibrinolytics are effective adjunctive agents in managing bleeds (oral, nasal, intracranial, possibly other) and providing haemostasis for surgeries (particularly oral surgeries). Antifibrinolytics can substitute for more expensive factor concentrates or can reduce the use of such concentrates. There is evidence to show that antifibrinolytics may be used in conjunction with factor concentrates/emicizumab for more effective/less costly prophylaxis. The use of LDP along with appropriate and increased use of antifibrinolytics offers less resourced countries good options for managing patients with haemophilia.

Use of Aminocaproic Acid With Bivalirudin for Hemostatic Management of Abdominal Surgery for Neonate on Extracorporeal Support.

Use of Aminocaproic Acid With Bivalirudin for Hemostatic Management of Abdominal Surgery for Neonate on Extracorporeal Support.

Intractable Gastrointestinal Bleeding Events After Left Ventricular Assist Device Implantation

<h3>Introduction</h3> There is evidence that continuous-flow left ventricular assist device (CF-LVAD) support may cause gastrointestinal (GI) angiodysplasias. Bleeding events are the most common complications after LVAD implantation emphasizing the importance of GI bleeding management. <h3>Case Report</h3> A 63-year-old male patient underwent CF-LVAD implantation for advanced heart failure in 2014. Anticoagulation consisted of warfarin with a target INR of 2.0 to 3.0 and acetylsalicylic acid (ASA) 100 mg o.d. Recurrent anemia, managed by transfusions of over 500 units of packed red blood cells and iron supplementation, has been of major concern since 2014. Gastroscopy and colonoscopy were negative. Capsule endoscopy revealed jejunal angioectasias and ileal angiodysplasias. ASA was cessated, warfarin was temporarily stopped and INR was lowered to 1.8. Octreotide and erythropoietin were initiated. Hydrocortisone suppository was added and ligation for haemorrhoids was performed for rectal bleeding. As anaemia deteriorated, warfarin was permanently stopped in 2018; thus, patient has been maintained without anticoagulation for 3 years. LVAD pump speed was reduced to increase pulsatility. As computed tomography presumed jejunal bleeding, small bowel resection was performed. Angiodysplasia was histologically confirmed and off-label therapy was initiated with thalidomide and bevacizumab. Diffuse angiodysplasias of the colon and ileum were treated by argon plasma coagulation. Aminocaproic acid and tranexamic acid were administered. Meanwhile, LVAD pump speed was increased due to worsening of heart failure. Patient has experienced several self-terminating pump-stops since 2020, suspected to be caused by damaged insulation of the driveline. Due to his poor overall condition and unability to tolerate any forms of anticoagulation, neither heart transplantation, nor pump replacement could be performed. The patient died of LVAD stoppage in 2021. Pump thrombosis was excluded on autopsy. The breaches in the wire insulation causing pump-stops were confirmed by factory investigation. <h3>Summary</h3> In case of GI bleeding, hemostasis and LVAD pump management are crucial as the management of anticoagulation should balance between bleeding and risk for thromboembolism. Reduction in bleeding events emphasizes the importance of experimental therapies in case of intractable bleeding events.

Synthesis and Hemostatic Activity of New Amide Derivatives.

Eight dipeptides containing antifibrinolytic agents (tranexamic acid, aminocaproic acid, 4-(aminomethyl)benzoic acid, and glycine—natural amino acids) were synthesized in a three-step process with good or very good yields. DMT/NMM/TsO− (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate) was used as a coupling reagent. Hemolysis tests were used to study the effects of the dipeptides on blood components. Blood plasma clotting tests were used to examine their effects on thrombin time (TT), prothrombin time (PT), and the activated partial thromboplastin time (aPTT). The level of hemolysis did not exceed 1%. In clotting tests, TT, PT, and aPTT did not differentiate any of the compounds. The prothrombin times for all amides 1–8 were similar. The obtained results in the presence of amides 1–4 and 8 were slightly lower than for the other compounds and the positive control, and they were similar to the results obtained for TA. In the case of amide 3, a significantly decreased aPTT was observed. The aPTTs observed for plasma treated with amide 3 and TA were comparable. In the case of amide 6 and 8, TT values significantly lower than for the other compounds were found. The clot formation and fibrinolysis (CFF) assay was used to assess the influence of the dipeptides on the blood plasma coagulation cascade and the fibrinolytic efficiency of the blood plasma. In the clot formation and fibrinolysis assay, amides 5 and 7 were among the most active compounds. The cytotoxicity and genotoxicity of the synthesized dipeptides were evaluated on the monocyte/macrophage peripheral blood cell line. The dipeptides did not cause hemolysis at any concentrations. They exhibited no significant cytotoxic effect on SC cells and did not induce significant DNA damage.

Lung Transplantation for Pulmonary Fibrosis Associated With Hermansky-Pudlak Syndrome. A Single-center Experience.

Background.Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, platelet storage defect with resultant bleeding diathesis, and pulmonary fibrosis. The bleeding diathesis associated with HPS had long been considered a contraindication to lung transplantation; consequently, few reports of successful lung transplantation for HPS exist.Methods.In the largest case series on lung transplant for HPS, we describe the characteristics of 11 lung transplant candidates with HPS-related pulmonary fibrosis, and the management and outcomes of 7 patients who underwent lung transplantation.Results.Of the 7 patients transplanted, 30-d survival was 85.7% (6/7). Six patients had at least 2 y of follow-up available with a 1-y survival of 83.3% and a 2-y survival of 83.3% (5/6). The median age at referral was 48 y (range 29–62 y). Eight patients (72.7%) were of Puerto Rican ancestry with confirmed type 1 HPS mutation. Six out of 7 patients received prophylaxis for bleeding diathesis, with a majority receiving desmopressin; 1 patient was administered aminocaproic acid infusion, and another received 2 units of platelets before surgery. Estimated blood loss and the amount of intraoperative blood product administered was highly variable with or without prophylaxis. Median blood loss was 400 mL (range 125–750) and estimated blood products administered was 700 mL (range 490–4043).Conclusions.HPS should not be considered a contraindication for lung transplantation. Although patients with HPS seem to have an increased risk of massive hemorrhage, the risk is unpredictable. Transplant teams should prepare a preoperative plan in consultation with hematology and consider the use of prophylactic platelet transfusion and desmopressin.

Effects of antifibrinolytics on systemic and cerebral inflammation after traumatic brain injury.

Administration of antifibrinolytic medications, including tranexamic acid (TXA), may reduce head injury-related mortality. The effect of these medications on post-traumatic brain injury (TBI) inflammatory response is unknown. The goal of this study was to investigate the role of available antifibrinolytic medications on both systemic and cerebral inflammation after TBI. An established murine weight drop model was used to induce a moderate TBI. Mice were administered 1, 10, or 100 mg/kg of TXA, 400 mg/kg of aminocaproic acid (Amicar, Hospira, Lake Forest, IL), 100 kIU/kg of aprotonin, or equivalent volume of normal saline (NS) 10 minutes after recovery. Mice were euthanized at 1, 6, or 24 hours. Serum and cerebral tissue were analyzed for neuron-specific enolase and inflammatory cytokines. Hippocampal histology was evaluated at 30 days for phosphorylated tau accumulation. One hour after TBI, mice given TXA displayed decreased cerebral cytokine concentrations of tumor necrosis factor α (TNF-α) and, by 24 hours, displayed decreased concentrations of cerebral TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein 1 compared with TBI-NS. However, serum concentrations of TNF-α and macrophage inflammatory protein 1α (MIP-1α) were significantly elevated from 1 to 24 hours in TBI-TXA groups compared with TBI-NS. The concentration of phosphorylated tau was significantly decreased in a dose-dependent manner in TBI-TXA groups compared with TBI-NS. By contrast, Amicar administration increased cerebral cytokine levels of IL-6 1 hour after TBI, with serum elevations noted in TNF-α, MIP-1α, and monocyte chemoattractant protein 1 at 24 hours compared with TBI-NS. Aprotonin administration increased serum TNF-α, IL-6, and MIP-1α from 1 to 24 hours without differences in cerebral cytokines compared with TBI-NS. Tranexamic acid administration may provide acute neuroinflammatory protection in a dose-dependent manner. Amicar administration may be detrimental after TBI with increased cerebral and systemic inflammatory effects. Aprotonin administration may increase systemic inflammation without significant contributions to neuroinflammation. While no antifibrinolytic medication improved systemic inflammation, these data suggest that TXA may provide the most beneficial inflammatory modulation after TBI.

Furanonyl amino acid derivatives as hemostatic drugs: design, synthesis and hemostasis performance.

Using 3,4-dihalo-2(5H)-furanones and easily available hemostatic drugs, such as tranexamic acid (TA), 4-aminomethylbenzoic acid (ABA), aminocaproic acid (AA) as starting materials, serial multi-functional molecules 2(5H)-furanonyl amino acids are designed by the combination of different pharmacophores, and successfully synthesized by a transition metal-free Michael addition-elimination reaction. The reaction is carried out under mild conditions with ethanol-dichloromethane as solvent and only stirring at room temperature for 24h, and the yield can be up to 91%. All products are well characterized by infrared spectroscopy (IR), nuclear magnetic resonance (NMR), high-resolution mass spectra (HRMS). Ten typical target compounds among them are selected out for the experiments of hemostasis performance by the evaluation of in vitro clot formation model and liver hemorrhage model. The test results show that, their hemostasis effect is better than the original drugs. Especially the target compound G, a TA derivative from 5-borneoloxy-3,4-dibromo-2(5H)-furanone, has the best hemostasis effect among all the tested compounds. These obtained target molecules are expected to be used as multi-functional hemostatic drugs.