Search Results (74)

Fibrinogen is an essential component of hemostasis and clot formation that stabilizes the platelet-dependent primary hemostatic process. Low fibrinogen levels can be primary (congenital) or secondary (acquired). Acquired hypofibrinogenemia may result from chronic diseases (e.g., liver, autoimmune diseases, and malignancies) or major hemorrhage (e.g., trauma, surgery). Low fibrinogen levels are both a symptom and a precipitating factor for coagulopathy and ongoing bleeding. Fibrinogen repletion with fibrinogen-containing products is important for managing coagulopathic bleeding with suspected or documented hypofibrinogenemia. Different available fibrinogen sources include fibrinogen concentrate, cryoprecipitate, and frozen plasma and vary based on multiple factors including fibrinogen content, purity, other clotting or non-clotting proteins (e.g., immunomodulating proteins or proteins of unknown function), preparation time, safety, volumes, and availability. Fibrinogen replacement strategies have been studied in trauma but also in patients undergoing spine, cytoreductive, and cardiac surgery. In this review, we discuss the physiological actions of fibrinogen, strategies for control of coagulopathic bleeding related to hypofibrinogenemia, and the therapeutic, logistical, and economic factors that influence treatment decisions. In addition, current guidelines and clinical studies were considered regarding the formation of evidence-based treatment strategies that can be individualized at the patient’s bedside. Full article

Background: Perioperative bleeding from cancellous bone remains a clinically relevant challenge in orthopaedic surgery. Bone wax has long been used as a simple and inexpensive mechanical hemostatic agent, but previous reviews have focused mainly on total joint arthroplasty or on the material history of bone wax and its substitutes. The broader clinical evidence across orthopaedic subspecialties has not been comprehensively mapped. Methods: This scoping review followed the Arksey and O’Malley framework, with methodological refinements proposed by Levac et al., and was reported in accordance with PRISMA-ScR. Five electronic sources and grey literature were searched through May 2025. Clinical studies evaluating bone wax in orthopaedic surgery were eligible regardless of study design; a relevant clinical trial registry record with sufficient methodological detail was also retained to map ongoing evidence. Preclinical and purely material-based studies were excluded. The protocol was registered in the Open Science Framework (DOI: 10.17605/OSF.IO/K3ZAV). Results: Of 486 identified records, 15 met the inclusion criteria. Eight records concerned joint replacement, two spinal surgery, three excision of abnormal bony structures, and two sealing applications. The strongest comparative evidence came from arthroplasty, where bone wax was generally associated with reduced intraoperative or perioperative blood loss without clear evidence of adverse effects on early postoperative recovery outcomes reported in the included studies. Evidence for spinal and nontraditional applications was more heterogeneous and was derived mainly from small observational studies, case series, technical reports, or a trial registry record. Complications such as foreign-body reaction and chronic inflammation were described primarily in spine-related reports of retained nonabsorbable wax. Conclusions: Bone wax remains a useful and inexpensive adjunct for hemostasis in orthopaedic surgery. The strongest clinical evidence is concentrated in arthroplasty, whereas spinal and nontraditional applications remain supported by limited and heterogeneous data. Future research should clarify indication-specific benefits and risks and evaluate the safety and effectiveness of bioresorbable alternatives in well-designed clinical studies. Full article

Background/Objectives: Ischemic stroke remains a major global health challenge, yet therapeutic options are severely restricted by narrow treatment windows and the risk of hemorrhagic transformation. Natural small molecules represent a valuable reservoir for discovering novel neuroprotective leads with favorable safety profiles. Cinchonidine, a natural quinoline alkaloid, has shown anti-inflammatory and cytoprotective properties, but its potential in treating ischemic stroke is largely unexplored. This study aimed to evaluate the neurovascular protective effects and hemostatic safety of cinchonidine in preclinical stroke models. Methods: We evaluated cinchonidine using a mouse model of middle cerebral artery occlusion (MCAO) and in vitro oxygen–glucose deprivation (OGD) models in cerebral endothelial cells (CECs) and Neuro2A cells. Infarct volume, brain edema, and neurological recovery were assessed. Blood–brain barrier (BBB) integrity was measured via Evans blue extravasation. Mechanistic markers, including microglial activation, pro-inflammatory mediators (iNOS, COX-2), and apoptosis-related signaling, were examined. Additionally, cinchonidine’s effect on platelet aggregation was also tested. Results: Cinchonidine significantly reduced infarct volume and brain edema while improving neurological functional recovery. It effectively preserved BBB integrity and enhanced cell viability under OGD conditions. Furthermore, cinchonidine suppressed microglial activation and decreased the expression of pro-inflammatory mediators. These protective effects were associated with the modulation of apoptotic signaling pathways. These protective effects were accompanied by reduced p53-associated stress signaling in endothelial cells and ischemic brain tissue. Importantly, cinchonidine did not significantly interfere with platelet aggregation, suggesting a potentially favorable hemostatic profile. Conclusions: Cinchonidine attenuates ischemic brain injury and is associated with endothelial protection, preservation of BBB integrity, and modulation of inflammatory and apoptotic responses. As a natural lead compound that does not compromise hemostasis, cinchonidine represents a promising lead compound for further development as a neurovascular protective strategy in ischemic stroke. Full article

Wound healing is a complex physiological process involving multiple stages, including hemostasis, inflammation, proliferation, and remodeling, which imposes high demands on the functionality and adaptability of wound repair materials. Hydrogels, as a class of novel materials, have become ideal wound dressings due to their excellent biocompatibility, breathability, and conformability. Sodium alginate-based composite hydrogels offer advantages such as readily available raw materials and mild preparation conditions. They can also endow materials with properties including antibacterial, anti-inflammatory, hemostatic, and pro-angiogenic effects, meeting the application requirements for multifunctional and highly efficient wound dressings. As a result, they have attracted considerable attention in the field of wound repair. This article introduces the preparation methods of physically and chemically crosslinked sodium alginate-based composite hydrogels, as well as the drug release mechanisms from these hydrogels. It elaborates on their applications in wound dressings, discusses key challenges including difficulties in large-scale preparation, high barriers to clinical translation, insufficient long-term in vivo stability, and low integration of intelligent functions, and outlines future research directions in terms of large-scale fabrication, regulatory compliance, long-term safety, and intelligent design. This review aims to provide a theoretical basis for the development of novel sodium alginate-based composite hydrogels for wound dressings and to promote their clinical translation and practical application in this field. Full article

Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer progression, cellular senescence, and age-associated immune dysregulation. A central argument of this review is that PAI-1 should be understood not only as a downstream biomarker of aging-associated pathology, but also as an active effector linking senescence-associated secretory phenotype (SASP) signaling, chronic low-grade inflammation, impaired immune surveillance, fibrotic extracellular matrix remodeling, and a prothrombotic state. In this framework, PAI-1 may function as an immune-aging checkpoint: a molecular node through which senescent, stromal, malignant, and inflammatory cells reinforce immune evasion and tissue dysfunction. Structure-guided drug discovery has enabled the development of small-molecule PAI-1 inhibitors, including TM5275, TM5441, TM5509, and TM5614. Among these, TM5614 is an orally available investigational compound that has progressed to clinical evaluation. Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia. This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds. Full article

Background/Objectives: Topical hemostatic biomaterials are used to control diffuse parenchymal bleeding during hepatectomy. TachoSil is a widely used standard fibrin sealant patch. We evaluated the efficacy and safety of InnoSEAL Plus DL, a novel bioinspired absorbable chitosan–catechol/gelatin hemostatic patch, compared with TachoSil. Methods: This multicenter, randomized, single-blind, active-controlled, parallel-group noninferiority trial enrolled adults undergoing hepatectomy who had persistent oozing from the hepatic transection surface despite primary hemostasis. Participants were randomized in a 1:1 ratio to receive InnoSEAL Plus DL or TachoSil. The primary endpoint was hemostatic success within 3 min of application, with a prespecified noninferiority margin of −19.4 percentage points (pp). Safety was assessed up to 30 days postoperatively. Results: Ninety patients were randomized (45 per group). In the per-protocol population, 3 min hemostatic success was achieved in 100.0% of both the InnoSEAL Plus DL (43/43) and TachoSil (41/41) groups. The risk difference was 0.0 pp, and the lower bound of the one-sided 97.5% confidence interval was −8.2 pp, confirming noninferiority. The mean time to hemostasis was similar between groups (1.2 vs. 1.3 min), and no intraoperative rebleeding occurred. Adverse events were reported in 78/90 patients (86.7%) and serious adverse events in 6/90 (6.7%); the latter were typical post-hepatectomy events unrelated to the study devices. No deaths were reported. Conclusions: InnoSEAL Plus DL was noninferior to TachoSil for achieving rapid intraoperative hemostasis during hepatectomy, with no unexpected safety concerns. This bioinspired hemostatic patch is an effective alternative to fibrin sealant, without the use of human-derived proteins. Full article

Achieving hemostasis is crucial in neurosurgery, yet conventional methods are not always feasible, making topical hemostatic agents necessary. Current resorbable hemostatic agents allow effective hemostasis but must remain in situ to prevent rebleeding. This can provoke foreign body reactions leading to prolonged microglia-mediated neuroinflammation, which may exacerbate damage and delay recovery. It highlights the need for new hemostatic materials that can be removed after controlling bleeding while being safe for neurons and microglia. One candidate is Hemo-Ionic, a non-resorbable hemostatic compress composed of calcium alginate and zinc (Zn²⁺). Hemo-Ionic previously demonstrated effective in vitro and in vivo hemostasis, comparable to Surgicel and TachoSil, and pro-repair properties. In this study, Hemo-Ionic’s effect on neuronal and microglial cells was investigated in vitro. Results showed that Hemo-Ionic preserved cell viability and had an antioxidant capacity through protection from lipid peroxidation. Hemo-Ionic also reduced nitric oxide and pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) expression and release by lipopolysaccharide (LPS)-stimulated microglial cells. Finally, neuronal viability was restored when exposed to supernatants of Hemo-Ionic-treated microglia. These findings indicate that Hemo-Ionic’s safety and capacity to reduce neuroinflammation, combined with its hemostatic efficacy and non-resorbable nature, make it a promising alternative to resorbable hemostatic agents used in neurosurgery. Full article

Mesenchymal stromal cells are increasingly used for their immunomodulatory and regenerative properties, yet their interaction with the hemostatic system remains incompletely understood. This review examines the mechanisms through which these cells influence coagulation within the broader framework of immunothrombosis. Evidence from in vitro studies, animal models, and early clinical observations indicates that mesenchymal stromal cells can promote thrombin generation through tissue factor expression and phosphatidylserine exposure, while also engaging complement pathways, platelets, and innate immune responses. Counter-regulatory mechanisms, including adenosine-mediated platelet inhibition and immune reprogramming after cellular clearance, contribute to a context-dependent biological effect. Functional assays, rather than tissue factor expression alone, appear necessary to estimate the effective procoagulant potential of these products. Clinical data suggest that major thrombotic events remain uncommon, although subclinical activation of coagulation pathways may occur. The hemostatic impact of mesenchymal stromal cells depends on multiple variables, including cell source, dose, route of administration, and host inflammatory status. The available evidence supports a working model in which early coagulation and complement activation may be followed by immune modulation, supporting integrated strategies to optimise both safety and therapeutic efficacy. A central conclusion is that tissue factor, although mechanistically necessary for MSC-associated procoagulant activity, is not by itself an independent predictor of clinical thrombotic risk; the effective coagulation response also depends on phosphatidylserine exposure, membrane context, and host inflammatory conditions. Full article

Gene therapy is reshaping the therapeutic paradigm in hemophilia by enabling sustained endogenous clotting factor production after a single administration. This approach moves disease management beyond lifelong replacement therapy. While clinical trials have demonstrated marked reductions in bleeding rates and treatment burden, real-world implementation has revealed emerging complexities. These include interindividual variability in transgene expression reflected by a progressive reduction in circulating FVIII or FIX activity over time, uncertainty regarding the long-term durability of expression, immune-mediated constraints, and episodes of transaminase elevation. This review addresses a critical transition point in the field: the shift from proof-of-concept efficacy toward integration of gene therapy into long-term hemophilia care. We examine determinants of therapeutic stability, host–vector immune interactions, and mechanisms underlying loss or fluctuation of expression, with emphasis on monitoring strategies and post-therapy management pathways. Immunogenic processes affecting vector transduction, hepatocellular responses, and transgene persistence are discussed alongside current approaches to immune modulation. This review uniquely focuses on post-gene therapy clinical integration rather than vector design or trial outcomes. Beyond direct factor correction, evolving therapeutic concepts targeting coagulation rebalancing and immune regulation are considered within a systems-based framework. Psychosocial adaptation and patient-reported outcomes are also explored, underscoring that therapeutic success extends beyond hemostatic control. In aggregate, these perspectives position gene therapy not as a singular curative event but as a component of an evolving, biologically integrated management strategy. Long-term follow-up translational research (LTFU) and coordinated global efforts will be essential to optimize durability, safety, and equitable access. Full article

Patient Blood Management (PBM) has evolved from a transfusion-centered practice to a structured, patient-focused perioperative strategy aimed at improving surgical outcomes while preserving blood resources. In the operating room, where bleeding risk is anticipated and modifiable, PBM requires proactive intervention rather than reactive transfusion. This review synthesizes current evidence on perioperative blood conservation strategies specifically relevant to surgeons and anesthesiologists. Preoperative optimization begins with systematic identification and correction of anemia, most commonly iron deficiency, using appropriately timed oral or intravenous iron therapy and, in selected cases, erythropoiesis-stimulating agents. Careful management of anticoagulant and antiplatelet therapies, early recognition of acquired or inherited coagulopathies, and protocol-driven reversal strategies further reduce perioperative hemorrhagic risk. Intraoperatively, blood conservation depends on meticulous surgical technique, respect for anatomical planes, minimally invasive approaches, and the judicious use of advanced energy devices and topical hemostatic agents. Pharmacologic interventions—particularly tranexamic acid administered with appropriate timing and dosing—have demonstrated consistent reductions in blood loss and transfusion requirements across multiple surgical disciplines. Goal-directed coagulation management guided by viscoelastic testing allows targeted correction of specific hemostatic deficits while minimizing unnecessary blood product exposure. Acute normovolemic hemodilution and intraoperative cell salvage provide additional benefit in selected high-blood-loss procedures. Collectively, these multimodal strategies shift perioperative care from product-driven transfusion toward physiology-based blood conservation. When embedded within institutional protocols and supported by multidisciplinary collaboration, perioperative PBM reduces transfusion exposure, decreases morbidity, shortens hospital stay, and promotes sustainable stewardship of blood resources without compromising patient safety. Full article

Hemostatic biomaterial agents are widely used during surgery and trauma care to control bleeding, yet their effects on wound healing remain incompletely understood. This study evaluated the impact of oxidized non-regenerated cellulose (ONRC), oxidized regenerated cellulose (ORC), and a gelatin-based hemostat (GELA) on wound healing at 14 and 30 days in a mouse model. Full-thickness wounds were created in C57BL/6J mice (n = 192) and compared to sham controls. Tissue samples were analyzed histologically, supported by immunohistochemistry for Ki-67 and α-SMA and qPCR for VEGF, TGF-β, and FGF-2. Histology demonstrated preserved tissue architecture across groups with progressive resorption of cellulose-based materials, whereas GELA showed localized fibrous structures and enhanced extracellular matrix formation. At day 14, no significant differences were observed in proliferation, contraction, VEGF, or FGF-2 expression; however, TGF-β was significantly reduced in the ORC group. By day 30, GELA significantly increased epidermal proliferation, while contraction markers were elevated in both GELA and ORC. VEGF expression was reduced in GELA and ORC, whereas ONRC showed increased TGF-β expression. FGF-2 remained unchanged across groups. All investigated hemostatic materials were well tolerated during the early postoperative phase (up to day 14), indicating short-term biocompatibility within the scope of this model. In contrast, material-specific differences in cellular activity and growth factor expression became apparent during the later remodeling phase (day 30). These findings suggest differential effects on cellular and molecular aspects of tissue remodeling; however, no conclusions can be drawn regarding overall healing quality or clinical safety, as no quantitative macroscopic or functional outcome measures were assessed. Full article

Objective: To compare perioperative outcomes between robotic and conventional total laparoscopic hysterectomy in terms of operative time, intraoperative blood loss, and postoperative recovery in surgically complex cases. Methods: This retrospective cohort study included patients that underwent total laparoscopic hysterectomy between 2020 and 2022. As robotic surgery was preferentially applied to more complex cases in an effort to minimize the risk of open conversion, propensity score matching based on uterine weight and history of abdominal surgery was performed. The normality of continuous variables was assessed using the Shapiro–Wilk test; non-normally distributed variables are reported as median [interquartile range] and compared using the Mann–Whitney U test. Multivariate linear regression with log-transformed estimated blood loss was conducted to evaluate the independent association of surgical approach with hemostatic outcomes. Results: After 1:1 matching, 93 patients were analyzed per group. Robotic surgery was associated with longer operative time but lower estimated blood loss when compared with conventional laparoscopy. Postoperative hemoglobin decline, length of hospital stay, and complication rates were comparable between groups. In multivariate analysis, uterine weight and operative time were the primary determinants of estimated blood loss; surgical approach showed a modest, independent association with lower log-transformed estimated blood loss after adjustment for these factors. Conclusions: Robotic and conventional total laparoscopic hysterectomy demonstrated comparable perioperative safety profiles with different operative trade-offs. Observed differences in estimated blood loss reflect complex interactions between surgical difficulty, operative time, and instrumentation rather than inherent platform superiority. These findings support an individualized approach to surgical modality selection based on case complexity, to minimize risk of intraoperative complication leading to open conversion. Full article

Background: The co-existence of hemophilia and cancer presents one of the most complex clinical scenarios, demanding individualised therapeutic planning to balance oncologic efficacy and hemostatic safety. This study evaluated the ability of two Large Language Models (LLMs)—ChatGPT (GPT-4) and Microsoft Copilot (GPT-4–based)—to generate clinically appropriate recommendations for real cases of hemophilia with concurrent malignancy. Methods: Six consecutive adult cases of hemophilia and cancer, managed at the Hemophilia Centre of Padua, Italy, were selected for evaluation. Identical structured prompts were submitted to both LLMs. Two independent expert clinicians rated the model outputs across five domains (Decision/Rationale, Strategy, Selected Drug, Regimen, and Assessment) using a four-level ordinal scale. Results: LLMs demonstrated uneven performances. Outputs were consistently rated as highly reliable in domains involving high-level synthesis, such as Assessment and Strategy. However, substantial limitations were observed in the clinically demanding domains of Selected Drug and Regimen. Critically, in the Selected Drug domain, there was complete agreement between the two expert raters for neither system. This severe lack of concordance signifies that clinicians assigned different adequacy ratings to the same output in every case, reflecting ambiguity, lack of specificity, and inconsistent clinical interpretability of the drug-related information provided by LLMs. Conclusions: While LLMs possess the capacity for high-level reasoning and strategic planning, their inability to translate principles into precise, consistent, and clinically interpretable therapeutic plans—particularly regarding drug selection and treatment regimens—is a significant constraint. These deficiencies, highlighted by the minimal expert concordance in critical domains, necessitate rigorous clinical validation before the responsible integration of LLMs into the management of this uniquely vulnerable patient population. Full article

Background: Coronary button reimplantation is a key determinant of operative safety in the modified Bentall procedure (MBP), and technical modifications aimed at improving anastomotic stability and hemostasis continue to evolve. This study investigated the early outcomes of a posterior Teflon-felt-reinforced coronary button technique in comparison with the conventional approach. Methods: Between January 2021 and May 2025, a total of 57 patients who underwent an elective modified Bentall procedure were included and divided into two groups: the conventional coronary button group (CCB, n = 30) and the posterior Teflon-felt-reinforced coronary button group (RCB, n = 27). Operative variables and early postoperative outcomes (including bleeding, re-exploration, and 30-day mortality) were compared between the two groups. Results: The CCB group included 9 women and 21 men with a mean age of 59.5 ± 9.6 years, whereas the RCB group consisted of 5 women and 22 men with a mean age of 57.3 ± 8.9 years. The mean maximum aortic root diameter was 49.6 ± 5.3 mm, and the mean ascending aortic diameter was 50.8 ± 4.9 mm. Aortic cross-clamp (ACC) and cardiopulmonary bypass (CPB) times were similar between the groups (p = 0.330 and p = 0.214, respectively). After excluding patients who underwent planned coronary artery bypass grafting (CABG; n = 8), the incidence of unplanned CABG was higher in the CCB group than in the RCB group [6 (24.0%) vs. 2 (8.3%); p = 0.136]. Postoperative 24-h chest tube drainage tended to be lower (p = 0.060), and re-exploration for bleeding occurred less frequently (11.1% vs. 30.0%, p = 0.076), with no coronary button-related bleeding after reinforcement. The RCB group required significantly fewer transfused blood products, including red blood cells, fresh frozen plasma, and platelets (all p < 0.01). Intensive care unit stay was shorter in the reinforced group (p < 0.01), with a trend toward reduced hospital stay (p = 0.085). Early mortality was comparable (p = 0.356). Conclusions: Posterior Teflon-felt-reinforced coronary button anastomosis may improve early hemostatic stability and provide additional mechanical support during coronary reimplantation in the modified Bentall procedure; confirmation in larger cohorts is required. Full article

Background/Objectives: Total knee arthroplasty (TKA) is often associated with extensive bleeding and the need for intraoperative and postoperative blood transfusions. Due to concern about the risks associated with them, a push has been made in surgery toward the development of new intraoperative blood management devices and innovative postoperative care strategies. Tranexamic acid (TXA), fibrin sealant and standard electrocautery are widely used in orthopedic surgery, since several studies provided evidence about their efficacy and safety. A new device, the bipolar sealer system (BSS), provides hemostasis at lower temperature (<100°) than conventional electrocautery. It does not produce smoke, necrosis or burn tissue. Methods: In this study, we retrospectively analyzed data from 480 patients who underwent TKA between January 2017 and December 2024. The cohort was divided into two groups based on the hemostatic protocol adopted. The control group enrolled 240 patients who received the standard protocol with TXA and fibrin sealant, while the study group enrolled 240 patients who followed protocol with Aquamantys BSS and TXA. Hematological parameters, including hemoglobin (Hb), hematocrit (HCT) and red blood cells (RBCs) were analyzed preoperatively (T0) and postoperatively: immediately after surgery (T1), at day one (T2) and day three (T3). Results: Changes in hemoglobin from baseline to postoperative follow-up were significantly lower among patients who received TXA plus BSS and those receiving TXA plus fibrin sealant, with p-values of 0.0003 at T1 (immediately after surgery), 0.027 at T2 (one day post-op), and 0.0001 at T3 (three days post-op). Comparable results were observed for HCT and RBC values. Conclusions: These data demonstrate that Aquamantys is more effective than fibrin glue in controlling blood loss after knee replacement surgery, not only immediately after the procedure but also in the following days. Full article