[Advances in hemophilia treatment].

Advances in replacement therapy with clotting factor (F) VIII or FIX product have contributed greatly to reducing the incidence of hemophilic arthropathy and improving quality of life (QOL) in patients with hemophilia. However, frequent intravenous administration of clotting factor products, blood access, and development of alloantibodies (inhibitors) have been important issues. Clinical studies aimed at addressing these issues have been conducted in Japan as well, including a multicenter study to determine factors involved in inhibitor development. Drug development has also progressed: several clotting factor products with extended half-life and non-clotting factor therapies have been introduced in quick succession. Anti-FIX/FX bispecific antibody in particular has a long half-life when administered subcutaneously and controls bleeding in patients with hemophilia A. Anti-antithrombin therapy and anti-TFPI monoclonal antibody products that work by rebalancing coagulation have also been developed. In addition, gene therapy has been approved for adults in U.S. and Europe, where improved vectors and codon optimization have enabled protein expression up to the near-therapeutic hemostatic range. Recent significant developments in hemophilia treatment are expected to overcome long-standing problems and further improve QOL.

Association of Activated Clotting Time-Guided Anticoagulation with Complications during Extracorporeal Membrane Oxygenation Support: A Systematic Review and Meta-Analysis.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) requires systemic anticoagulation to reduce the risk of thromboembolic events. Despite its historic role, activated clotting time (ACT) remains a widely used heparin monitoring method. Systematic evidence on the association of ACT-guided monitoring with hemorrhagic or thromboembolic complications does not exist. DESIGN: Systematic literature review and meta-analysis (Scopus and PubMed, July 2023). SETTING: All cohort studies. PARTICIPANTS: Patients receiving ECMO support. INTERVENTION: Anticoagulation monitoring with ACT. MEASUREMENTS AND MAIN RESULTS: We identified 3,177 publications, with 8 studies reporting the average ACT values for patients with and without bleeding. Meta-analysis revealed no significant difference in the compared groups (SMD = 0.69; 95% CI -0.05 to 1.43, p = 0.069; I2 = 87.4%). Three studies (n = 117 patients) reported on the average ACT values for patients with thrombosis, without significant differences in ACT between patients with and without thrombosis (SMD = 0.47; 95% CI -0.50 to 1.44, p = 0.342; I2 = 81.1%). CONCLUSIONS: Even though ACT is a widely used heparin monitoring tool, the evidence on its association with hemorrhagic or thromboembolic events is still controversial and limited. Further studies are essential to elucidate the role of ACT in anticoagulation monitoring during ECMO support.

Heparin resistance management during cardiac surgery: a literature review and future directions.

INTRODUCTION: Heparin, a commonly used anticoagulant in cardiac surgery, binds to antithrombin III (ATIII) to prevent clot formation. However, heparin resistance (HR) can complicate surgical procedures, leading to increased thromboembolic risks and bleeding complications. Proper diagnosis and management of HR are essential for optimizing surgical outcomes. METHODOLOGY: Diagnosis of HR involves assessing activated clotting time (ACT) and HR assays. Management strategies were identified through a comprehensive review of the literature, including studies exploring heparin dosage adjustments, antithrombin supplementation, and alternative anticoagulants in cardiac surgery patients with HR. A thorough search of relevant studies on HR was conducted using multiple scholarly databases and relevant keywords, resulting in 59 studies that met the inclusion criteria. DISCUSSION: HR occurs when patients do not respond adequately to heparin therapy, requiring higher doses or alternative anticoagulants. Mechanisms of HR include AT III deficiency, PF4 interference, and accelerated heparin clearance. Diagnosis involves assessing ACT and HR assays. HR in cardiac surgery can lead to thromboembolic events, increased bleeding, prolonged hospital stays, and elevated healthcare costs. Management strategies include adjusting heparin dosage, supplementing antithrombin levels, and considering alternative anticoagulants. Multidisciplinary management of HR involves collaboration among various specialities. Strategies include additional heparin doses, fresh frozen plasma (FFP) administration, and antithrombin concentrate supplementation. Emerging alternatives to heparin, such as direct thrombin inhibitors and nafamostat mesilate, are also being explored. CONCLUSION: Optimizing the management of HR is crucial for improving surgical outcomes and reducing complications in cardiac surgery patients. Multidisciplinary approaches and emerging anticoagulation strategies hold promise for addressing this challenge effectively.

Clinical Outcomes of 5000 IU Heparin Versus Activated Clotting Time-Guided Heparinization During Noncardiac Arterial Procedures: A Propensity Score Matched Analysis.

PURPOSE: Previous studies have shown that activated clotting time (ACT)-guided heparinization leads to better anticoagulation levels during noncardiac arterial procedures (NCAP) than a standardized bolus of 5000 IU. Better anticoagulation should potentially result in lower incidence of thrombo-embolic complications (TEC). Comparative investigations on clinical outcomes of these heparinization strategies are scarce. This study investigated clinical outcomes of ACT-guided heparinization with a starting dose of 100 IU/kg in comparison with a single standardized bolus of 5000 IU heparin during NCAP. MATERIALS AND METHODS: Analysis from a prospectively collected database of patients undergoing NCAP in 2 vascular centers was performed. Patients receiving ACT-guided heparinization were matched 1:1 with patients receiving 5000 IU heparin using propensity score matching (PSM). Primary outcomes were TEC, bleeding complications, and mortality within 30 days of procedure or during the same admission. RESULTS: A total of 759 patients (5000 IU heparin: 213 patients, ACT-guided heparinization: 546 patients) were included. Propensity score matching resulted in 209 patients in each treatment group. After PSM, the groups were comparable, with the exception of a higher prevalence of peripheral arterial disease in the ACT-guided heparinization group (103 patients, 49% vs 82 patients, 39%, p=0.039). The target ACT (>200 seconds) was reached in 198 patients (95%) of the ACT-guided group versus 71 patients (34%) of the 5000 IU group (p<0.001), indicating successful execution of the ACT-guided protocol. Incidence of TEC (13 patients, 6.2% vs 10 patients, 4.8%, p=0.52), mortality (3 patients, 1.4% vs 0 patients, p=0.25), and bleeding complications (32 patients, 15% vs 25 patients, 12%, p=0.32) did not differ between patients receiving ACT-guided heparinization and 5000 IU heparin. Protamine was administered in 118 patients (57%) in the ACT group versus 11 patients (5.3%) in the 5000 IU group (p<0.001), but did not influence incidence of TEC (17 patients, 5.9% vs 6 patients, 4.7%, p=0.61) or bleeding complications (34 patients, 12% vs 22 patients, 17%, p=0.14). CONCLUSION: No difference in TEC, bleeding complications, or mortality was found between ACT-guided heparinization and a single bolus of 5000 IU heparin during NCAP. CLINICAL IMPACT: Previous studies have shown that activated clotting time (ACT)-guided heparinization leads to better anticoagulation levels during non-cardiac arterial procedures (NCAP) then a standardized bolus of 5000 IU. Comparative investigations on clinical outcomes are scarce. This study focussed on clinical outcomes of both protocols in NCAP in a propensity score matched cohort. Thrombo-embolic complications (TEC), bleeding complications and mortality within 30 days after NCAP or during the same admission were comparable between groups. Future studies should focus on optimizing ACT-guided protocols, specifically in patients with a high risk of TEC and bleeding complications.

A single-center study of patients with rare isolated acquired clotting factor deficiencies other than acquired hemophilia A.

Background: Isolated acquired clotting factor deficiencies (ACFDs) are mainly caused by the existence of anti-factor antibodies or adsorption of clotting factors onto substances such as amyloid. Besides acquired factor (F)VIII deficiency (acquired hemophilia A), the remaining factor deficiencies are rare and diverse, posing challenges in both diagnosis and management. Objectives: To describe different features of isolated ACFDs to improve our understanding of these diseases and provide practical recommendations for their management. Methods: Clinical characteristics of patients with isolated acquired FII, FV, FIX, FX, FXI, FXII, FXIII, and von Willebrand factor deficiencies were collected from a single center between July 1997 and December 2021 and analyzed retrospectively. Results: A total of 54 rare isolated ACFD patients were enrolled in our study, mainly including 20 acquired FV deficiency patients and 16 acquired FX deficiency patients. The median age at diagnosis of all rare isolated ACFD patients was 55 years. The median time to diagnose all rare isolated ACFD patients was 60 days. Ten (18.5%) rare isolated ACFD patients had no bleeding and 2 (3.7%) rare isolated ACFD patients showed venous thromboembolism. Hemostatic treatment was applied to 41 (41/54; 75.9%) rare isolated ACFD patients. Thirty-seven (68.5%) rare isolated ACFD patients received immunosuppressive therapy, and 10 (18.5%) rare isolated ACFD patients received chemotherapy targeting primary diseases. Twenty-two (61.9%) rare isolated ACFD patients achieved complete remission, and 9 (21.4%) rare isolated ACFD patients died. Conclusion: Rare isolated ACFDs are underestimated, associated with delayed diagnosis, and lack effective therapy. Clinicians should raise awareness for recognizing and managing rare isolated ACFD patients to avoid morbidity and mortality.

Systematic review of clinical guidelines and consensus statements concerning heparin and protamine dosing and monitoring of anticoagulation levels for non-cardiac arterial procedures.

OBJECTIVES: This systematic review was performed to examine all published practice Guidelines and Consensus Statements (together: GCS) on heparin dosing and monitoring during non-cardiac arterial procedures (NCAP). The objective was to scrutinize the recommendations and advice outlined within these GCS documents and to evaluate the supporting evidence for these recommendations. Additionally, the use of the activated clotting time (ACT) and target ACT values were explored. METHODS: This systematic review was performed in accordance with the PRISMA Guidelines. Medline and Embase databases were searched to identify all GCSs in the English language on NCAP. The final literature search was performed in January 2023. This search was supplemented by searching websites of relevant professional vascular surgical organizations for GCSs. Titles and abstracts were assessed by two independent reviewers. RESULTS: Of 9716 titles identified, 27 GCSs met the predefined inclusion criteria: six GCSs regarding carotid intervention, seven regarding procedures for aneurysmal disease of the abdominal aorta and iliac arteries, 12 regarding interventions for acute and chronic peripheral arterial occlusive disease and two regarding open and endovascular interventions of thoraco-abdominal aortic aneurysms. Administration of heparin is advised for al NCAP. There was high variability concerning heparin dose: both standard dose as weight based dosing (30-150 IU/kg) was advised. Recommendations on repeated doses, ACT monitoring and heparin reversal using protamine also varied widely. In none of the GCSs, the type of the ACT measuring device or used cartridges were specified. CONCLUSIONS: Large variability was found between the included GCSs with regard to the recommendations on heparin dose and target ACT values during NCAP. Advice and recommendations in GCSs were based on low-quality studies or without providing any reference at all. The described variability in recommendations emphasizes the need for large prospective (randomized) studies or the incorporation of data on heparin and the use of ACT monitoring into verified vascular surgery registries, to develop evidence-based, practical and uniform applicable recommendations.

Anticoagulation management for cardiopulmonary bypass using TEG® 6 s in a patient receiving both heparin and dabigatran.

BACKGROUND: It is difficult to evaluate adequate dose of heparin for cardiopulmonary bypass (CPB) by activated clotting time (ACT) in a patient receiving both heparin and dabigatran because dabigatran can also prolong ACT. We evaluated the effect of dabigatran by thromboelastography (TEG) to determine adequate heparin dose for CPB. CASE PRESENTATION: An 81-year-old woman receiving both heparin and dabigatran was scheduled for an emergency surgical repair of iatrogenic atrial septal perforation. Although ACT was prolonged to 419 s, we performed TEG to distinguish anticoagulation by dabigatran from heparin comparing R in CK and CHK. As the results of TEG indicated residual effect of dabigatran, we reversed dabigatran by idarucizumab and then dosed 200 U/kg of heparin to achieve adequate anticoagulation for CPB by heparin. CONCLUSIONS: TEG could help physicians to determine need for idarucizumab and also an adequate dose of heparin to establish appropriate anticoagulation for CPB.

Coagulo-Net: Enhancing the mathematical modeling of blood coagulation using physics-informed neural networks.

Blood coagulation, which involves a group of complex biochemical reactions, is a crucial step in hemostasis to stop bleeding at the injury site of a blood vessel. Coagulation abnormalities, such as hypercoagulation and hypocoagulation, could either cause thrombosis or hemorrhage, resulting in severe clinical consequences. Mathematical models of blood coagulation have been widely used to improve the understanding of the pathophysiology of coagulation disorders, guide the design and testing of new anticoagulants or other therapeutic agents, and promote precision medicine. However, estimating the parameters in these coagulation models has been challenging as not all reaction rate constants and new parameters derived from model assumptions are measurable. Although various conventional methods have been employed for parameter estimation for coagulation models, the existing approaches have several shortcomings. Inspired by the physics-informed neural networks, we propose Coagulo-Net, which synergizes the strengths of deep neural networks with the mechanistic understanding of the blood coagulation processes to enhance the mathematical models of the blood coagulation cascade. We assess the performance of the Coagulo-Net using two existing coagulation models with different extents of complexity. Our simulation results illustrate that Coagulo-Net can efficiently infer the unknown model parameters and dynamics of species based on sparse measurement data and data contaminated with noise. In addition, we show that Coagulo-Net can process a mixture of synthetic and experimental data and refine the predictions of existing mathematical models of coagulation. These results demonstrate the promise of Coagulo-Net in enhancing current coagulation models and aiding the creation of novel models for physiological and pathological research. These results showcase the potential of Coagulo-Net to advance computational modeling in the study of blood coagulation, improving both research methodologies and the development of new therapies for treating patients with coagulation disorders.

Integration of clotting and fibrinolysis: central role of platelets and factor XIIIa.

PURPOSE: The aim of the present study was to establish the role of platelets and activated factor XIIIa (FXIIIa) in the structuring of the fibrin network as well as to clarify the effect of network compaction on clot lysis. METHODS: Turbidimetry was used for the one-stage clotting test where platelet-free plasma (PFP) is regarded as single factor-deficient plasma (platelets as lacking factor) and autologous platelet-rich plasma (PRP) as deficiency corrected plasma. Structural features of the developed and subsequently lysed fibrin network, formed under static and flow conditions, were visualized by confocal microscopy. RESULTS: Thrombin-initiated plasma clotting revealed changes in the shape of the absorption curve, more pronounced in the presence of platelets. These changes correlate with the transformation of the fibrin scaffold during clot maturing. With the combined action of platelets, thrombin and Ca2+, plasma clotting passes through two phases: initial formation of a platelet-fibrin network (first peak in the polymerization curve), and then the compaction of fibrin, driven by FXIIIa (the second peak) which can be further modulate by the contractile action of platelets. These structural changes, mediated by platelets and FXIIIa, have been shown to determine subsequent clot lysis. CONCLUSIONS: Platelet aggregates serve as organizing centers that determine the distribution of fibrin in clot volume. The openwork structure of the platelet-transformed fibrin provides the necessary prerequisites for its timely lysis. The revealed aspects of the interaction of platelets and FXIIIa, which accompanies the maturation of a fibrin clot, may lead to new approaches in the pharmacological correction of disorders associated with both thrombotic episodes and bleeding tendency.

Kinetic analysis of prothrombinase assembly and substrate delivery mechanisms.

Prothrombinase complex, composed of coagulation factors Xa (FXa) and Va (FVa) is a major enzyme of the blood coagulation network that produces thrombin via activation of its inactive precursor prothrombin (FII) on the surface of phospholipid membranes. However, pathways and mechanisms of prothrombinase formation and substrate delivery are still discussed. Here we designed a novel mathematical model that considered different potential pathways of FXa or FII binding (from the membrane or from solution) and analyzed the kinetics of thrombin formation in the presence of a wide range of reactants concentrations. We observed the inhibitory effect of large FVa concentrations and this effect was phospholipid concentration-dependent. We predicted that efficient FII activation occurred via formation of the ternary complex, in which FVa, FXa and FII were in the membrane-bound state. Prothrombin delivery was mostly membrane-dependent, but delivery from solution was predominant under conditions of phospholipid deficiency or FXa/FVa excess. Likewise, FXa delivery from solution was predominant in the case of FVa excess, but high FII did not switch the FXa delivery to the solution-dependent one. Additionally, the FXa delivery pathway did not depend on the phospholipid concentration, being the membrane-dependent one even in case of the phospholipid deficiency. These results suggest a flexible mechanism of prothrombinase functioning which utilizes different complex formation and even inhibitory mechanisms depending on conditions.

A rare case of glanzmann thrombasthenia with concomitant factor VII deficiency.

Glanzmann thrombasthenia and clotting factor VII deficiency are rare autosomal recessive bleeding disorders. But the occurrence of both in the same person is an extremely rare phenomenon. Here, we present the case of a young female from Sindh, Pakistan that got diagnosed with Glanzmann thrombasthenia and concomitant moderate factor VII deficiency, a combination not previously reported in the country. The patient exhibited typical clinical manifestations including menorrhagia, nasal bleeds, and prolonged bleeding after minor injuries, compounded by a positive family history and consanguinity. Laboratory investigations revealed marked anemia, prolonged bleeding time, and abnormal platelet aggregation studies consistent with Glanzmann thrombasthenia. The identification of this rare combination relied on comprehensive clinical evaluation, emphasizing the importance of family history in suspected cases. Management involved platelet transfusions, tranexamic acid, and Factor VII replacement, resulting in clinical improvement.

Fe3O4@silica-thermolysin: A robust, advantageous, and reusable microbial nanobiocatalyst for proteolysis and milk-clotting.

Thermolysin (TLN) is a microbial highly-priced thermostable metallo-endoprotease with complementary substrate specificity to those of proteases widely used in science and industry for protein digestion and milk-clotting. This study is the first to immobilize TLN on aminated superparamagnetic nanoparticles (Fe3O4@silica-NH2) aiming for higher stability, recoverability, reusability, and applicability in proteolysis and as a microbial rennet-like milk-clotting enzyme. The nanobiocatalyst developed (Fe3O4@silica-TLN) displays hydrolytic activity on a synthetic TLN substrate and, apparently, was fully recovered from reaction media by magnetic decantation. More importantly, Fe3O4@silica-TLN retains TLN catalytic properties in the presence of calcium ions even after exposure to 60 °C for 48 h, storage at 4 °C for 80 days and room temperature for 42 days, use in proteolyses, and in milk-clotting for up to 11 cycles. Its proteolytic activity on bovine milk casein in 24 h furnished 84 peptides, of which 29 are potentially bioactive. Also, Fe3O4@silica-TLN catalyzed the digestion of bovine serum albumin. In conclusion, Fe3O4@silica-TLN showed to be a new, less autolytic, thermostable, non-toxic, magnetically-separable, and reusable nanobiocatalyst with highly attractive properties for both science (peptide/protein chemistry and structure, proteomic studies, and the search for new bioactive peptides) and food industry (cheese manufacture).

Clinical and Humanistic Burden of Non-inhibitor Haemophilia A in Five European Countries: Insights from the CHESS II Study.

INTRODUCTION: Haemophilia A (HA) is a congenital bleeding disorder caused by a deficiency/absence of factor VIII (FVIII) and characterised by frequent, acute and prolonged spontaneous or traumatic bleeding events, often leading to haemophilic arthropathy and progressive joint deterioration. HA severity is characterized by endogenous FVIII activity: mild (> 5-40%), moderate (1-5%), or severe (< 1%). HA poses a substantial clinical and socioeconomic burden on people with HA (PWHA), their caregivers, and society. This analysis evaluates clinical and patient-centric outcomes of a cohort of individuals with non-inhibitor HA sampled from France, Germany, Italy, Spain, and the UK in the 'Cost of Haemophilia in Europe: A Socioeconomic Survey II' (CHESS II) study. METHODS: CHESS II was a cross-sectional burden-of-illness study collecting clinical and socioeconomic data on adult (≥ 18 years) individuals with haemophilia A or B of any severity with or without inhibitors from eight European countries. Descriptive analyses were conducted examining physician-reported demographics, clinical and health resource utilisation information. PWHA-reported health-related quality of life (HRQoL) using the EQ-5D-5L and Work Productivity and Activity Impairment (WPAI) were also examined. Outcomes were stratified by HA severity and reported at country level. RESULTS: Demographics and clinical characteristics of the cohort (N = 880) were generally consistent across countries. Individuals with severe HA experienced more frequent bleeding events and joint disease despite broad use of factor replacement therapy long-term prophylaxis. A minority of those with mild or moderate HA also experienced such challenges. HRQoL and workforce participation diminished, and chronic pain increased, with increasing HA severity. CONCLUSION: This analysis provides up-to-date insights on the impact of HA across five European countries. Increasing HA severity was generally associated with worse clinical outcomes, HRQoL and workforce participation. These findings suggest a place for continued evidence-based tailored treatment and clinical management approaches in addressing the residual burden of HA.

Unveiling the potency of ready-to-use brodifacoum blocks in lesser bandicoot rats: exploring toxicity, blood clotting factors, and organ histology.

Background: The present study unveiled the effectiveness of ready-to-use brodifacoum blocks (0.005%) against the prevalent field rat species in southeast Asia, Bandicota bengalensis. Brodifacoum, a more potent second-generation anticoagulant, offers a solution for managing rodents resistant to other anticoagulants of its class. Methodology: Male and female bandicoot rats caught wild were exposed to brodifacoum for 1, 2, and 3 days in both the no-choice and bi-choice tests. The observations included mortality rates, impact on body weight, food consumption, blood clotting factors, organ weights, and histological changes. Results: Results indicated 100% mortality within 2-3 days in the no-choice tests, and 50.00%-83.33% mortality in the bi-choice tests within 5 to 8 days. The median lethal feeding periods were determined to be 2.10 and 2.33 days for male and female rats, respectively. Toxicity symptoms included bleeding from the nose, gums, and feet. While no significant effects were observed on body weight or organ weights, food consumption decreased notably in no-choice tests. Additionally, significant increases in prothrombin time and activated partial thromboplastin time were noted 24 h post-treatment in the no-choice tests, with post-treatment international normalized ratios of 9.45-14.20 and 1.52-3.03 in the no-choice and the bi-choice tests, respectively. Histological analysis revealed mild to severe necrotic changes in the liver and kidneys after brodifacoum treatment. Conclusions: Overall, this study underscores the potential of ready-to-use brodifacoum blocks as an effective tool for rodent population control, offering a viable alternative to other second-generation anticoagulant rodenticides.

Relation between antithrombin-III activity and activated clotting time for cardiopulmonary bypass.

Heparin resistance (HR) is observed before cardiopulmonary bypass (CPB), despite with normal antithrombin III (AT-III) levels. The relationships between preoperative AT-III activity and activated clotting time (ACT) after the first heparin dose should be clarified. We retrospectively analyzed the data of 818 patients who underwent CPB surgery, with the initial heparin of 300, 400, and 500 IU/kg, between 2017 and 2021. We defined HR as the failure to achieve ACT after the initial heparin dose (Post ACT) of > 480 s.There were no significant correlations between the AT-III activity and Post ACT in all patients, including 143 patients with AT-III activity < 80% and 675 patients with AT-III activity of ≥ 80%. Also, there were no significant correlations between the AT-III activity and Post ACT in 74 patients who received heparin of 300 IU/kg, in 186 patients with 400 IU/kg, and in 339 patients with 500 IU/kg. After identifying smoking, HR, activated partial thromboplastin time, fibrinogen degradation products (FDP), and ACT as influencing factors, multiple comparisons using the Steel-Dwass test showed significant difference in FDP and HR among the patients who received heparin of 300 IU/kg, 400 IU/kg, and 500 IU/kg. There is no association between preoperative AT-III activity and ACT after the first heparin administration for CPB, even in different dose of heparin. Rather, the higher the initial UFH dose is, the higher ACT may be, regardless of the AT-III activity.

Western Diet Modifies Platelet Activation Profiles in Male Mice.

The correlation between obesity and cardiovascular disease has long been understood, yet scant investigations endeavored to determine the impact of an obesogenic diet on platelet activation or function. As platelets drive clot formation, the terminus of cardiovascular events, we aimed to elucidate the longitudinal effect of an obesogenic diet on platelet phenotype by assessing markers of platelet activation using flow cytometry. Male, weanling mice were fed either a Western diet (30% kcal sucrose, 40% kcal fat, 8.0% sodium) or Control diet (7% kcal sucrose, 10% kcal fat, 0.24% sodium). At 12, 16 and 20 weeks on diets, platelets were collected and stained to visualize glycoprotein Ibα (GPIbα), P-selectin and the conformationally active state of αIIbß3 (a platelet specific integrin) after collagen stimulation. At all time points, a Western diet reduced GPIbα and αIIbß3 expression in platelets broadly while P-selectin levels were unaffected. However, P-selectin was diminished by a Western diet in the GPIbα- subpopulation. Thus, a Western diet persistently primed platelets towards a blunted activation response as indicated by reduced active αIIbß3 and P-selectin surface expression. This study provides a first look at the influence of diet on platelet activation and revealed that platelet activation is susceptible to dietary intervention.

Anticoagulation Monitoring Using Activated Clotting Time in Patients Receiving Extracorporeal Membrane Oxygenation: A Meta-Analysis of Correlation Coefficients.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) requires systemic anticoagulation to maintain the circuit patency. However, the use of anticoagulation carries a risk of severe hemorrhage, necessitating rigorous monitoring. Activated clotting time (ACT) is a widely used monitoring tool; however, the evidence of its correlation with unfractionated heparin (UFH) infusion dose is limited. Here we aimed to analyze the correlation between ACT and UFH infusion during ECMO. DESIGN: Systematic literature review and meta-analysis of correlation coefficients (Scopus and PubMed, up to July 13, 2024). PROSPERO: CRD42023448888 SETTING: All retrospective and prospective studies PARTICIPANTS: Patients receiving ECMO support INTERVENTION: Anticoagulation monitoring during ECMO support MEASUREMENTS AND MAIN RESULTS: Nineteen studies were included in the analysis, and the meta-analysis encompassed 16 studies. The vast majority of studies (n = 15) found a weak correlation, and no study reported a strong correlation between ACT and UFH infusion dose. The meta-analysis (n = 12,625 samples) identified a weak correlation, with a pooled estimate of correlation coefficients of 0.132 (95% confidence interval 0.03-0.23). The most common adverse events were hemorrhage (pooled incidence, 45%) and thrombosis (30%), and 47% of the patients died during their hospital stay. CONCLUSIONS: Even though ACT is a widely used UFH monitoring tool in ECMO patients, our meta-analysis found a weak correlation between ACT and UFH infusion dose. New trials are needed to investigate the role of emerging tools and to clarify the most appropriate monitoring strategy for patients receiving ECMO support.

Statins during Anticoagulation for Emergency Life-Threatening Venous Thromboembolism: A Review.

Venous thromboembolism (VTE) is the leading cause of morbidity and death worldwide, after cancer and cardiovascular diseases. VTE is defined to include pulmonary embolism (PE) and/or deep vein thrombosis (DVT). Approximately 25% of PE patients experience sudden death as an initial symptom of VTE, and between 10% and 30% of patients die within the first month after diagnosis. Currently, the only drugs approved for the treatment of both acute and chronic VTE are vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). However, their effectiveness is limited due to their associated risk of bleeding. Ideally, therapy should be able to treat VTE and limit the risk of VTE recurrence without increasing the risk of bleeding. Several studies have shown that the use of statins during anticoagulation for VTE reduces the risk of death and VTE recurrence. However, to date, there are conflicting data on the impact of statins during anticoagulation for VTE. A biological protective function of statins during anticoagulation has also been reported. Statins affect D-dimer levels; tissue factor (TF) gene expression; and VIII, VII, and Von Willebrand clotting factors-the major clotting factors they are able to affect. However, the usefulness of statins for the treatment and prevention of VTE is currently under debate, and they should not be substituted for guideline-recommended VTE prophylaxis or anticoagulation treatment. In this review of the literature, we illustrate the advances on this topic, including data on the role of statins in primary VTE prevention and secondary VTE prevention, related biological mechanisms, the risk of bleeding during their use, and their ability to reduce the risk of death.

Immobilized Drugs on Dual-Mode Imaging Ag2S/BaSO4/PVA Embolic Microspheres for Precise Localization, Rapid Embolization, and Local Antitumor Therapy.

Transcatheter arterial embolization (TAE) in interventional therapy and tumor embolism therapy plays a significant role. The choice of embolic materials that have good biocompatibility is an essential component of TAE. For this study, we produced a multifunctional PVA embolization material that can simultaneously encapsulate Ag2S quantum dots (Ag2S QDs) and BaSO4 nanoparticles (BaSO4 NPs), exhibiting excellent second near-infrared window (NIR-II) fluorescence imaging and X-ray imaging, breaking through the limitations of traditional embolic microsphere X-ray imaging. To improve the therapeutic effectiveness against tumors, we doped the doxorubicin (DOX) antitumor drug into microspheres and combined it with a clotting peptide (RADA16-I) on the surface of microspheres. Thus, it not only embolizes rapidly during hemostasis but also continues to release and accelerate tumor necrosis. In addition, Ag2S/BaSO4/PVA microspheres (Ag2S/BaSO4/PVA Ms) exhibited good blood compatibility and biocompatibility, and the results of embolization experiments on renal arteries in rabbits revealed good embolic effects and bimodal imaging stability. Therefore, they could serve as a promising medication delivery embolic system and an efficient biomaterial for arterial embolization. Our research work achieves the applicability of NIR-II and X-ray dual-mode images for clinical embolization in biomedical imaging.

An i-type lysozyme from a crustacean, Pacifastacus leniusculus, functions as a clot-destabilising enzyme.

Lysozymes are hydrolytic enzymes, and they are ubiquitous among all living organisms. They are mostly associated with antibacterial properties through their muramidase activity, while other properties such as iso-peptidase activity are also common. Invertebrate-type (i-type) lysozymes include the enzyme Destabilase, which is present in the salivary secretions of the medicinal leach Hirundo medicinalis. Destabilase has the ability to hydrolyse the ε-(γ-glutamyl)-lysine iso-peptide bonds formed by transglutaminase in fibrin of vertebrate blood, thereby destabilising blood clots. We have identified an i-type lysozyme from the hemocytes of the freshwater crayfish Pacifastacus leniusculus, which was found to be upregulated at the protein level in response to an injection of the ß-1,3-glucan laminarin. Based on its sequence we predicted that this lysozyme would lack muramidase activity, and therefore we decided to determine its putative immune function. The P. leniusculus i-type lysozyme (Pl-ilys), is a protein with 159 amino acid residues, including a 29 residue signal peptide, with a predicted molecular weight of 16 kDa and a predicted pI of 5.6. It is expressed primarily in the hemocytes and to a lesser extent in the hematopoietic tissue. A recombinant mature Pl-ilys using an E. coli expression system was produced, and we could ascertain that this enzyme was deficient of muramidase activity. Moreover, no iso-peptidase activity could be detected against the substrate l-γ-glutamine-p-nitroanilide. Analysis of the conserved domains in Pl-ilys showed a putative destabilase domain, and thus we tested the clot dissolving activity of this enzyme. We could show that the purified P. leniusculus clotting protein which had been coagulated and clotted with transglutaminase was dissolved by the addition of Pl-ilys. Taken together our results indicate that Pl-ilys has a clot dissolving or destabilising activity in crustacean blood.