Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and stage 5 chronic kidney disease under dialysis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: In patients with atrial fibrillation (AF) and normal or slightly impaired renal function, the use of direct oral anticoagulants (DOACs) is preferable to vitamin K antagonists (VKAs). However, in patients undergoing hemodialysis, the efficacy, and safety of DOACs compared with VKAs are still unknown. PURPOSE: To review current evidence about the safety and efficacy of DOACs compared to VKAs, in patients with AF and chronic kidney disease under hemodialysis. METHODS: We systematically searched PubMed, Scopus, and Cochrane databases for RCTs comparing DOACs with VKAs for anticoagulation in patients with AF on dialysis therapy. Outcomes of interest were: (1) stroke; (2) major bleeding; (3) cardiovascular mortality; and (4) all-cause mortality. Statistical analysis was performed using RevMan 5.1.7 and heterogeneity was assessed by I2 statistics. RESULTS: Three randomized controlled trials were included, comprising a total of 383 patients. Of these, 218 received DOACs (130 received apixaban; 88 received rivaroxaban), and 165 were treated with VKAs (116 received warfarin; 49 received phenprocoumon). The incidence of stroke was significantly lower in patients treated with DOACs (4.7%) compared with those using VKAs (9.5%) (RR 0.42; 95% CI 0.18-0.97; p = 0.04; I2 = 0%). However, the difference was not statistically significant in the case of ischemic stroke specifically (RR 0.42; 95% CI 0.17-1.04; p = 0.06; I2 = 0%). As for the major bleeding outcome, the DOAC group (11%) had fewer events than the VKA group (13.9%) but without statistical significance (RR 0.75; 95% CI 0.45-1.28; p = 0.29; I2 = 0%). There was no significant difference between groups regarding cardiovascular mortality (RR 1.23; 95% CI 0.66-2.29; p = 0.52; I2 = 13%) and all-cause mortality (RR 0.98; 95% CI 0.77-1.24; p = 0.84; I2 = 16%). CONCLUSION: This meta-analysis suggests that in patients with AF on dialysis, the use of DOACs was associated with a significant reduction in stroke, and a numerical trend of less incidence of major bleeding compared with VKAs, but in this case with no statistical significance. Results may be limited by a small sample size or insufficient statistical power.

Telemedicine-Based Management of Oral Anticoagulation Therapy: Systematic Review and Meta-analysis.

BACKGROUND: Oral anticoagulation is the cornerstone treatment of several diseases. Its management is often challenging, and different telemedicine strategies have been implemented to support it. OBJECTIVE: The aim of the study is to systematically review the evidence on the impact of telemedicine-based oral anticoagulation management compared to usual care on thromboembolic and bleeding events. METHODS: Randomized controlled trials were searched in 5 databases from inception to September 2021. Two independent reviewers performed study selection and data extraction. Total thromboembolic events, major bleeding, mortality, and time in therapeutic range were assessed. Results were pooled using random effect models. RESULTS: In total, 25 randomized controlled trials were included (n=25,746 patients) and classified as moderate to high risk of bias by the Cochrane tool. Telemedicine resulted in lower rates of thromboembolic events, though not statistically significant (n=13 studies, relative risk [RR] 0.75, 95% CI 0.53-1.07; I2=42%), comparable rates of major bleeding (n=11 studies, RR 0.94, 95% CI 0.82-1.07; I2=0%) and mortality (n=12 studies, RR 0.96, 95% CI 0.78-1.20; I2=11%), and an improved time in therapeutic range (n=16 studies, mean difference 3.38, 95% CI 1.12-5.65; I2=90%). In the subgroup of the multitasking intervention, telemedicine resulted in an important reduction of thromboembolic events (RR 0.20, 95% CI 0.08-0.48). CONCLUSIONS: Telemedicine-based oral anticoagulation management resulted in similar rates of major bleeding and mortality, a trend for fewer thromboembolic events, and better anticoagulation quality compared to standard care. Given the potential benefits of telemedicine-based care, such as greater access to remote populations or people with ambulatory restrictions, these findings may encourage further implementation of eHealth strategies for anticoagulation management, particularly as part of multifaceted interventions for integrated care of chronic diseases. Meanwhile, researchers should develop higher-quality evidence focusing on hard clinical outcomes, cost-effectiveness, and quality of life. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020159208; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=159208.

Innovations in RNA therapy for hemophilia.

Given the shortcomings of current factor-, nonfactor-, and adeno-associated virus gene-based therapies, the recent advent of RNA-based therapeutics for hemophilia is changing the fundamental approach to hemophilia management. From small interfering RNA therapeutics that knockdown clot regulators antithrombin, protein S, and heparin cofactor II, to CRISPR/Cas9 gene editing that may personalize treatment, improved technologies have the potential to reduce bleeds and factor use and avoid inhibitor formation. These novel agents, some in preclinical studies and others in early phase trials, have the potential to simplify treatment and improve hemostasis and quality of life. Furthermore, because these therapies arise from manipulation of the coagulation cascade and thrombin generation and its regulation, they will enhance our understanding of hemostasis and thrombosis and ultimately lead to better therapies for children and adults with inherited bleeding disorders. What does the future hold? With the development of novel preclinical technologies at the bench, there will be fewer joint bleeds, debilitating joint disease, orthopedic surgery, and improved physical and mental health, which were not previously possible. In this review, we identify current limitations of treatment and progress in the development of novel RNA therapeutics, including messenger RNA nanoparticle delivery and gene editing for the treatment of hemophilia.

[8] and [10]-Gingerol reduces urothelial damage in ifosfamide-induced hemorrhagic cystitis via JAK/STAT/FOXO signaling pathway via IL-10.

Acrolein is the main toxic metabolite of ifosfamide (IFO) that causes urothelial damage by oxidative stress and inflammation. Here, we investigate the molecular mechanism of action of gingerols, Zingiber officinale bioactive molecules, as an alternative treatment for ifosfamide-induced hemorrhagic cystitis. Female Swiss mice were randomly divided into 5 groups: control; IFO; IFO + Mesna; and IFO + [8]- or [10]-gingerol. Mesna (80 mg/kg, i.p.) was given 5 min before, 4 and 8 h after IFO (400mg/kg, i.p.). Gingerols (25 mg/kg, p.o.) were given 1 h before and 4 and 8 h after IFO. Animals were euthanized 12 h after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and inflammation were assessed by malondialdehyde (MDA) or myeloperoxidase assays, respectively. mRNA gene expression was performed to evaluate mesna and gingerols mechanisms of action. Mesna was able to protect bladder tissue by activating NF-κB and NrF2 pathways. However, we demonstrated that gingerols acted as an antioxidant and anti-inflammatory agent stimulating the expression of IL-10, which intracellularly activates JAK/STAT/FOXO signaling pathway.

Safety and efficacy of short-term dual antiplatelet therapy combined with intensive rosuvastatin in acute ischemic stroke.

OBJECTIVE: To investigate the safety and efficacy of short-term (7-day) Dual Antiplatelet Therapy (DAPT) with intensive rosuvastatin in Acute Ischemic Stroke (AIS). METHODS: In this study, patients with AIS in the emergency department of the hospital from October 2016 to December 2019 were registered and divided into the control group (Single Antiplatelet Therapy [SAPT] + rosuvastatin) and the study group (7-day DAPT + intensive rosuvastatin) according to the therapy regimens. The generalized linear model was used to compare the National Institute of Health Stroke Scale (NIHSS) scores between the two groups during the 21-day treatment. A Cox regression model was used to compare recurrent ischemic stroke, bleeding events, Statin-Induced Liver Injury (SILI), and Statin-Associated Myopathy (SAM) between the two groups during the 90-day follow-up. RESULTS: Comparison of NIHSS scores after 21-day treatment: NIHSS scores in the study group decreased significantly, 0.273-times as much as that in the control group (Odds Ratio [OR] 0.273; 95% Confidence Interval [95% CI] 0.208-0.359; p < 0.001). Comparison of recurrent ischemic stroke during the 90-day follow-up: The therapy of the study group reduced the risk of recurrent stroke by 65% (7.76% vs. 22.82%, Hazard Ratio [HR] 0.350; 95% CI 0.167-0.730; p = 0.005). Comparison of bleeding events: There was no statistical difference between the two groups (7.79% vs. 6.71%, HR = 1.076; 95% CI 0.424-2.732; p = 0.878). No cases of SILI and SAM were found. CONCLUSIONS: Short-term DAPT with intensive rosuvastatin effectively relieved the clinical symptoms and significantly reduced the recurrent stroke for patients with mild-to-moderate AIS within 90 days, without increasing bleeding events, SILI and SAM.

Evaluation of the Efficacy of Lactobacillus acidophilus in the Treatment of Cyclophosphamide-induced Hemorrhagic Cystitis in Wistar Rats.

BACKGROUND: Hemorrhagic cystitis is an inflammatory complication that can be caused by the administration of cyclophosphamide, which is widely used as an antineoplastic agent. In the search for new therapeutic alternatives, probiotics can suppress the inflammatory process and, therefore, can be used to prevent this disease. OBJECTIVE: Thus, this study aimed to evaluate the effects of using Lactobacillus acidophilus NCFM in the treatment of cyclophosphamide-induced hemorrhagic cystitis in Wistar rats. METHODS: Lactobacillus acidophilus NCFM (2x108 CFU) was used in the treatment of cyclophosphamide- induced hemorrhagic cystitis (200 mg/kg, intraperitoneal) in 77 female Wistar rats. Rats were distributed into experimental groups (n = 9): control group (GC), zero control group (GCZ), inflammation group (GI), 24-hour acute treatment groups: 24-hour lactobacilli treatment group (GL24H) and mesna group (GM), and 30-day chronic treatment groups: lactobacilli treatment group (GTL) and mesna+lactobacilli group (GM+L). After treatment, animals were euthanized and biological materials were collected for blood count, biochemical analyses, examination of abnormal sediment elements (EAS), and histopathological analysis. RESULTS: GI results showed development of edema, macroscopic alterations, and signs of bleeding in the bladder; in addition, lesions in the urothelium and hemorrhage were also found. GL24H and GM presented intact urothelium, without inflammatory reaction and hematological or biochemical urine alterations. CONCLUSION: Therefore, this study demonstrated that L. acidophilus presented uroprotective effect against the action of cyclophosphamide in both the short and long term.

Inhibitory Effects of Varespladib, CP471474, and Their Potential Synergistic Activity on Bothrops asper and Crotalus durissus cumanensis Venoms.

Snakebite is a neglected tropical disease that causes extensive mortality and morbidity in rural communities. Antivenim sera are the currently approved therapy for snake bites; however, they have some therapeutic limitations that have been extensively documented. Recently, small molecule toxin inhibitors have received significant attention as potential alternatives or co-adjuvant to immunoglobulin-based snakebite therapies. Thus, in this study, we evaluated the inhibitory effects of the phospholipase A2 inhibitor varespladib and the metalloproteinase inhibitor CP471474 and their synergistic effects on the lethal, edema-forming, hemorrhagic, and myotoxic activities of Bothrops asper and Crotalus durissus cumanensis venoms from Colombia. Except for the preincubation assay of the lethal activity with B. asper venom, the mixture showed the best inhibitory activity. Nevertheless, the mix did not display statistically significant differences to varespladib and CP471474 used separately in all assays. In preincubation assays, varespladib showed the best inhibitory activity against the lethal effect induced by B. asper venom. However, in independent injection assays, the mix of the compounds partially inhibited the lethal activity of both venoms (50%). In addition, in the assays to test the inhibition of edema-forming activity, the mixture exhibited the best inhibitory activity, followed by Varespladib, but without statistically significant differences (p > 0.05). The combination also decreased the myotoxic activity of evaluated venoms. In these assays, the mix showed statistical differences regarding CP471474 (p < 0.05). The mixture also abolished the hemorrhagic activity of B. asper venom in preincubation assays, with no statistical differences to CP471474. Finally, the mixture showed inhibition in studies with independent administration in a time-dependent manner. To propose a mode of action of varespladib and CP471474, molecular docking was performed. PLA2s and SVMPs from tested venoms were used as targets. In all cases, our molecular modeling results suggested that inhibitors may occupy the substrate-binding cleft of the enzymes, which was supported by specific interaction with amino acids from the active site, such as His48 for PLA2s and Glu143 for the metalloproteinase. In addition, varespladib and CP471474 also showed interaction with residues from the hydrophobic channel in PLA2s and substrate binding subsites in the SVMP. Our results suggest a synergistic action of the mixed inhibitors and show the potential of varespladib, CP471474, and their mixture to generate new treatments for snakebite envenoming with application in the field or as antivenom co-adjuvants.

Long-term prophylaxis: what are our options and how to define success?

Currently, we are at an enviable place in hemophilia treatment. Although full prophylaxis with standard half-life recombinant or plasma-derived factor concentrates has been definitively shown to be inadequate for full protection against bleeding and arthropathy, a number of novel therapies with improved hemostatic enhancement are clinically available or in promising clinical trials. In order to compare outcomes among a number of very efficacious therapies, it is necessary to have sensitive tools employed in long-term follow-up for several years for participants with no or minimal joint disease. The tool kit must be comprehensive, with outcomes of bleeding, factor level restoration or hemostatic capacity, joint structure, joint function, pain, quality of life, and patient satisfaction. This article reviews the history of prophylaxis, the promise of emerging therapies, and the sensitive tools used to assess long-term efficacy for joint structure and function.

A First Look at the Inhibitory Potential of Urospatha sagittifolia (Araceae) Ethanolic Extract for Bothrops atrox Snakebite Envenomation.

Bothrops atrox snakebites are a relevant problem in the Amazon basin. In this biodiverse region, the ethnomedicinal approach plays an important role as an alternative to antivenom therapy. Urospatha sagittifolia (Araceae) is a plant used for this purpose; however, its neutralizing properties have not been scientifically accessed. To fill this gap, we investigated the ability of U. sagittifolia to modulate the catalytic activity of Bothrops atrox venom, and their toxic consequences, such as local damage and lethality. The venom profile of B. atrox was assessed by chromatography and electrophoresis. Inhibition of the three main enzymatic and medically important toxins from the venom was evaluated using synthetic substrates and quantified by chromogenic activity assays. Additionally, the neutralization of lethality, hemorrhage and edema were investigated by in vivo assays. The possible interactions between venom proteins and plant molecules were visualized by polyacrylamide gel electrophoresis. Finally, the phytochemical constituents present in the ethanolic extract were determined by qualitative and quantitative analyses. The ethanolic extract reduced the activity of the three main enzymes of venom target, achieving ranges from 19% to 81% of inhibition. Our in vivo venom neuralizations assays showed a significant inhibition of edema (38.72%) and hemorrhage (42.90%). Additionally, lethality was remarkably counteracted. The highest extract ratio evaluated had a 75% survival rate. Our data support the biomedical value of U. sagittifolia as a source of natural enzyme inhibitors able to neutralize catalytically active B. atrox venom toxins and their toxic effects.

Red propolis reduces inflammation in cyclophosphamide-induced hemorrhagic cystitis in rats. / El propóleos rojo reduce la inflamación en la cistitis hemorrágica inducida por ciclofosfamida en ratas

Introduction. Cyclophosphamide (CP) is used to treat malignant neoplasias and control autoimmune diseases. Still, one of its metabolites, acrolein, is toxic to the urothelium and can lead to hemorrhagic cystitis and severe discomfort. Objective. To evaluate the ability of red propolis to prevent and treat CP-induced hemorrhagic cystitis in rats. Materials and methods. Red propolis was extracted in 1% gum arabic and administered subcutaneously (sc). In the first experiment, groups IA, IIA, and IIIA and groups IB, IIB, and IIIB received water, gum arabic (GA), or propolis, respectively, for 30 days. Then water (controls) or CP (treatment) was administered i.p. In the second experiment, groups IVA, VA, and VIA received water i.p. while groups IVB, VB, and VIB received CP i.p. This was followed by 5 injections at 2-hour intervals with either water, GA, or propolis. Bladder tissue was examined according to Gray's criteria. Results. The total inflammatory histology score was significantly smaller in group VIB (11.33 ± 2.07). Mild inflammation predominated in group VIB while most of the animals in group IVB had severe inflammation (p=0.0375). Ulcers were predominantly multiple in Groups IVA and VB but rare or absent in Group VIB (p=0.0118). Urothelial cells were mostly absent in groups IVB and VB and present/normal in group VIB (p=0.0052). Fibrin was abundant in groups IVB and VA but mostly absent in group VIB (p=0.0273). Conclusions. Red propolis can reduce inflammation in CP-induced hemorrhagic cystitis in rats.

Introducción. La ciclofosfamida se usa para tratar neoplasias malignas y controlar enfermedades autoinmunitarias, pero uno de sus metabolitos, la acroleína, es tóxico para el urotelio y puede provocar cistitis hemorrágica y malestar grave. Objetivo. Evaluar la capacidad del propóleos rojo para prevenir y tratar la cistitis hemorrágica inducida por ciclofosfamida en ratas. Materiales y métodos. Se extrajo propóleos rojo en goma arábiga al 1 % y se administró por vía subcutánea. En el primer experimento, los grupos IA, IIA, IIIA, IB, IIB y IIIB recibieron agua, goma arábiga y propóleos, respectivamente, durante 30 días. Luego se les administró agua (controles) o el tratamiento (ciclofosfamida) por inyección intraperitoneal. En el segundo experimento, los grupos IVA, VA, VIA recibieron agua por vía intraperitoneal, y los grupos IVB, VB, VIB recibieron el tratamiento por la misma vía, a lo que le siguieron cinco inyecciones con intervalos de dos horas entre ellas, con agua, goma arábiga o propóleos. El tejido de la vejiga se examinó de acuerdo con los criterios de Gray. Resultados. La puntuación total de la inflamación según la histología fue significativamente menor en el grupo VIB (11,33 ± 2,07). La inflamación leve predominó en este grupo, en tanto que la mayoría de los animales del IVB presentó inflamación grave (p=0,0375). Predominaron las úlceras múltiples en los grupos IVA y VB, pero fueron raras o estuvieron ausentes en el VIB (p=0,0118). En general, no se observaron células uroteliales en los grupos IVB y VB, pero sí en el VIB (p=0,0052). La fibrina fue abundante en los grupos IVB y VA, pero predominantemente ausente en el VIB (p=0,0273). Conclusiones. El propóleos rojo puede reducir la inflamación en la cistitis hemorrágica inducida por ciclofosfamida en ratas.

Immune complications and their management in inherited and acquired bleeding disorders.

Disorders of coagulation, resulting in serious risks for bleeding, may be caused by autoantibody formation or by mutations in genes encoding coagulation factors. In the latter case, antidrug antibodies (ADAs) may form against the clotting factor protein drugs used in replacement therapy, as is well documented in the treatment of the X-linked disease hemophilia. Such neutralizing antibodies against factors VIII or IX substantially complicate treatment. Autoantibody formation against factor VIII leads to acquired hemophilia. Although rare, antibody formation may occur in the treatment of other clotting factor deficiencies (eg, against von Willebrand factor [VWF]). The main strategies that have emerged to address these immune responses include (1) clinical immune tolerance induction (ITI) protocols; (2) immune suppression therapies (ISTs); and (3) the development of drugs that can improve hemostasis while bypassing the antibodies against coagulation factors altogether (some of these nonfactor therapies/NFTs are antibody-based, but they are distinct from traditional immunotherapy as they do not target the immune system). Choice of immune or alternative therapy and criteria for selection of a specific regimen for inherited and autoimmune bleeding disorders are explained. ITI serves as an important proof of principle that antigen-specific immune tolerance can be achieved in humans through repeated antigen administration, even in the absence of immune suppression. Finally, novel immunotherapy approaches that are still in the preclinical phase, such as cellular (for instance, regulatory T cell [Treg]) immunotherapies, gene therapy, and oral antigen administration, are discussed.

Antiagregación plaquetaria: stents, isquemia y sangrado ¿Qué sabemos al respecto? / Platelet antiaggregation: stents, ischemia and bleeding What do we know about it?

Antiplatelet therapy and percutaneous coronary intervention are two of the most important interventions in the management of coronary artery disease. In the last 20 years there has been groundbreaking advances in the pharmacotherapy and stent technology. Bleeding is the most feared complication of antiplatelet therapy, mainly due to the increase in major adverse cardiovascular events besides the bleeding itself. Different clinical decision tools have developed with the aim to define which patients have a high ischemic or bleeding risk, thus individualizing treatment.

[MANAGEMENT RECOMMENDATIONS FOR DIRECT ORAL ANTICOAGULANTS (DOACs) ANTI Xa AND ANTI IIa]. / RECOMENDACIONES DE MANEJO DE LOS ANTICOAGULANTES ORALES DIRECTOS (DOACS) ANTI Xa Y ANTI IIa.

Direct oral anticoagulants have emerged as the drugs that have changed the management of the antithrombotic treatment in the last 15 years. Their advantages, like a more friendly way of anticoagulation and their lower risk of bleeding, especially in the brain, have positioned these new anticoagulants as the first drug of choice in the two most frequent indications of anticoagulation, atrial fibrillation, and the venous thromboembolic disease. However, not all the patients can receive these agents, not all the direct oral anticoagulants have the same characteristics, and most importantly, not all the diseases with an indication of an anticoagulant drug can be treated with them. Therefore, it is mandatory that all the faculties involved in the management of these drugs must know them in depth, to decide the best treatment for the patient. This position paper, from a group of experts in anticoagulation in Argentina, can help the general practitioner in the daily use of direct oral anticoagulants based on the new evidence and the experience of a wide group of professionals. The way we relate to the anticoagulant treatment has changed in the last years. The doctors who work with them must also do so.

Los anticoagulantes orales directos han surgido como una de las herramientas que ha cambiado el manejo de la enfermedad trombótica en los últimos 15 años. Sus ventajas, desde el punto de vista de la facilidad de uso y menor riesgo de sangrado, especialmente de sangrado cerebral, han posicionado a estos nuevos anticoagulantes como la primera alternativa de tratamiento en las dos indicaciones más frecuentes en que necesitamos estas drogas, la fibrilación auricular y la enfermedad tromboembólica venosa. Sin embargo, no todos los pacientes pueden recibir estos agentes, no todos los anticoagulantes directos tienen las mismas propiedades y fundamentalmente, no todas las enfermedades con indicación de un anticoagulante pueden tratarse con ellos;con lo cual es necesario que todos los profesionales que están involucrados en el manejo de estos medicamentos estén obligados a conocerlos en profundidad, para poder decidir el mejor tratamiento en cada caso particular. Este documento de posición de expertos de diferentes especialidades de Argentina, presenta lineamientos para el uso correcto de los anticoagulantes directos en base a nueva evidencia y a la experiencia de uso de un amplio grupo de profesionales. La forma de relacionarnos con el tratamiento anticoagulante ha cambiado. Los médicos que trabajamos con ellos también debemos hacerlo.

Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis.

BACKGROUND: Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. OBJECTIVE: To compare the effects of factor replacement therapies in patients with hemophilia. METHODS: We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). RESULTS: Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. CONCLUSIONS: Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

Biological compatibility of oxidized cellulose vs. porcine gelatin to control bleeding in liver lesions in rats.

PURPOSE: To compare biological compatibility, hemostasis, and adhesion formation between oxidized regenerated cellulose and lyophilized hydrolyzed porcine collagen in liver trauma. METHODS: Forty male Wistar rats constituted two groups: group A (oxidized cellulose) and group B (lyophilized hydrolyzed collagen). Standardized liver trauma was made, and the hemostatic agent was applied. Animals in subgroups A7 and B7 were submitted to euthanasia and relaparotomy after seven days, and in subgroups A14 and B14 after 14 days. Macroscopic and microscopic results were evaluated. RESULTS: There was no fluid in the cavity in any of the animals, and adhesions were present in all of them. In the analysis after seven days, the adhesions were grades 3 or 4 and consisted of omentum, small intestine, and abdominal wall (p<0.05). In both groups, the mesh was surrounded by a capsule, which was not observed after 14 days. In the evaluation after 14 days, adhesions were grades 2 or 3 (p>0.05). The microscopic examination showed subacute and chronic reactions, in both groups and in both timepoints, with similar frequency. The intensity of fibrosis always presented positive scores. Microabscesses and xanthomatous macrophages were observed in both groups. CONCLUSIONS: There was no superiority of one agent over the other.

Use of Antifibrinolytics in Pediatric Life-Threatening Hemorrhage: A Prospective Observational Multicenter Study.

OBJECTIVES: To assess the impact of antifibrinolytics in children with life-threatening hemorrhage. DESIGN: Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four children's hospitals in the United States, Canada, and Italy. PATIENTS: Children 0-17 years old who received greater than 40 mL/kg of total blood products over 6 hours or were transfused under activation of massive transfusion protocol. INTERVENTION/EXPOSURE: Children were compared according to receipt of antifibrinolytic medication (tranexamic acid or aminocaproic acid) during the bleeding event. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, medications administered, and clinical outcomes were analyzed using Cox proportional hazard and Kaplan-Meier survival analysis. The primary outcome was 24-hour mortality. Of 449 patients analyzed, median age was 7 years (2-15 yr), and 55% were male. The etiology of bleeding was 46% traumatic, 34% operative, and 20% medical. Twelve percent received antifibrinolytic medication during the bleeding event (n = 54 unique subjects; n = 18 epsilon aminocaproic acid, n = 35 tranexamic acid, and n = 1 both). The antifibrinolytic group was comparable with the nonantifibrinolytic group on baseline demographic and physiologic parameters; the antifibrinolytic group had longer massive transfusion protocol duration, received greater volume blood products, and received factor VII more frequently. In the antifibrinolytic group, there was significantly less 6-hour mortality overall (6% vs 17%; p = 0.04) and less 6-hour mortality due to hemorrhage (4% vs 14%; p = 0.04). After adjusting for age, bleeding etiology, Pediatric Risk of Mortality score, and plasma deficit, the antifibrinolytic group had decreased mortality at 6- and 24-hour postbleed (adjusted odds ratio, 0.29 [95% CI, 0.09-0.93]; p = 0.04 and adjusted odds ratio, 0.45 [95% CI, 0.21-0.98]; p = 0.04, respectively). CONCLUSIONS: Administration of antifibrinolytic medications during the life-threatening event was independently associated with improved 6- and 24-hour survivals in bleeding children. Consideration should be given to use of antifibrinolytics in pediatric patients with life-threatening hemorrhage.

Uso do ácido tranexâmico na prática clínica: discussão sobre particularidades na artroplastia de quadril / Use of tranexamic acid in clinical practice: discussion on particularities in hip arthroplasty

Introdução: O ácido tranexâmico (TXA) reduz o sangramento ao inibir competitivamente a fibrinólise, prevenindo a lise de coágulos de fibrina, além de atuar bloqueando parcialmente a agregação plaquetária. O TXA é recomendado em uma variedade de procedimentos cirúrgicos eletivos, como a artroplastia total do quadril (ATQ), na redução da perda de sangue, bem como no tratamento de hemorragias importantes. Objetivo: Revisar a literatura atual buscando sintetizar as evidências clínicas relacionadas ao uso do TXA, com foco em sua aplicação na ATQ. Método: Trata-se de um trabalho de caráter exploratório, baseado no método de revisão da literatura. A base de dados utilizada nesta pesquisa foi a PUBMED, empregando a seguinte estratégia de busca: "tranexamic acid"[title] AND "hip arthroplasty"[title]. Resultados: Foram extraídos 11 artigos da base de dados que responderam à estratégia citada. Somente ensaios clínicos randomizados foram selecionados. Conclusão: Todos os artigos revisados demonstraram a eficácia do TXA na diminuição da perda sanguínea, no controle positivo da concentração de hemoglobina, na manutenção do hematócrito e parâmetros volêmicos em ATQ e demais procedimentos cirúrgicos relacionados. A dose intravenosa mais comumente utilizada foi de 15 mg/kg. Já as doses intra-articulares tópicas ficaram entre 1 e 2 g, enquanto os protocolos orais variaram de 1300 e 2000 mg. A escolha de qual protocolo utilizar deve ser realizada pela equipe médica, com base na gravidade dos casos, ambiente cirúrgico e disponibilidade do fármaco. Palavras-chave: Ácido Tranexâmico. Artroplastia Total do Quadril. Cirurgia Eletiva. Sangramento.

Synergistic effect of serine protease inhibitors and a bothropic antivenom in reducing local hemorrhage and coagulopathy caused by Bothrops jararaca venom.

Snakebite accidents are a public health problem that affects the whole world, causing thousands of deaths and amputations each year. In Brazil, snakebite envenomations are caused mostly by snakes from the Bothrops genus. The local symptoms are characterized by pain, swelling, ecchymosis, and hemorrhages. Systemic disturbances can lead to necrosis and amputations. The present treatment consists of intravenous administration of bothropic antivenom, which is capable of reversing most of the systemic symptoms, while presenting limitations to treat the local effects, such as hemorrhage and to neutralize the snake venom serine protease (SVSP). In this context, we aimed to evaluate the activity of selective serine protease inhibitors (pepC and pepB) in combination with the bothropic antivenom in vivo. Further, we assessed their possible synergistic effect in the treatment of coagulopathy and hemorrhage induced by Bothrops jararaca venom. For this, we evaluated the in vivo activity in mouse models of local hemorrhage and a series of in vitro hemostasis assays. Our results showed that pepC and pepB, when combinated with the antivenom, increase its protective activity in vivo and decrease the hemostatic disturbances in vitro with high selectivity, possibly by inhibiting botropic proteases. These data suggest that the addition of serine protease inhibitor to the antivenom can improve its overall potential.

Direct oral anticoagulant reversal: An update.

ABSTRACT: The rise in direct oral anticoagulant (DOAC) use means nurses must understand the reversal of these agents in case of bleeding. Depending on bleed severity, as well as other criteria, pharmacologic reversal can be considered in place of supportive care alone. Knowledge of literature surrounding DOAC reversal is crucial.

Clinical protocols for oral anticoagulant reversal during high risk of bleeding for emergency surgical and nonsurgical settings: a narrative review.

BACKGROUND AND OBJECTIVES: Oral anticoagulants prevent thromboembolic events but expose patients to a significant risk of bleeding due to the treatment itself, after trauma, or during surgery. Any physician working in the emergency department or involved in the perioperative care of a patient should be aware of the best reversal approach according to the type of drug and the patient's clinical condition. This paper presents a concise review and proposes clinical protocols for the reversal of oral anticoagulants in emergency settings, such as bleeding or surgery. CONTENTS: The authors searched for relevant studies in PubMed, LILACS, and the Cochrane Library database and identified 82 articles published up to September 2020 to generate a review and algorithms as clinical protocols for practical use. Hemodynamic status and the implementation of general supportive measures should be the first approach under emergency conditions. The drug type, dose, time of last intake, and laboratory evaluations of anticoagulant activity and renal function provide an estimation of drug clearance and should be taken into consideration. The reversal agents for vitamin K antagonists are 4-factor prothrombin complex concentrate and vitamin K, followed by fresh frozen plasma as a second-line treatment. Direct oral anticoagulants have specific reversal agents, such as andexanet alfa and idarucizumab, but are not widely available. Another possibility in this situation, but with less evidence, is prothrombin complex concentrates. CONCLUSION: The present algorithms propose a tool to help healthcare providers in the best decision making for patients under emergency conditions.