Uncontrolled Bleeding Research Articles

Engineering High-Performance Composite Cellulose Materials for Fast Hemostasis.

The development of an effective hemostatic agents is of vital importance for saving wounded individuals from uncontrolled hemorrhage, which is the main reason for preventable death after accidental injury. However, current high-performance hemostatic agents suffer from a cumbersome preparation procedures and poor biocompatibility. Here, we engineered a cellulosic-derived aerogel material by simply controlling the drying process of cellulose regeneration for fast hemostasis. Four different freeze-drying pretreatments were investigated. As compared with the other three, the cellulosic aerogel material prepared without freezing pretreatment exhibited the lowest crystallinity (21.3%) and the highest body fluid absorption capacity (20.3 times that of its own weight) due to its super hierarchical porous structure, which led to an excellent hemostatic performance in vitro blood coagulation (≈100 s). Moreover, the addition of gelatin and diatomite in the material could tune the functional groups and electrostatic properties of the aerogel and further enhance its hemostatic performance. Various characterizations, including X-ray diffraction (XRD), fourier transform infrared spectroscopy (FTIR), X-ray nanocomputed tomography (CT), scanning electron microscopy (SEM), and zeta potential analysis, were carried out to probe the structure-function relationship of the prepared material, and its mechanism of fast hemostasis was thereafter revealed. The results indicate that the developed aerogel is a cost-effective and feasibly scalable hemostatic material suitable for practical use in industry.

Tannic acid coating gauze immobilized with thrombin with ultra-high coagulation activity and antimicrobial property for uncontrollable hemorrhage

Rapid and safe hemostasis is crucial for the survival of bleeding patients in prehospital care. It is urgent to develop high performance hemostatic material to control the massive hemorrhage in the military field and accidental trauma. In this work, an efficient protein hemostat of thrombin was immobilized onto commercial gauze, which was mediated by self-polymerization and anchoring of tannic acid (TA). Through TA treatment, the efficient immobilization of thrombin was achieved, preserving both the biological activity of thrombin and the physical properties of the dressing, including absorbency, breathability, and mechanical performance. Moreover, in the presence of TA coating and thrombin, Gau@TA/Thr could obviously shortened clotting time and enriched blood components such as plasma proteins, platelets, and red blood cells, thereby exhibiting an enhanced in vitro coagulation effect. In SD rat liver volume defect and artery transection hemorrhage models, Gau@TA/Thr still had outstanding hemostatic performance. Besides, the Gau@TA/Thr gauze had inherent antibacterial property and demonstrated excellent biocompatibility. All results suggested that Gau@TA/Thr would be a potential candidate for treating uncontrollable hemorrhage in prehospital care.

Dental management of Fanconi anemia: a rare congenital disorder

PurposeFanconi anemia is a rare inherited genetic disorder that is characterized by all three defective blood cell lines such as reduced red blood cells, platelets, and white blood cells. This makes the individual susceptible to spontaneous oral bleeding and prone to oral infections including periodontal diseases.MethodDental management of individuals with Fanconi anemia can be a difficult task as these individuals have a tendency for uncontrolled hemorrhage and infections after any simple dental procedure. This case report highlights the oral manifestations and management of the same in such individuals taking into consideration the complications in such rare diseases.ResultIn this case report, the individuals’ oral manifestations and spontaneous oral bleeding were successfully managed by preventive single-donor platelet transfusion, factor VII transfusion, and local tranexamic acid usage during the dental interventions along with parental counseling.ConclusionFanconi anemia being a rare inherited disorder is often difficult to manage due to a lack of knowledge and awareness among the dental clinicians. This case report attempts in highlighting the same and spreading awareness among the clinicians.

POST-TRAUMATIC HEMORRHAGE IN A PREGNANT WOMAN IN THE PRACTICE OF PRIMARY EMERGENCY MEDICAL TEAMS

Pregnancy is a unique period in a woman's life. It involves physiological changes, as well as mental and emotional ones for the mother-to-be. Pregnant women are at a higher risk of death from trauma compared to the rest of the female population. Medical activities aimed at treating pregnant trauma patients are issues that pose serious challenges for members of emergency medical teams. They require interdisciplinary medical knowledge, that of anatomy, physiology, trauma, but also obstetric and possibly neonatal care. In the pre-hospital setting, diagnosis and assistance is severely limited, so it is crucial that the pregnant woman be brought as quickly as possible to a hospital with appropriate diagnostic and specialty facilities. The aim of this study was to discuss the problem of uncontrolled internal hemorrhage in a pregnant woman, its consequences and the pre-hospital management of primary emergency medical teams. The research method was a review of the literature and recommendations of specialists of international organizations established to develop guidelines for emergency medicine. Based on the analysis, the following conclusions were drawn: 1. A traumatized pregnant woman should be given priority and special treatment in prehospital care due to measures that affect at least two lives - that of the mother and that of the child/children. 2. Due to the changes taking place in the body of the mother-to-be, injuries in pregnant women occur more frequently than in women who are not pregnant. 3. In pregnant women, the forces acting during the trauma, lead to different injuries than in non-pregnant women. 4. The effects of injuries sustained during pregnancy depend on the mechanism of injury, the severity of the injury and the stage of pregnancy. 5. Hypovolemia associated with decompensation of traumatic shock in a pregnant woman indicates an inauspicious prognosis for the health and life of the mother and baby. 6. Medical emergency procedures in pregnant trauma patients are similar to those used for other patients, but require some modifications related to the anatomical and physiological changes that occur during pregnancy. 7. Examining a pregnant patient may be difficult due to the anatomical and physiological changes occurring during this period. Increased heart rate and decreased blood pressure should not be considered a consequence of pregnancy if other causes are not ruled out. 8. It seems reasonable to introduce TXA acid into the regimens of basic emergency teams for victims with symptoms of hemorrhagic shock.

Embolization with or without portal vein stenting for bleeding ectopic jejunal varices in hepatopetal portal collaterals due to extrahepatic portal vein occlusion or stenosis after hepatobiliary and pancreatic surgery.

To evaluate the efficacy and safety of embolization with or without portal vein stenting for bleeding ectopic jejunal varices in the hepatopetal portal collateral due to extrahepatic portal vein occlusion or stenosis after hepatobiliary and pancreatic surgery. This study included consecutive patients who underwent embolization for bleeding ectopic jejunal varices in the hepatopetal collateral due to extrahepatic portal vein occlusion or stenosis after hepatobiliary and pancreatic surgery between September 2012 and December 2020. The safety, technical and clinical success rates (no re-bleeding within 1month) and re-bleeding-free survival after the first therapy and overall survival were assessed. Fourteen sessions in 11 patients were included. Four patients (7 sessions) underwent variceal embolization only, and the remaining seven patients (7 sessions) underwent portal vein stenting and variceal embolization. Technical success was achieved in all 14 sessions (100%). Clinical success was achieved in 13 of 14 sessions (92.9%). No treatment-related serious complications including liver failure were observed. One-year and 2-year re-bleeding-free survival rate after the first endovascular therapy in all 11 patients was 90.9 and 60.6%, respectively. Two patients who experienced re-bleeding had repeat embolization treatment. There was no significant difference in re-bleeding-free survival after endovascular therapy between the combination with stenting and embolization group and the embolization-only group (p = 0.13). Embolization with or without portal vein stenting of bleeding ectopic jejunal varices in the hepatopetal portal collateral due to extrahepatic portal vein occlusion or stenosis after hepatobiliary and pancreatic surgery can be considered a safe, effective, and repeatable therapy for long-term hemostasis of uncontrollable bleeding.

Acquired High Flow Arteriovenous Malformation of the Lower Lip Induced by Hormonal Variation- Report of a Rare Case and Review

Arteriovenous malformations (AVMs) are uncommon vascular lesions. AVMs are the most serious type of vascular malformations, causing substantial deformity and functional disability. AVMs of the acquired type are rarely confronted in the head and neck region. They may present as a medical emergency while performing dental procedures due to their potential for uncontrollable haemorrhage. Dental professionals should be aware of their potentially fatal complications and management. Accurate diagnosis of AVMs is critical and their management remains challenging. Vascular anomalies involving the lips can negatively impact the functionality and facial appearance. In this article, we discuss a very rare case of acquired AVM of the lower lip triggered by hormonal variation occurring during menopause in a female patient, 58 years of age. There are no reported cases of acquired AVM of the lip with hormonal variation occurring during menopause as the trigger for proliferation of the lesion. An overview of the clinical, etiological, diagnostic and management aspects of head and neck region-acquired AVMs is also presented in this paper.

An Injectable Hydrogel with Ultrahigh Burst Pressure and Innate Antibacterial Activity for Emergency Hemostasis and Wound Repair.

Uncontrolled bleeding and wound infections following severe trauma pose significant challenges for existing tissue adhesives, primarily due to their weak wet adhesion, slow adhesion formation, cytotoxicity concerns, and lack of antibacterial properties. Herein, an injectable hydrogel (denoted as ES gel) with rapid, robust adhesive sealing and inherent antibacterial activity based on ε-polylysine and a poly(ethylene glycol) derivative is developed. The engineered hydrogel exhibits rapid gelation behavior, high mechanical strength, strong adhesion to various tissues, and can sustain an ultrahigh burst pressure of 450mmHg. It also presents excellent biocompatibility, biodegradability, antibacterial properties, and on-demand removability. Significantly improved hemostatic efficacy of ES gel compared to fibrin glue is demonstrated using various injury models in rats and rabbits. Remarkably, the adhesive hydrogel can effectively halt lethal non-compressible hemorrhages in visceral organs (liver, spleen, and heart) and femoral artery injury models in fully anticoagulated pigs. Furthermore, the hydrogel outperforms commercial products in sutureless wound closure and repair in the rat liver defect, skin incision, and infected full-thickness skin wound models. Overall, this study highlights the promising clinical applications of ES gel for managing uncontrolled hemorrhage, sutureless wound closure, and infected wound repair.

Platelet-Rich Plasma-Embedded Porous Polycaprolactone Film with a Large Surface Area for Effective Hemostasis.

Uncontrollable and widespread bleeding caused by surgery or sudden accidents can lead to death if not treated with appropriate hemostasis. To prevent excessive life-threatening bleeding, various hemostatic agents based on polymeric biomaterials with various additives for accelerated blood coagulation have been adopted in clinical fields. In particular, platelet-rich plasma (PRP), which contains many blood coagulation factors that can accelerate blood clot formation, is considered as one of the most effective hemostatic additives. We investigated a PRP-embedded porous film using discarded (expired) PRP and a film with a leaf-stacked structure (FLSS), as a hemostatic agent to induce rapid hemostasis. The film, which contained an LSS on one side (PCL-FLSS), was fabricated by a simple heating-cooling technique using tetraglycol and polycaprolactone (PCL) film. Activated PRP was obtained by the thawing of frozen PRP at the end of its expiration date (the platelet cell membrane is disrupted during the freezing and thawing of PRP, thus releasing various coagulation factors) and embedded in the PCL-FLSS (PRP-FLSS). From in vitro and in vivo experiments using a rat hepatic bleeding model, it was recognized that PRP-FLSS is not only biocompatible but also significantly accelerates blood clotting and thus prevents rapid bleeding, probably due to a synergistic effect of the sufficient supply of various blood coagulants from activated PRP embedded in the LSS layer and the large surface area of the LSS itself. The study suggests that PRP-FLSS, a combination of a porous polymer matrix with a unique morphology and discarded biofunctional resources, can be an advanced hemostatic agent as well as an upcycling platform to avoid the waste of biofunctional resources.

Emergent robot-to-open conversion – Multidisciplinary simulation training in crisis management

Anticipating and addressing unexpected intraoperative events and anatomies are some of the most challenging aspects of pediatric urologic practice; uncontrolled hemorrhage is one of the most anxiety provoking and precarious. The increasing application of the robotic platform in pediatric urology adds another layer of complexity as surgeons are not immediately at the patient's bedside. Should hemorrhage occur in robotic cases, clear communication and seamless coordination between members of the operating room team are paramount to optimize patient safety and minimize errors. This is especially important in pediatric cases for which the margin of error is narrow. Non-technical skills, including leadership, decision-making, situational awareness, stress management, and team-communication, become increasingly critical. While many programs have focused on robotic training, few prepare the operating room team and surgical trainees to manage these unforeseen, emergent intraoperative scenarios. This review discusses the role of a multidisciplinary, in situ robot-to-open conversion simulation program in addressing this educational gap, ways to approach establishing these programs, and potential barriers.

The Efficacy of Whole Blood Resuscitation During Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) to Mitigate Post-occlusion Circulatory Collapse: A Translational Model in Large Swine.

Uncontrolled torso hemorrhage is the primary cause of potentially survivable deaths on the battlefield. Zone 1 Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA), in conjunction with damage control resuscitation, may be an effective management strategy for these patients in the prehospital or austere phase of their care. However, the effect of whole blood (WB) transfusion during REBOA on post-occlusion circulatory collapse is not fully understood. Yorkshire male swine (n = 6 per group, 70-90 kg) underwent a 40% volume-controlled hemorrhage. After a 10-minute hemorrhagic shock period, a REBOA balloon was inflated in Zone 1. Fifteen minutes after inflation, 0, 1, or 3 units (450 mL/unit) of autologous WB was infused through the left jugular vein. Thirty minutes after initial balloon inflation, the balloon was deflated slowly over 3 minutes. Following deflation, normal saline was administered (up to 3,000 mL) and swine were observed for 2 hours. Survival (primary outcome), hemodynamics, and blood gas values were compared among groups. Statistical significance was determined by log-rank test, one-way ANOVA, and repeated measures ANOVA. Survival rates were comparable between groups (P = .345) with 66% of control, 33% of the one-unit animals, and 50% of the 3-unit animals survived until the end of the study. Following WB infusion, both the 1-unit and the 3-unit groups had significantly higher blood pressure (P < .01), pulmonary artery pressure (P < .01), and carotid artery flow (P < .01) compared to the control group. WB transfusion during Zone 1 REBOA was not associated with increased short-term survival in this large animal model of severe hemorrhage. We observed no signal that WB transfusion may mitigate post-occlusion circulatory collapse. However, there was evidence of supra-normal blood pressures during WB transfusion.

INVESTIGATING THE RELATIONSHIP BETWEEN BLEEDING, CLOTTING, AND COAGULOPATHY DURING AUTOMATED PARTIAL REBOA STRATEGIES IN A HIGHLY LETHAL PORCINE HEMORRHAGE MODEL.

Background: Death due to hemorrhagic shock, particularly, noncompressible truncal hemorrhage, remains one of the leading causes of potentially preventable deaths. Automated partial and intermittent resuscitative endovascular balloon occlusion of the aorta (i.e., pREBOA and iREBOA, respectively) are lifesaving endovascular strategies aimed to achieve quick hemostatic control while mitigating distal ischemia. In iREBOA, the balloon is titrated from full occlusion to no occlusion intermittently, whereas in pREBOA, a partial occlusion is maintained. Therefore, these two interventions impose different hemodynamic conditions, which may impact coagulation and the endothelial glycocalyx layer. In this study, we aimed to characterize the clotting kinetics and coagulopathy associated with iREBOA and pREBOA, using thromboelastography (TEG). We hypothesized that iREBOA would be associated with a more hypercoagulopathic response compared with pREBOA due to more oscillatory flow. Methods: Yorkshire swine (n = 8/group) were subjected to an uncontrolled hemorrhage by liver transection, followed by 90 min of automated pREBOA, iREBOA, or no balloon support (control). Hemodynamic parameters were continuously recorded, and blood samples were serially collected during the experiment (i.e., eight key time points: baseline (BL), T0, T10, T30, T60, T90, T120, T210 min). Citrated kaolin heparinase assays were run on a TEG 5000 (Haemonetics, Niles, IL). General linear mixed models were employed to compare differences in TEG parameters between groups and over time using STATA (v17; College Station, TX), while adjusting for sex and weight. Results: As expected, iREBOA was associated with more oscillations in proximal pressure (and greater magnitudes of peak pressure) because of the intermittent periods of full aortic occlusion and complete balloon deflation, compared to pREBOA. Despite these differences in acute hemodynamics, there were no significant differences in any of the TEG parameters between the iREBOA and pREBOA groups. However, animals in both groups experienced a significant reduction in clotting times (R time: P < 0.001; K time: P < 0.001) and clot strength (MA: P = 0.01; G: P = 0.02) over the duration of the experiment. Conclusions: Despite observing acute differences in peak proximal pressures between the iREBOA and pREBOA groups, we did not observe any significant differences in TEG parameters between iREBOA and pREBOA. The changes in TEG profiles were significant over time, indicating that a severe hemorrhage followed by both pREBOA and iREBOA can result in faster clotting reaction times (i.e., R times). Nevertheless, when considering the significant reduction in transfusion requirements and more stable hemodynamic response in the pREBOA group, there may be some evidence favoring pREBOA usage over iREBOA.

Facile Synthesis of Multifunctional Mesoporous Starch-Based Microparticle for Effective Hemostasis and Wound Healing.

Uncontrolled hemorrhage and infection are the principal causes of mortality associated with trauma in both military and civilian medical settings. Modified starch granules have emerged as a safe hemostatic agent for irregular and noncompressible wounds, but their performance is constrained by limited hemostasis efficiency and modest antibacterial activity. This study reported a directed self-assembly approach for a multifunctional mesoporous starch-based microparticle loaded with chitosan and calcium ions (Ca@MSMP) used for rapid hemostasis and wound healing. Directed self-assembly of uniform Ca@MSMP with a hierarchical hollow structure in the presence of chitosan was confirmed by scanning electron microscopy (SEM) analysis and pore structure analysis. The resulting Ca@MSMP exhibited a well-defined spherical shape and uniform size of 1 μm and demonstrated excellent antibacterial activity (>95%) without hemolytic activity. Importantly, Ca@MSMP enhanced blood coagulation and platelet aggregation via the synergistic effect of rapid calcium release and chitosan-mediated electrostatic interactions, leading to a significant decrease in blood loss and reduction in hemostasis time in rat tail amputation and liver injury models. In comparative analyses, Ca@MSMP significantly outperformed the commercial hemostatic agent Quickclean, notably enhancing the healing of full-thickness skin wounds in vivo by effectively preventing infection. These results underscore the potential of this innovative hemostatic material in diverse clinical scenarios, offering effective solutions for the management of bleeding in wounds that are irregularly shaped and noncompressible.

Injectable hemostatic hydrogel adhesive with antioxidant, antibacterial and procoagulant properties for hemorrhage wound management

In emergencies, uncontrolled severe bleeding can result in undesired complications and even death of the injured. Designing advanced hemostatic agents is a potential solution for emergency hemostasis, yet it remains challenging to realize the persistent adhesion in a wet wound environment. In this study, based on dynamic reversible Schiff base bond and photo-initiated double-bond polymerization, a novel injectable hemostatic hydrogel (L-COC) consisting of methacrylated carboxymethyl chitosan (CMCSMA), oxidized konjac glucomannan (OKGM) and (+)-catechin hydrate (CH) was synthesized for emergency hemostasis. To our delight, the incorporated CH imparted enhanced blood procoagulantion to the L-COC hydrogel by intensifying the hydrogel-red blood cell interactions. As a result, the hemostatic effect of the engineered L-COC hydrogel was significantly superior to that of fluid gelatin SurgifloTM for liver bleeding wounds in rats (Blood loss: 0.62 ± 0.11 g (L-COC), 0.90 ± 0.08 g (SurgifloTM); hemostasis time: 69.0 ± 2.9 s (L-COC), 84.0 ± 2.2 s (SurgifloTM)). With the favorable antioxidant and antibacterial activities, as well as multifunctional properties, the bio-adhesive L-COC hydrogel and the underlying design principles may facilitate further development of practical hemostatic hydrogels.

All-in-one polysaccharide hydrogel with resistant vascular burst pressure and cooperative wound microenvironment regulation for fatal arterial hemorrhage and diabetic wound healing

Fatal massive hemorrhage and diabetic wound healing are world widely challenging in surgical managements, and uncontrolled bleeding, chronic inflammation and damaged remodeling heavily hinder the whole healing processes. Considering hemostasis, inflammation and wound microenvironment cooperatively affect the healing progression, we design all-in-one beta-glucan (BG) hybrid hydrogels reinforced with laponite nanoclay that demonstrate tunable tissue adhesion, resistant vascular burst pressure and cooperative wound microenvironment regulation for arterial hemostasis and diabetic wound prohealing. Those hydrogels had honeycomb-like porous microstructure with average pore size of 7–19 μm, tissue adhesion strength of 18–46 kPa, and vascular burst pressure of 58–174 mmHg to achieve superior hemostasis in rat liver and femoral artery models. They could effectively scavenge reactive oxygen species, transform macrophages from proinflammatory M1 into prohealing M2, and shorten the inflammation duration via synergistic actions of BG and nitric oxide (NO). Single treatment of NO-releasing BG hybrid hydrogels attained complete closure of diabetic wounds within 14 days, orchestrated to accelerate the epithelization and dermis growth, and restored normal vascularization, achieving high performance healing with optimal collagen deposition and hair follicle regeneration. Consequently, this work opens up a new avenue to design all-in-one polysaccharide hydrogels for applications in massive bleeding hemostats and diabetic wound dressings.

Intermediate and long-term survival prediction using prognostic scores in patients undergoing salvage TIPS for uncontrolled variceal bleeding

Intermediate and long-term survival prediction using prognostic scores in patients undergoing salvage TIPS for uncontrolled variceal bleeding

A phase 1, open-label, dose escalation study on the safety and tolerability of ANK-101 in advanced solid tumors.

TPS2689 Background: IL-12 is a cytokine that can stimulate both innate and adaptive tumor immunity. Clinical trials of intravenous IL-12 demonstrated anti-tumor activity limited by significant systemic toxicity, including patient deaths. ANK-101 is an anchored immunotherapy that links IL-12 to aluminum hydroxide through an alum-binding protein (ABP). The ANK-101 complex anchors IL-12 in the tumor microenvironment (TME), resulting in prolonged local retention and low levels of systemic absorption. Preclinical studies in murine tumor models showed that ANK-101 is retained at the injection site for up to 28 days, recruits and activates T and NK cells, promotes M1 myeloid cell differentiation, induces regression of both injected and un-injected tumors, and induces immunologic memory. Methods: This is a first-in-human, open-label dose escalation study of ANK-101 in advanced solid tumors with a planned sample size of 12-36 participants. The first three dose escalation cohorts include a single participant, and then study enrollment follows a standard 3+3 dose escalation design. If no dose limiting toxicity (DLT) is observed, the dose level will be escalated until ≥1/3 or ≥2/6 patients experience a DLT. An additional ten patients will be enrolled at the recommended dose for expansion (RDE). Participants will be treated with intratumoral ANK-101 every 3 weeks for 4 cycles. Imaging or clinical assessments will be performed at week 12. If there is no significant clinical deterioration or unacceptable toxicity at this visit, participants may receive four more cycles. Eligible patients must have an advanced solid malignancy refractory to standard treatment and be accessible for injection and biopsy, measurable disease by RECIST v1.1, and ECOG PS of 0-1. Key exclusion criteria include tumors close to vital structures, uncontrolled bleeding disorders, and active autoimmune disease. Primary objectives of the study are to determine the safety and tolerability of ANK-101 and identify the RDE. Secondary objectives include pharmacokinetics (PK) and immunogenicity (ADA) of ANK-101 and clinical activity as measured by ORR, DCR, DOR and PFS by RECIST v1.1. Exploratory objectives include assessment of QOL using FACT-G and profiling immune-based pharmacodynamic (PD) changes. PD assessments will include serum cytokines and circulating immune cells, and local levels of PD-L1, CD8+ T cells, and CD68+ macrophages, and changes in gene expression within the TME. This clinical trial is in progress. Clinical trial information: NCT06171750 .

Structural basis for inhibition of coagulation factor VIII reveals a shared antigenic hotspot on the C1 domain

BackgroundHemophilia A arises from dysfunctional or deficient coagulation factor (F)VIII and leads to inefficient fibrin clot formation and uncontrolled bleeding events. The development of antibody inhibitors is a clinical complication in hemophilia A patients receiving FVIII replacement therapy. LE2E9 is an anti-C1 domain inhibitor previously isolated from a mild/moderate hemophilia A patient and disrupts FVIII interactions with von Willebrand factor and FIXa, though the intermolecular contacts that underpin LE2E9-mediated FVIII neutralization are undefined. ObjectivesTo determine the structure of the complex between FVIII and LE2E9 and characterize its mechanism of inhibition. MethodsFVIII was bound to the antigen binding fragment (Fab) of NB2E9, a recombinant construct of LE2E9, and its structure was determined by cryogenic electron microscopy. ResultsThis report communicates the 3.46 Å structure of FVIII bound to NB2E9, with its epitope comprising FVIII residues S2040 to Y2043, K2065 to W2070, and R2150 to H2155. Structural analysis reveals that the LE2E9 epitope overlaps with portions of the epitope for 2A9, a murine-derived inhibitor, suggesting that these residues represent a shared antigenic region on the C1 domain between FVIII−/− mice and hemophilia A patients. Furthermore, the FVIII:NB2E9 structure elucidates the orientation of the LE2E9 glycan, illustrating how the glycan sterically blocks interactions between the FVIII C1 domain and the von Willebrand factor D′ domain. A putative model of the FVIIIa:FIXa complex suggests potential clashing between the NB2E9 glycan and FIXa light chain. ConclusionThese results describe an antigenic “hotspot” on the FVIII C1 domain and provide a structural basis for engineering FVIII replacement therapeutics with reduced antigenicity.

Water-triggered shape memory cellulose / sodium alginate / montmorillonite composite sponges for rapid hemostasis

Uncontrollable bleeding caused by severe trauma is life-threatening. Therefore, it is of great significance to develop hemostatic materials that meet the rapid hemostasis of wounds. In this study, a water-triggered shape memory carboxylated cellulose nanofiber/sodium alginate/montmorillonite (CNSAMMTCa) composite hemostatic sponge was prepared, which can promote coagulation by concentrating the blood and activating intrinsic pathway. The anisotropic three-dimensional porous structure formed by directional freeze-drying technology improved the performance of composite sponges which showed good prospects in rapid hemostasis. The results showed that CNSAMMTCa composite sponge had good porous structure, water absorption ability, cytocompatibility and blood cell aggregation capacity. Simultaneously, we confirmed that CNSA3MMT2Ca has best coagulation performance in the mouse censored bleeding model and liver rupture bleeding model. Therefore, CNSAMMTCa composite hemostatic sponge is a safe and efficient rapid hemostatic material which is expected to become an alternative material for clinical hemostatic materials.

Idarucizumab in dabigatran-treated patients with acute stroke: a review and clinical update.

Idarucizumab is an antibody fragment specific for the immediate reversal of dabigatran anticoagulation effects. The use of idarucizumab is approved for dabigatran-treated patients suffering from life-threatening or uncontrolled bleeding and those in need of urgent surgery or invasive procedures. Data from randomized controlled clinical trials and real-world experience provide reassuring evidence about the efficacy and safety of idarucizmab use in patients with acute stroke. In this narrative review, we summarize the available real-world evidence and discuss the relevance and importance of idarucizumab treatment in acute stroke patients in everyday clinical practice. In addition, we also discuss special issues like prothrombin complex concentrate application as an alternative to idarucizumab, its application before endovascular therapy, sensitivity of thrombi to lysis, and necessary laboratory examinations.

Tannic acid-crosslinked gelatin composite microspheres adsorbed with CQAS or Ca2+ for rapid hemostasis

In the case of massive blood loss due to natural disasters and wars, timely and rapid hemostasis is of great significance to improve the survival rate of injured people. Nevertheless, uncontrolled, noncompressible, and irregular bleeding wounds remain a giant challenge for rapid hemostasis. In this study, the tannic acid-crosslinked gelatin was first obtained by Michael addition reaction, and then the tannic acid-crosslinked gelatin composite microspheres (TGMs) were prepared by the emulsion cross-linking method. TGMs could significantly improve the water absorption and hemostatic performance compared with single component gelatin microspheres (GMs). Increasing the water absorption ratio and introducing blood coagulation factors into composite materials are simple and effective strategies to enhance the hemostatic properties. Therefore, chitosan quaternary ammonium salt (CQAS) and Ca2+ were electrostatic adsorbed to obtain two kinds of functional TGMs, which were respectively CQAS-absorbed TGMs (T2GMs-CQAS) and calcium ion-absorbed TGMs (T2GMs-Ca2+). Notably, T2GMs-CQAS, and T2GMs-Ca2+ could absorb water rapidly within 3 seconds, in addition, especially the water absorption ratio of T2GMs-CQAS could reach 2.95 times compared with GMs. Benefited from rapid water absorption, coagulation pathway activation, and red blood cells aggregation of T2GMs-CQAS and T2GMs-Ca2+, resulting in rapid blood coagulation in vitro. In addition, CQAS and Ca2+ provided strong and intrinsic antibacterial activity due to positive charge. Moreover, in the tail amputation and liver hemostatic models, T2GMs-CQAS and T2GMs-Ca2+ demonstrated superior hemostatic effects compared to commercial Yunnan Baiyao®. In conclusion, T2GMs-CQAS and T2GMs-Ca2+ have potential applications as hemostatic dressings in uncontrolled, noncompressible, and irregular bleeding wounds.