Bleeding Disorder

Massive transfusion, defined as the transfusion of total body blood volume (10 units of erythrocyte suspension or 8 units and above in some definitions) or more within 24 hours, remains one of the greatest challenges for the anesthetist. Despite all the medical advances, in cardiac surgery, obstetric surgery, trauma-orthopedic surgery, neurosurgery, major gastrointestinal-genitor-urinary system surgeries, which are among the major bleeding surgeries, massive hemorrhage continues to be an important mortality and morbidity factor. In addition to major surgeries with known expected bleeding, massive transfusion requirement may arise with any undesirable intraoperative event. While the process is easier to manage with proper preparation and an organized procedure in expected bleeding, a chaotic response may be encountered in unexpected situations. Special protocols for each division have been developed by clinicians to manage this critical process, and work continues on these protocols to improve the outcome. Massive bleeding management mainly focuses on transfusion and fluid resuscitation. Regardless of the situation requiring massive transfusion, the goals of treatment in massive bleeding are to maintain organ perfusion pressure and oxygen delivery, immediately stop bleeding and coagulopathy. While these goals can be achieved through resuscitation with blood products and surgical intervention, the triad of hypothermia, acidosis, and coagulopathy that occurs with the process contributes to increased morbidity and mortality in such scenarios. The literature on major bleeding from trauma has highlighted some issues contributed to improved clinical outcomes such as, damage-controlled resuscitation, including timely initiation of transfusion, early use of clotting factors, minimizing the use of crystalloids. The landmark PROPPR study found that in the resuscitation of trauma patients, a 1:1:1 ratio of FFP:platelet:ES transfusion during massive bleeding resulted in hemostasis in a greater number of patients (86% versus 78%) compared to a 1:1:2 ratio, additionally, they found fewer deaths from bleeding within 24 hours (14.6% versus 9.2%). However, no significant difference was found in 24-hour or 30-day overall mortality. In a systematic review evaluating retrospective data on transfusions for obstetric bleeding, it was shown that the amount of FFP administered was greater than the amount of ES. Since the mortality rate from massive obstetric hemorrhage is lower than that of traumatic hemorrhage, it is difficult to prospectively evaluate the effects of massive transfusion. This review recommends a FFP/ES ratio of ≥1, with the results of all retrospective studies described on transfusions for obstetric hemorrhage. Studies in cardiac surgery also suggest that higher rates of FFP/ES transfusion are associated with better outcomes in patients with massive bleeding. In general, the high ratio of transfused FFP to ES in bleeding surgeries requiring massive transfusion has been associated with positive results. FFP contains all coagulation factors and fibrinogen, as well as restoring the volume deficit that occurs with major bleeding, which reduces the crystalloid requirement and prevents extra dilution of coagulation factors. Fibrinogen is the clotting factor whose level drops the fastest during bleeding. Fibrinogen is a unique coagulation building block that plays a role in both primary and secondary hemostasis. Based on the results of the RETIC trial, the effectiveness of fibrinogen supplementation in limiting blood loss appears to be strongly dependent on timing of fibrinogen administration and increasing levels above 200 mg·dL-1. The 5th Edition of the European Guidelines for the Management of Major Posttraumatic Hemorrhage and Coagulopathy recommends early and repeated monitoring of fibrinogen concentrations and/or polymerization and rapid correction of deficiencies. Accordingly, 3-4 g of fibrinogen concentrate or 15-20 units of cryoprecipitate is recommended as an initial dose in massive bleeding. While RETIC stands out as a randomized controlled prospective study on the role of fibrinogen in massive transfusion in trauma patients, there are few cardiac and transplantation surgery studies in various types of research. Regardless of the cause, early restoration of fibrinogen levels in case of massive bleeding reduces transfusion requirement by preventing ongoing bleeding. In the FIBRES study, which evaluated the efficacy of fibrinogen concentrate in cardiac surgery patients with bleeding, it was emphasized that fibrinogen concentrate was not inferior to cryoprecipitate, easy to apply, and a predictable robust effect. Further it is hypothesized that early replacement of fibrinogen in severely injured trauma patients may improve outcomes. However, there is little evidence to support this and, in addition, little evidence to support or refute the effects of cryoprecipitate or fibrinogen concentrate for fibrinogen replacement. Fibrinogen supplementation as cryoprecipitate within the first 90 minutes of major bleeding was considered feasable in a randomized controlled trial. As a matter of fact, in the E-FIT 1 study conducted with a very small number of patients, it was found that it is not effective to administer fibrinogen in the first 45 minutes. On the other hand, there is not only fibrinogen in the scene, results of the FIIRST 2 study comparing the use of combinations of fibrinogen concentrate and prothrombin complex concentrate (PCC) in hemorrhagic trauma patients are also eagerly awaited. Ideally, fibrinogen concentrate and/or cryoprecipitate are used in fibrinogen replacement, and FFP is used as a weaker fibrinogen source. During massive transfusion, repeated doses of FFP/cryoprecipitate/fibrinogen concentrate are used. All of these blood products have different amounts of fibrinogen content. In many previous studies, the formula for improving the results was investigated by looking at transfusion rates such as FFP/ES, ES/platelet, FFP/ES/Platelet. In the light of this information, our hypothesis is that mortality and morbidity can be reduced with a high rate of total fibrinogen from various sources. In order to combine the fibrinogen amounts from different sources under a single name, we determined an equalization according to the fibrinogen amounts they contain. In accordance with this formula, it was considered to investigate the effect of the overall ADEF/ES ratio on mortality and outcome in massive transfusion cases that fit the definitions. The primary aim of this study to determine the effect of the ratio of total fibrinogen to erythrocyte suspension (ADE Fibrinogen/ES) transfused at 24 hours on the composite outcome, which includes 30-day all-cause mortality, bleeding-specific mortality, and the Katz index of independence in activities of daily living (scored 0, 1, 2- i.e. extremely dependent to highly dependent). The secondary aim of this study to determine the relationship of ADEF/ES ratio with other parameters: * Postoperative 24-hour and 3-month all-cause and bleeding specific mortality * Morbidity(\>90 day) Morbidity defined as events continuing after 90 days (ICD code 9) * thrombotic event (DVT, Pulmonary Embolism, DIC) * respiratory event (ventilator-associated pneumonia, other surgery-related respiratory complications) * ischemic event (Myocardial infarction, TIA, Cerebrovascular accident) * infection (sepsis, surgical site infection, any drug-resistant infection) * permanent kidney damage * Mortality predictors Mortality predictors as defined ; * Age * Gender * ASA score * Glasgow coma scale * Charlson Comorbidity index * Euroscore II * TASH score * Shock index * ISTH (International Society on Thrombosis and Haemostasis) score * ISS score * AC SURGICAL RISK CALCULATOR * History of antiplatelet-anticoagulant and ACEI or ARBs drug use * Emergency surgery * Temperature * Surgery specific details (Type of surgery, Duration of surgery periods, cement use etc\] * Intraoperative Vasopressor-inotropic medicine Requirement * Laboratory data over time \- when statistic testing mortality the data will be adjusted for these predicting/contributing factors * Complications Complications as defined; \--- Cardiac complications * Arrest * New developed unstable Arrhythmia * MI * KKY * Aortic dissection \--- Kidney complications * AKI I/II/III/IV (defined by KDIGO Criteria) * CRRT (temporary) * Continuous dialysis/CRF \--- Lung complications * Pulmonary edema * Pneumothorax * Pleural effusion * ARDS/respiratory failure * Bronchospasm * Aspiration pneumonitis \--- Neurological complications * Ischemic cerebral events * Hemorrhagic cerebral events (non-traumatic) * Permanent sequelae * TIA * Seizure \--- Infective complications * Pneumonia * Mediastinitis * Meningitis * Urinary tract infection * Wound site infection (Surgical Site Infections) * Catheter location infection * Sepsis \--- Thrombotic complications * Deep vein thrombosis * Pulmonary embolism * Mesentery thromboembolism * Stroke * Other * MODS/SIRS * MT Complications * Hematological Complications * Hemolytic rxns (Acute/delayed) * Febrile non-hemolytic reactions * DIC * Allergic reactions * TRALI (transfusion related acute lung injury) * TRAHI (transfusion related acute hepatic injury) * TACO (transfusion assoc. circulatory overload) * Abdominal compartment syndrome \--- Ischemic hepatitis, shock liver * Length of stay in the ICU Length of stay in the hospital * Functional state at discharge (can perform daily activities, can perform daily activities with assistance, completely in need of help) * All cause and bleeding specific mortality- Surgery specific postoperative 24-hour, 30 day and 3-month * Katz index of independence in activities of daily living (0,1,2 bad and 5,6 good scores)- Surgery specific postoperative 24-hour, 30 day and 3-month * Tranexamic acid use and mortality relationship * Initial(admission) plasma fibrinogen level and amount of bleeding Initial(admission) plasma fibrinogen level and amount of ADEF

The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of NXT007 prophylaxis compared with emicizumab prophylaxis in people age 12 years and older with severe or moderate congenital hemophilia A without factor VIII (FVIII) inhibitors or with hemophilia A of any severity (severe, moderate, and mild) with FVIII inhibitors.

The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of NXT007 prophylaxis compared with Factor VIII (FVIII) prophylaxis in participants with severe or moderate congenital hemophilia A without inhibitors. The study will include people aged ≥12 years old with severe or moderate congenital hemophilia A without inhibitors on previous FVIII prophylaxis treatment.

The GENESIS study is a multicenter, prospective, non-interventional, clinical study with a target of 12,000 subjects and an anticipated total duration of 36 months. The aim of study GENESIS is to provide a pilot map of HLA genetic variation in the Greek population in order to be used in medical research and for possible clinical applications (evaluation of possible correlations with selected underlying diseases). During the study, each subject will conduct one visit to the participating cite, in which they will provide: 1. Demographic information \[i.e. date of birth, gender, race, ancestry (including information about the subject's grandparents' birthplace), height, weight\], 2. Other information about smoking/vaping, alcohol consumption, arterial blood pressure, diagnosed diseases (if any), current treatments (if any), and 3. Recent (up to 12 months prior to sample collection) results if/when are available from clinical lab tests such as blood count (Hct, Hb, RBC, WBC, PLT count), including a metabolic panel, liver enzymes and biochemical parameters (Glu, HbA1c, TC, TG, LDL-C, HDL-C, ALT, AST, ALP, γGT, bilirubin, LDH, insulin, C-peptide). Upon completion of the data registry, two buccal swabs will be collected per subject and they will be stored at ALTP premises until their shipment to Galatea.Bio. All buccal swab samples will be subjected to genetic material (DNA) extraction. The DNA samples will be further proceeded for HLA genotyping analysis. A follow up analysis will be performed in selected DNA samples via full low-pass whole genome sequencing (LP-WGS), which aims to further investigate the association between the HLA region and autoimmune diseases. Upon completion of the analysis, an individualized ancestry report will be securely made available to all study subjects which they can access, as and if they elect to.

The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called marstacimab) for the potential treatment of hemophilia in pediatric patients. This study will enroll pediatric participants from ages 1 to 17 years in a sequential manner. The study will open enrollment to adolescent participants aged 12 to 17 years first. Then children aged 6 to 11 years will be permitted to enroll. Lastly, children aged 1 to 5 years will be permitted to enroll. This study will enroll participants who: * have severe Hemophilia A or moderately severe to severe Hemophilia B (with or without inhibitors) * have accurate historical records documenting all factor VIII, factor IX, or bypass agent infusions and hemophilia bleed events for at least 1 year prior to entering the study * if a non-inhibitor patient, must be on a stable routine prophylaxis regimen with factor VIII or factor IX replacement products for at least 12 months prior to study entry * if an inhibitor patient, must be on an on-demand bypass treatment regimen during the 12 months prior to study entry All participants in this study will receive marstacimab to use prophylactically. Marstacimab will be given once a week as a subcutaneous (under the skin) shot. The first dose of marstacimab will be given at the study site by the study site staff. During the 12-month treatment period, weekly doses of marstacimab can be given at home, or if preferred, the doses may be given by the study site staff. To help us determine if the study medicine is safe and effective, we will compare participant experiences when they are taking the study medicine to a historical period when they were not. Researchers want to see if the study medicine works to prevent the bleeding episodes commonly experienced by patients with Hemophilia. Participants will be in this study for about 14 months (approximately 1 month in a Screening period, 12 months receiving treatment, and 1 month in a follow-up period) during which they will visit the study site at least 10 times. If preferred, and if local regulations allow it, 2 of the study visits can be completed at the participant's home instead of at the study site. There will also be 6 scheduled telephone calls approximately every 2 months.

Primary immune thrombocytopenia (ITP) is a condition where the immune system mistakenly destroys platelets, which are cells that help stop bleeding. This leads to a lower number of platelets, making it easier to bruise or bleed. The main aim of this study is to check how safe mezagitamab is and how well it is tolerated by adults with chronic primary ITP, if given over a longer time. Other aims are to learn how effective treatment with mezagitamab is and how the body processes it (called pharmacokinetics or PK) over a longer time. Participants of the following previous mezagitamab studies will be invited to join this continuation study: TAK-079-3002 and TAK-079-1004. In this continuation study, participants will receive mezagitamab when certain protocol criteria are met. During the study, participants will visit their study clinic several times.

Principal Investigators: The principal investigators (PIs) will be transplant physicians at all participating U.S. transplant centers. Study Design: This study is an access and distribution protocol for unlicensed cryopreserved cord blood units (CBUs) in pediatric and adult patients with hematologic malignancies and other indications. Primary Objective: The primary objective of this study is to examine the incidence of neutrophil recovery of ≥500/mm3 after cord blood transplantation in a multi-institution setting using CBUs that are not Food and Drug Administration (FDA) licensed. Secondary Objectives: In patients receiving a non-licensed CBU: * Assess incidence of transmission of infection * Assess incidence of serious infusion reaction * Determine 1 year overall survival after cord blood transplantation * Assess cumulative incidence of acute graft vs. host disease (GVHD) grades II to IV and grades III to IV * Assess cumulative incidence of chronic GVHD * Determine platelet engraftment of \>20,000 mcL and \>50,000 mcL

The EMPOWER trial is a pilot multi-center, placebo-controlled (normal saline), double-blind (patient and outcome assessor), crossover, 2-year randomized trial in female outpatients with von Willebrand disease (VWD) and heavy menstrual bleeding to determine trial feasibility and viability, and explore assay sensitivity of the proposed efficacy clinical outcomes for a definitive randomized controlled trial. For the first treatment period, patients will be randomized to receive either plasma derived von Willebrand factor:Factor VIII (pdVWF:FVIII) concentrate (plus standard of care) or placebo (plus standard of care) for VWD-associated heavy menstrual bleeding for 4 cycles, crossing over to the comparator treatment during the second treatment period. The first treatment period will be followed by a 1 cycle washout period when no study-based treatment will be delivered. The main purpose of the pilot will be to evaluate viability and feasibility of the trial design, as well as to explore assay sensitivity to inform determination of the primary efficacy outcome for the definitive randomized trial which will evaluate the effect of prophylaxis with pdVWF:FVIII concentrate compared with placebo on HMB in women with VWD. A secondary objective is to conduct a preliminary assessment of the effect on clinical outcomes of 2-3 doses of prophylaxis with pdVWF:FVIII concentrate when provided on the first 4 days of menstruation compared with placebo.

This study will test how different doses of study medicine (Inno8) work in the bodies of people with haemophilia A. The purpose of the study is to see if Inno8 is safe to use for people with haemophilia A. The study medicine is a new medicine that cannot yet be prescribed by doctors. The study will last for about 11 weeks.

The purpose of this study is to test a new medicine called Inno8. The study will test how eating and drinking before and after taking Inno8 affects how well it is absorbed in the stomach. The study consists of four arms. Participants will take the study medicine after an overnight fast. How long participants will need to fast depends on which group participants are in. After taking the study medicine, participants will need to fast again. The study will last for up to 9.5 weeks.