Antitrombóticos: investigación y aplicaciones en la atención médica / Antithrombotics: Research and applications in healthcare

Resumen: Los antitrombóticos son fármacos que se utilizan para prevenir la formación de coágulos sanguíneos, también conocidos como trombos. Estos coágulos pueden causar graves problemas de salud, como infartos o enfermedades cerebrovasculares. En este artículo se analizan diferentes tipos de antitrombóticos, como los antiplaquetarios y los anticoagulantes, y se discuten sus mecanismos de acción. Además, se examinan los beneficios y los riesgos asociados con el uso de antitrombóticos. Por un lado, estos fármacos pueden reducir el riesgo de eventos trombóticos, lo que puede ser especialmente beneficioso en pacientes con condiciones de alto riesgo, como aquellos que han sufrido un infarto o que tienen fibrilación auricular. Por otro lado, también se discuten los posibles efectos secundarios de los antitrombóticos, como el aumento del riesgo de sangrado. Además, se proporcionan pautas para su uso seguro en diferentes escenarios clínicos. Finalmente, se abordan las estrategias de monitoreo y ajuste de la dosis de estos medicamentos para garantizar su eficacia y seguridad en los pacientes.

Abstract: Antithrombotics are drugs used to prevent the formation of blood clots, also known as thrombi. These clots can cause serious health problems, such as heart attacks or strokes. Different types of antithrombotics, such as antiplatelets and anticoagulants, are analyzed and their mechanisms of action are discussed. Additionally, the benefits and risks associated with the use of antithrombotics are examined. On the one hand, these drugs can reduce the risk of thrombotic events, which may be especially beneficial in patients with high-risk conditions, such as those who have suffered a heart attack or who have atrial fibrillation. On the other hand, the possible side effects of antithrombotics, such as the increased risk of bleeding, are also discussed and guidelines for their safe use in different clinical scenarios are provided. Additionally, monitoring and dose adjustment strategies for these medications are addressed to ensure their effectiveness and safety in patients.

A novel gene editing lexicon strategy for the haemophilia community: Research plan for development and preliminary results.

INTRODUCTION: Despite the progress in gene editing platforms like CRISPR/Cas9 with the potential to transform the standard of care for haemophilia, the language used to explain and discuss gene editing is not aligned across the haemophilia community. Here, we present the objective and rationale for developing a clear, consistent, and globally aligned gene editing lexicon to address these communication gaps. METHODS: Effectively communicating complex gene editing concepts requires a clear and consistent vocabulary. Through collaboration with a diversity of haemophilia stakeholders, our main goal is to develop an accurate, informative lexicon which avoids overpromising or highly technical terminology. Using an innovative process, representatives from several patient and scientific haemophilia organizations and select biotechnology companies will develop and refine language concepts to be tested with approximately seventy participants across the United States of America, United Kingdom, and Germany. Participants will include lived experience experts (LEEs) and haematologists. The process will be overseen by the Lexicon Steering Committee of global experts from leading scientific and patient organizations in the haemophilia and gene editing fields. RESULTS: Initial feedback provided a robust foundation and rationale for building clear, consistent language around gene editing. This lexicon development framework will allow for increased understanding across the haemophilia community, including the development of valid informed consent and shared decision-making materials. CONCLUSION: Results provide important building blocks for stimuli development and highlight the need for a novel gene editing lexicon. In the next phase, language stimuli will be tested with LEEs and haematologists to better understand audience preferences and help shape the final lexicon.

Autoantibodies to protein S may explain rare cases of coagulopathy following COVID-19 vaccination.

While Coronavirus disease 2019 (COVID-19) vaccines have proven to be both effective and generally safe, rare but severe adverse events following immunization (AEFIs) are described. Autoantibodies to platelet factor-4 are associated with catastrophic thrombotic AEFIs, but comprehensive investigations of other autoantibodies are lacking. We aimed to detect and describe autoantibodies targeting coagulation-related proteins in a population-wide cohort (SWEDEGENE) including AEFIs attributed to COVID-19 vaccines in Sweden. Subjects were recruited from December 2020 to October 2022 and were stratified based on diagnosis and COVID-19 exposure. Screening was carried out in two phases, with a multiplex bead-based assay in the first subset (until September 2021) and with targeted assays for the second (until October 2022). Positivity was defined based on absolute, relative, and biological/technical thresholds. Patients with coagulation-related AEFIs were older and the Vaxzevria vaccine was overrepresented in this group. Two cases had antiphospholipid antibodies but none had PF4 antibodies. We identified six positives for protein S autoantibodies. Protein S concentrations were negatively correlated with autoantibody response in patients with immunoreactivity and functional analysis revealed low protein S activity in three subjects. Our population-wide analysis reveals cases with autoantibodies against protein S which possibly underlie coagulopathic AEFIs.

Adherence and Quality of Life in Adult Patients With Haemophilia A, Haemophilia B and Von Willebrand Disease: A National Cross-Sectional Survey.

BACKGROUND: New treatments for patients with bleeding disorders (PWB) have emerged, including products with extended half-life and subcutaneous administration. These less frequent treatments can potentially enhance quality of life (QoL), but adherence becomes critically important. AIM: To investigate adherence and QoL among PWB and explore the correlation between treatment adherence and QoL in adult patients with haemophilia A (HA), haemophilia B (HB) and Von Willebrand disease (vWD) in Denmark. METHOD: This survey used disease-specific patient-reported questionnaires: Veritas-PRO and Veritas-PRN to measure adherence, and Haemo-A-QoL and VWD-QoL to assess QoL. RESULTS: Responses were obtained from 149 patients with HA, 32 with HB and 118 with vWD. Adherence was reported by 87.1% of patients on prophylaxis and 71.2% of patients treated on demand, according to Veritas-PRO and Veritas-PRN cut-off scores. High QoL was generally reported, decreasing with age in HA and HB, but not in vWD. CONCLUSION: Danish patients with HA, HB and vWD reported high QoL and high adherence to prescribed treatments. There was no correlation between treatment adherence and QoL among the different patient groups. These findings highlight the need for further research to better understand adherence behaviours and identify opportunities to further improve QoL in PWB.

Predictors of diagnostic delays and loss to follow-up in women with von Willebrand disease: a single-center retrospective cohort study.

Background: Women with von Willebrand disease (VWD) often face diagnostic delays, leading to increased bleeds, stress, and healthcare use. The factors influencing these delays and their effects on gynecologic outcomes are not well understood. Objectives: This study aimed to 1) identify the prevalence and predictors of diagnostic delays and loss to follow-up in women with VWD and 2) determine how these delays affect severe gynecologic bleeding, emergency visits, transfusions, and hysterectomies. Methods: We conducted a single-center retrospective cohort study and included women aged ≥18 years diagnosed with VWD. Delayed diagnosis was defined as ≥3 bleeding events prior to VWD diagnosis, excluding easy bruising due to its subjectivity. Loss to follow-up was defined as ≥5 years since the last hematology visit. We used logistic regression for analysis. Results: Among 178 diagnosed women (median age, 27 years), 71 (40%) experienced ≥3 bleeding events before diagnosis. The median time from the first bleeding event to VWD diagnosis was 14.2 years. Severe bleeding events significantly predicted diagnostic delays (adjusted odds ratio, 3.1; 95% CI, 1.5-6.2). Fifty-four (30%) women were lost to follow-up, with remote era of initial bleed and VWD type identified as significant predictors. Delays were associated with increased risks of hysterectomies (odds ratio, 2.7; 95% CI, 1.2-6.3) and other gynecologic procedures. Conclusion: Delayed diagnosis and loss to follow-up in VWD are common even in a specialized Hemophilia Treatment Centre. Such delays lead to more severe bleeding and increased gynecologic interventions. Prompt diagnosis is paramount for better patient outcomes and reduced healthcare utilization.

Spontaneous postoperative bleeding after periodontal procedure: An alarming sign of bleeding disorder.

The prevalence of inherited bleeding disorders (BDs) is low in the general population (10-20 per 100,000 individuals), particularly hemophilia B cases, which may remain undiagnosed for a very long time until exposed to some surgical procedure. The dental professional must be aware of the possibility that patients with no previous history of abnormal bleeding may manifest their first bleeding episode in the dental office. Particularly as periodontists, we often encounter patients with bleeding gums and severe bleeding complications may precipitate while performing routine periodontal procedures. Hence, we must have a thorough knowledge of BDs and their management in challenging hemorrhagic situations. Management of such patients necessitates a multidisciplinary approach by involving the patient's hematologist and advanced laboratory facilities. The present case report is an attempt to discuss the diagnosis and management of a bleeding episode that occurred post periodontal flap surgery in an undiagnosed hemophilia B patient.

Trauma-induced coagulopathy across age pediatric groups: A retrospective cohort study evaluating testing and frequency.

BACKGROUND: Trauma-induced coagulopathy (TIC) is associated with negative outcomes. Pediatric TIC has been described most often in older children. Children undergo normal developmental hemostasis, but it is unknown how this process impacts the risk of TIC across childhood. AIMS: To understand variations in coagulation testing and TIC across pediatric age groups. METHODS: We evaluated testing patterns of coagulation studies at presentation and over the first 72 h of hospitalization by pediatric age group at a large, Level I trauma center, 2015-2020. The frequency of TIC was determined using published, age-specific reference ranges and controlling for injury severity. We performed subgroup analyses of those with isolated severe traumatic brain injury (TBI) and those who presented directly from the scene of injury. RESULTS: Data from 2409 pediatric patients were available; 333 patients had isolated severe TBI. Children <1 year were least likely to be tested for TIC at presentation and over the first 72 h, even among the most injured. Fibrinogen testing was uncommon, regardless of injury severity. TIC was common: 22% of patients had TIC at presentation and 35% by 72 h. Greater injury severity was associated with TIC. Children 1-4 and 5-9 years had a higher frequency of TIC at presentation and over 72 h compared to older children in the least injured cohort. We saw no difference in frequency of TIC between age groups in the subset with isolated severe TBI. Using age-specific criteria, patients most often met TIC criteria by INR/PT, followed by platelet count, and least commonly by aPTT. The presence of TIC was associated with in-hospital mortality (OR 4.10, 95% CI 2.06-8.17). CONCLUSIONS: Significant sampling bias exists in clinical data collection among injured children and adolescents. Contrary to previous reports and using age-specific TIC criteria, younger children are not at lower risk of TIC than older children when controlling for injury severity.

Haemophilia testing of young girls in Canada: Describing the current recommendations for factor level and genetic testing and the experiences of Canadian parents.

INTRODUCTION: It is widely acknowledged that haemophilia affects women and girls, yet current testing recommendations for factor level and genetic testing vary and do not universally incorporate updated research. Canadian parents have expressed frustration at inconsistent recommendations and reported instances where delayed testing led to missed diagnosis and preventable bleeding. AIM: Study aim was to explore and describe the practice of haemophilia-related testing of young girls in Canada. METHODS: A mixed methods study was carried out with two populations: (1) Nurses working in haemophilia care completed a survey regarding the current testing recommendations of their Haemophilia Treatment Centre (HTC), (2) Parents of obligate or potential haemophilia carriers completed a structured interview with questions about their family experience of haemophilia and testing decisions for daughters. RESULTS: Twenty-six survey responses were received and showed wide variation in the usual recommendations of Canadian HTCs. Different factor level testing recommendations may be given to obligate and potential carriers despite no difference in bleeding risk. Only a minority of HTCs currently recommend an early baseline factor level (< 10 years) to obligate carriers (27%) or potential carriers (15%). For genetic testing of potential carriers, 70% of HTC would approve a family request for genetic testing of a minor with specific conditions. The majority of parents interviewed felt dissatisfied with their testing experience (58%) and highlighted many issues related to delayed testing recommendations. CONCLUSION: Updated, nationally affirmed testing recommendations are needed that align with research on bleeding in women and girls affected by haemophilia.

Bleeding outcomes in critically ill patients on heparin with discordant aPTT and anti-Xa activity.

Activated partial thromboplastin time (aPTT) and unfractionated heparin (UFH) level via the anti-factor Xa activity assay (anti-Xa) are commonly used assays for UFH monitoring. While discordance between the two assays is common, its impact on critically ill patient outcomes is unclear. This study aimed to compare the incidence of major bleeding events among critically ill patients with discordant aPTT and anti-Xa activity while on UFH, to patients with no discordance. This was a single-center, retrospective cohort study of critically ill adult patients who had simultaneous anti-Xa and aPTT levels while receiving continuous UFH infusion. The primary outcome was the incidence of a major bleeding event up to 24 h after UFH discontinuation. Secondary outcomes included incidence of 30-day thrombosis and hospital length of stay (LOS). Among 264 included patients, 156 patients (59%) had at least one discordant paired level. Patients with discordance had an increased risk of major bleeding events (14% versus 5%; unadjusted risk ratio, 3.0; 95% CI 1.2-7.8; p = 0.01), and increased risk of thrombotic events (4% versus 0%; p = 0.04). Hospital LOS was similar between the two groups (13.8 days versus 11.4 days; p = 0.08). In this cohort of critically ill patients receiving continuous UFH, discordance in aPTT and anti-Xa activity was frequently observed and was associated with an increased risk of major bleeding events. While both assays remain viable monitoring options, evaluating simultaneous levels may aid in the management of critically ill patients. In patients with discordance, an individualized approach balancing bleeding and thrombotic risks should be considered.

Pregnancy loss in individuals with von Willebrand disease and unspecified mucocutaneous bleeding disorders: A multicentre cohort study.

BACKGROUND: While bleeding around pregnancy is well described in von Willebrand disease (VWD), risk of pregnancy loss is less certain. We aimed to describe the frequency of pregnancy loss in females with VWD, compared with those with a similar mucocutaneous bleeding phenotype and no VWD, or compared with non-bleeding disorder controls. METHODS: Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014-2023. The VWD group was defined as having VWF:Antigen (Ag) and VWF:Activity (Act) levels, each <0.50 IU/mL on ≥2 occasions, and a Condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥0.50 IU/mL on ≥2 occasions and a MCMDM-1 score ≥4. A non-bleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic. RESULTS: There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%, 82/145) (-11.2%, 97.5% CI -24.2, 1.8%), and the non-bleeding disorder control group (37.2%, 51/137) (8.1%, 97.5% CI -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group versus non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared to the literature. CONCLUSIONS: There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and with non-bleeding disorder controls.

Evaluation of Red Blood Cell Biochemical Markers and Coagulation Profiles Following Cell Salvage in Cardiac Surgery: A Systematic Review and Meta-Analysis.

Background: Individuals undergoing cardiac surgery face an increased risk of bleeding, as well as alterations in biochemical and coagulation patterns. Therefore, assessing the effectiveness of systems such as Cell Salvage is necessary to prevent potential surgical complications. Objective: To evaluate the efficacy of Cell Salvage in relation to the biochemical parameters of the red blood series and coagulation, as well as the risk of hemorrhage. Methods: A systematic review, accompanied by a meta-analysis, was executed via an extensive literature exploration encompassing Medline, CINAHL, Scopus, Web of Science, and the Cochrane Library. The inclusion criteria comprised studies in English or Spanish, without year restrictions, conducted in adults and with a randomized controlled trial design. Results: Twenty-six studies were included in the systematic review, involving a total of 2850 patients (experimental group = 1415; control group = 1435). Cell Salvage did not demonstrate superior outcomes compared to allogeneic transfusions in the management of post-surgical hemorrhage, as well as in total blood loss, platelet count, fresh frozen plasma, and fibrinogen. However, Cell Salvage showed a greater effectiveness for hemoglobin (moderate evidence), hematocrit (low evidence), post intervention D-dimer (low evidence), and some coagulation-related parameters (low evidence) compared to allogeneic transfusions. Finally, better results were found in the control group for INR parameters. Conclusions: The use of the Cell Salvage system holds high potential to improve the postoperative levels of biochemical and coagulation parameters. However, the results do not provide definitive evidence regarding its effectiveness for hemorrhage control, platelet count, fresh frozen plasma, and fibrinogen. Therefore, it is recommended to increase the number of studies to assess the impact of the Cell Salvage system on improvements in the red blood cell count and patient coagulation patterns. In addition, protocols should be homogenized, and variables such as the sex of the participants should be taken into account.

Mental, emotional and social dimensions of quality of life and their relationship with physical and functional status in adults with haemophilia.

INTRODUCTION: A comprehensive treatment for patients with haemophilia (PwH) should focus on how the disease interferes with their mental, emotional and social environment to analyse if all the therapeutic efforts invested in their physical status have positive impact on a life worth living. AIM: To analyse the correlation between the physical status of a cohort of adults with haemophilia and their mental, emotional and social states regarding their treatment modality; Also, to investigate which variables are most related to quality of life (QoL), joint health and emotional, mental and social states. METHODS: In this cross-sectional, 102 adults with haemophilia divided into a prophylactic group (G1, n = 77) and on-demand group (G2, n = 25) were included. Demographic and clinical characteristics, health joint (HJHS), presence of synovitis with ultrasound, self-perceived functionality (HAL) and QoL (A36-HaemoQoL), were analysed. RESULTS: In G1 all the variables that defined the physical status correlated (rho: 0.33 to 0.72) to the mental and social spheres. The emotional state correlated with the self-perceived ones. In G2 physical status did not correlate with the three states. According to the regression models, HAL was the variable that most influenced the QoL (together with the bleedings in the last year, R2 = 0.61), emotional (R2 = 0.16), mental (together with HJHS, R2 = 0.41) and social states (R2 = 0.39). In addition, the HJHS was influenced by synovitis, HAL, mental health, age and the bleeding history (R2 = 0.83). CONCLUSION: Emotional, mental and social states of PwH in prophylaxis are correlated to their physical status, being the self-perceived functionality the variable that most influenced in their QoL.

Persistent Splenic-Derived IgM Preferentially Recognize Factor VIIIA2 and C2 Domain Epitopes but Do Not Alter Antibody Production.

BACKGROUND: The most significant treatment complication for patients with hemophilia A is the development of neutralizing immunoglobin G (IgG), termed inhibitors, against factor VIII (FVIII) which prevent FVIII replacement therapy. Low titers of FVIII-specific immunoglobin M (IgM) have been identified in hemophilia A patients with and without inhibitors, as well as healthy individuals. However, the duration and influence of IgM on the immune response to FVIII remains unclear. OBJECTIVE: To characterize the binding interactions of persistently secreted FVIII-specific IgM in hemophilia A mice and assess their effect on IgG antibody development. METHODS: Splenic-derived monoclonal antibodies (MAbs) from immunized FVIII knockout mice were isolated and purified using hybridoma technology. Binding interactions were assessed utilizing a novel fluid-phase ELISA and computational modeling with HADDOCK to account for weak IgM binding. RESULTS: Sixteen porcine cross-reactive and non-inhibitory FVIII-specific IgM MAbs were identified. RNA sequencing of FVIII-specific IgM revealed 13 unique VDJ/VJ sequences indicating derivation from 13 unique B cell clones. IgM demonstrated polyclonal and polyreactive binding to FVIII in vitro and in silico. Molecular docking studies with reconstructed IgM VDJ/VJ regions identified frequent IgM interactions with amino acid residues K376, T381, K437, R2215 or K2249 within the FVIII A2 and C2 domains. Injections of individual IgM prior to FVIII exposure and co-injection of FVIII/IgM immune complexes did not affect de novo FVIII antibody production. CONCLUSION: Persistent FVIII-specific IgM are polyclonal but preferentially bind the A2 and C2 domains and FVIII/IgM immune complex formation do not significantly alter inhibitor development.

New insights in cardiovascular anesthesia: a dual focus on clinical practice and research.

Accumulation of the results of basic and clinical research has advanced the safety and quality of management in cardiovascular anesthesia. To address recent developments in this field, a symposium was held during the 71th Japanese Society of Anesthesiologists annual meetings in 2024, focusing on new advancements in both clinical and basic research in cardiovascular anesthesia. During this symposium, four experts reviewed recent findings in their respective areas of study, covering the following topics: clinical reliability and concerns regarding volatile anesthetics during cardiopulmonary bypass; novel basic and clinical findings regarding the cardioprotective effects of dexmedetomidine; advancements in optimizing blood and hemostasis management during cardiovascular surgery; and innovative strategies for managing postoperative cognitive disorders following cardiovascular and thoracic surgery. Each expert summarized recent novel findings, clinical reliability and concerns, as well as future directions in their respective topics. We believe that this special article provides valuable insights into both clinical practice and basic research in cardiovascular anesthesia while also inspiring anesthesiologists to pursue further research in this field.

Preparation and Biochemical Activity of Copper-Coated Cellulose Nonwoven Fabric via Magnetron Sputtering and Alginate-Calcium Ion Complexation.

Alginate-based materials have gained significant recognition in the medical industry due to their favorable biochemical properties. As a continuation of our previous studies, we have introduced a new composite consisting of cellulose nonwoven fabric charged with a metallic copper core (CNW-Cu0) covered with a calcium alginate (ALG-Ca2+) layer. The preparation process for these materials involved three main steps: coating the cellulose nonwoven fabric with copper via magnetron sputtering (CNW → CNW-Cu0), subsequent deposition with sodium alginate (CNW-Cu0 → CNW-Cu0/ALG-Na+), followed by cross-linking the alginate chains with calcium ions (CNW-Cu0/ALG-Na+ → CNW-Cu0/ALG-Ca2+). The primary objective of the work was to supply these composites with such biological attributes as antibacterial and hemostatic activity. Namely, equipping the antibacterial materials (copper action on representative Gram-positive and Gram-negative bacteria and fungal strains) with induction of blood plasma clotting processes (activated partial thromboplastin time (aPTT) and prothrombin time (PT)). We determined the effect of CNW-Cu0/ALG-Ca2+ materials on the viability of Peripheral blood mononuclear (PBM) cells. Moreover, we studied the interactions of CNW-Cu0/ALG-Ca2+ materials with DNA using the relaxation plasmid assay. However, results showed CNW-Cu0/ALG-Ca2+'s cytotoxic properties against PBM cells in a time-dependent manner. Furthermore, the CNW-Cu0/ALG-Ca2+ composite exhibited the potential to interact directly with DNA. The results demonstrated that the CNW-Cu0/ALG-Ca2+ composites synthesized show promising potential for wound dressing applications.

A surface-functionalized whole blood-based dielectric microsensor for assessment of clot firmness in a fibrinolytic environment.

Accurate assessment of fibrin clot stability can predict bleeding risk in coagulopathic conditions such as thrombocytopenia and hypofibrinogenemia. Hyperfibrinolysis - a clinical phenotype characterized by an accelerated breakdown of the fibrin clot - makes such assessments challenging by obfuscating the effect of hemostatic components including platelets or fibrinogen on clot stability. In this work, we present a biofunctionalized, microfluidic, label-free, electronic biosensor to elicit unique, specific, and differential responses from the multifactorial processes of blood coagulation and fibrinolysis ex vivo. The microsensor tracks the temporal variation in the normalized real part of the dielectric permittivity of whole blood (<10 µL) at 1 MHz as the sample coagulates within a three-dimensional, parallel-plate, capacitive sensing area. Surface biofunctionalization of the microsensor's electrodes with physisorption of tissue factor (TF) and aprotinin permits real-time assessment of the coagulation and fibrinolytic outcomes. We show that surface coating with TF and manual addition of TF result in a similar degree of acceleration of coagulation kinetics in human whole blood samples. We also show that surface coating with aprotinin and manual addition of aprotinin yield similar results in inhibiting tissue plasminogen activator (tPA)-induced upregulated fibrinolysis in human whole blood samples. Validated through a clinically relevant, complementary assay - rotational thromboelastometry for clot viscoelasticity - we finally establish that a microsensor dual-coated with both TF and aprotinin detects the hemostatic rescue in the tPA-induced hyperfibrinolytic profile of whole blood and the hemostatic dysfunction due to concurrent platelet depletion in the blood sample, thus featuring enhanced ability in evaluating complex, combinatorial coagulopathies.

Tissue Factor and Its Cerebrospinal Fluid Protein Profiles in Parkinson's Disease.

Background: Prior investigations have elucidated pathophysiological interactions involving blood coagulation and neurodegenerative diseases. These interactions pertain to age-related effects and a mild platelet antiaggregant function of exogenous α-Synuclein. Objective: Our study sought to explore whether cerebrospinal fluid (CSF) levels of tissue factor (TF), the initiator of the extrinsic pathway of hemostasis, differ between controls (CON) compared to patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB), considering that these conditions represent a spectrum of α-Synuclein pathology. We further investigated whether TF levels are associated with longitudinal progression in PD. Methods: We examined CSF levels of TF in 479 PD patients, 67 patients diagnosed with DLB, and 16 CON in order to evaluate potential continuum patterns among DLB, PD, and CON. Of the 479 PD patients, 96 carried a GBA1 variant (PD GBA1), while the 383 non-carriers were classified as PD wildtype (PD WT). We considered both longitudinal clinical data as well as CSF measurements of common neurodegenerative markers (amyloid-ß 1-42, h-Tau, p-Tau, NfL, α-Synuclein). Kaplan-Meier survival and Cox regression analysis stratified by TF tertile levels was conducted. Results: Higher CSF levels of TF were associated with an older age at examination in PD and a significant later onset of postural instability in PD GBA1. TF levels were lower in male vs. female PD. DLB GBA1 exhibited the lowest TF levels, followed by PD GBA1, with CON showing the highest levels. Conclusions: TF as representative of blood hemostasis could be an interesting CSF candidate to further explore in PD and DLB.

Parkinson's disease is a common age-related condition, primarily affecting older individuals. However, it shows a wide range of symptoms and clinical courses, influenced by genetic mutations, neuroinflammatory processes and lifestyle factors. Research into the disease's mechanisms is important for developing new therapies that could potentially slow its progression. Early diagnosis is also essential, as new disease-modifying therapies are most effective when started at an early stage of the disease. In this paper, we focus on a protein called tissue factor, which plays a role in both blood coagulation and neuroinflammation. Proteins involved in blood-coagulation also exhibit an increase in blood-concentration with higher age. Also, a subtle platelet antiaggregant function of exogenous α-Synuclein was found, a protein which aggregates in the brain of patients with Parkinson's disease. Additionally, higher tissue factor levels were found in plaques of proteins (amyloid-ß 1-42) found in Alzheimer's disease. Thus, tissue factor could be a promising biomarker candidate for neurodegenerative diseases. We analyzed the concentration of this protein in the cerebrospinal fluid of 479 patients with Parkinson's disease, 16 control participants, and 67 patients with dementia with Lewy bodies, a sub-type of Parkinson's disease with exceptionally high levels of α-Synuclein in the brain. Our findings showed the lowest levels of tissue factor in patients with dementia with Lewy bodies, followed by those with typical Parkinson's disease, and the highest levels in controls. Additionally, older patients had higher tissue factor levels than younger patients, and levels were lower in male patients compared to female patients. Thus, measuring tissue factor levels could help in diagnosing Parkinson's disease. Further studies, especially with larger control groups, are needed to confirm these results. Additionally, exploring the connections between blood coagulation and Parkinson's disease could improve our understanding of the disease's mechanisms, potentially leading to new pharmaceutical developments.

Enhanced venous thrombosis and hypercoagulability in murine and human metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Patients with metabolic dysfunction-associated steatohepatitis (MASH) are at an increased risk of developing venous thromboembolic events, including deep vein thrombosis (DVT). To date, the study of DVT in MASH has been hampered by the lack of reliable models that mimic the pathologic aspects of human disease. OBJECTIVES: To evaluate DVT severity and hypercoagulability in murine and human MASH. METHODS: Transcriptional changes in the liver, plasma markers of coagulation, and DVT severity were evaluated in mice fed a standard chow diet or a high-fructose, high-fat, and high-cholesterol MASH diet for 24 weeks. Plasma analyses of coagulation markers and thrombin generation assays were performed in a well-characterized cohort of patients with or without MASH. RESULTS: Mice fed the MASH diet developed steatohepatitis and fibrosis, mimicking human MASH. Liver RNA sequencing revealed a significant upregulation of pathways related to inflammation and coagulation concomitant with increased levels of plasma coagulation markers including increased prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor-1 levels, and endothelin 1. MASH exacerbated DVT severity in mice, as evidenced by increased thrombus weight and higher thrombosis incidence (15/15 vs 11/15 in controls, P = .0317). Higher endothelin 1 release and increased apoptosis were found in endothelial cells stimulated with supernatants of palmitate-stimulated HepG2 cells. Patients with MASH exhibited increased levels of plasma coagulation markers and delayed thrombin generation. CONCLUSION: We report enhanced DVT severity and hypercoagulability, both in murine and human MASH. Our model of MASH-DVT can facilitate a better understanding of the fundamental mechanisms leading to increased venous thromboembolic events in patients with MASH.

A Serendipitous Finding of Coagulation Factor VII Deficiency in Two Asymptomatic Patients.

Congenital Factor VII (FVII) deficiency is a rare autosomal recessive disorder with a prevalence of approximately 1:500,000. It plays a crucial role in initiating coagulation by activating Factors IX and X. Diagnosis typically involves prolonged prothrombin time (PT) and varies widely in clinical presentation. Management includes fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), and recombinant activated FVII (rFVIIa), with rFVIIa often preferred due to its safety and efficacy. We present two pediatric cases: a five-year-old boy with a prolonged PT at 55% and FVII levels at 25.1%, and a two-year-old boy with a PT at 24% and FVII levels at 4.6%. Both cases highlight the importance of thorough hemostatic evaluation and tailored management strategies in FVII deficiency.

Synergistic Procoagulant Mechanism and Application of Kaolin-Zeolite Composite Hemostat for Effective Hemorrhage Control.

Achieving timely and effective hemorrhage control is imperative for the survival of individuals with severe bleeding. Hemostatic materials, by enhancing the natural cell-based coagulation response, are essential tools in modern and military medical practice for controlling bleeding, especially in emergency and surgical settings. Here, we report a new type of composite hemostatic material with two different aluminosilicate-based components, kaolin and zeolite, which synergistically work together in different stages of the coagulation cascade reactions. Kaolin can effectively activate the clotting factor FXII in the early stage, and zeolite can accumulate and assemble FXa and FVa on its surface and thereafter lead to the formation of highly active thrombin in the later stage. The synergistic action mechanism between kaolin and zeolite significantly boosts the levels of FXIIa and FXa, and it also greatly enhances plateau thrombin activity. For practical application, a kaolin-modified zeolite gauze is fabricated, and it demonstrates excellent hemostatic effectiveness. Compared to the combat gauze currently used in front-line treatment, it reduces blood loss by 75% and shortens hemostasis time by 33% in a rabbit femoral artery injury model. In addition, this kaolin-zeolite gauze has no heat release problem and a nearly zero particle shedding rate, which greatly decreases the safety risk compared to current commercial inorganic-based hemostatic gauzes.