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Inhibitors develop in many patients with hemophilia who receive recombinant factor VIII. Prophylaxis with emicizumab, an antibody that functionally replaces factor VIII in the clotting pathway, reduced the rate of bleeding events among patients with hemophilia with inhibitors.

Rapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures. In a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (≤1·3 at 0·5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than −10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101. 181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 14·3%, 95% CI 2·8–25·8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 45·3%, 95% CI 31·9–56·4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients). 4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures. CSL Behring.

Thrombin generation (TG) is reduced after cardiac surgery using cardiopulmonary bypass (CPB), contributing to coagulopathy and bleeding. Plasma transfusion or four-factor prothrombin complex concentrate (PCC) are commonly used to treat coagulopathic bleeding after CPB without knowledge of how each may restore TG. To determine the effect of PCC infusion on restoration of thrombin generation compared with plasma transfusion, we performed a laboratory-based secondary analysis of a randomized, controlled trial of adult patients undergoing cardiac surgery to assess efficacy and safety of 4 F-PCC versus plasma for treatment of perioperative coagulopathic bleeding after CPB. Participants were randomized to receive either PCC (15 IU/kg) or plasma (10–15 ml/kg) after separation from CPB. Participant blood samples were obtained at pre-specified serial timepoints, with laboratory assays for TG and factor levels subsequently performed. The primary outcome was change in thrombin generation (TG) parameters after each randomized treatment through postoperative day 5. Secondary outcomes included serially derived clotting factor levels. Of 100 randomized participants, 99 were included in this laboratory analysis (PCC group, N  = 51; plasma group, N  = 48). After treatment, participants in the PCC group compared with those in the plasma group showed higher endogenous thrombin potential (ETP, Median, Interquartile range, IQR: 688 [371–1069] vs. 1088 [550–1691] nM minutes, P  = 0.01), a greater increase din ETP ( P  = 0.002) and peak TG ( P  = 0.01) in the timepoints between heparin reversal and after treatment administration. Both groups demonstrated similar values in all TG assays by postoperative day 1 ( P  > 0.05). The PCC group also demonstrated higher levels of proteins C, S, and Factors II, VII, IX and X, early after treatment ( P  < 0.001 for all comparisons). Antithrombin levels were initially higher in the plasma group after treatment (Median, IQR: 66% [61-71%] vs. 56% [51-65%], P  = 0.002) but differences did not persist beyond postoperative day 3. In this laboratory analysis from a recent randomized trial in adult cardiac surgery, PCC administration restored thrombin generation more rapidly than plasma in the early postoperative period without laboratory evidence of hypercoagulability. ClinicalTrials.gov identifier: NCT02557672 [1]. Key points Question How does prothrombin complex concentrate (PCC) compare with plasma to restore thrombin generation (TG) in patients with coagulopathic bleeding after cardiopulmonary bypass? Findings In this subanalysis of a randomized clinical trial in 99 adult cardiac surgical patients, TG was restored more rapidly in the PCC group compared with the plasma group after treatment: endogenous thrombin potential (PCC, 688 [371–1069] vs. plasma, 1088 [550–1691], P  = 0.01nM minutes). Both groups displayed similar post-treatment TG by postoperative day one. Meaning These results support PCC administration to restore TG while avoiding acquired hypercoagulability in the early period after cardiac surgery.

haemophilia is an inherited bleeding disorder caused by a deficiency in one of the blood coagulation factors. For people affected by severe haemophilia, the deficiency can cause spontaneous internal bleeding. Most young people with severe haemophilia in the UK follow a preventative treatment regimen (prophylaxis) consisting of several intravenous injections of factor concentrate each week. There is good evidence that prophylaxis reduces bleeds whilst also improving quality of life. However, levels of adherence among young people with haemophilia reported in the existing literature vary widely and are predominately based on estimations made by healthcare professionals and parents. Additionally, drivers of (non)adherence among young people specifically have not been evidenced. to assess self-reported adherence among young people with haemophilia, provide evidence of psychosocial predictors of adherence, and to establish the associations between non-adherence and number of bleeds and hospital visits. 91 participants were recruited during outpatient appointments in 13 haemophilia centres across England and Wales, and invited to complete a questionnaire assessing self-reported adherence (VERITAS-Pro), Haemophilia-related pain and impact of pain, Illness Perceptions, Beliefs about Medications, Self-efficacy, Outcome expectations, Positive and Negative Affect, and Social support. Number of hospital visits and bleeds during the previous six months were collected from medical files. Of 78 participants with complete data, just 18% had scores indicating non-adherence. Psychosocial predictors differed between intentional (skipping) and un-intentional (forgetting) non-adherence. Overall, however, better adherence was reported where participants perceived the need for prophylaxis was greater than their concern over taking it as well as having a positive expectancy of its effectiveness, good social support and a stronger emotional reaction to having haemophilia. The findings indicate that adherence is generally good, and that assessing illness and treatment beliefs, social support and outcome expectations may play a valuable role in identifying which individuals are at risk of non-adherence. Interventions aimed at improving adherence should particularly consider improving social support, reducing patients' concerns about prophylaxis, increasing their belief in the necessity of prophylaxis, and increasing positive outcome expectations.

IntroductionReduced thrombin generation is an important component of post cardiopulmonary bypass (CPB) coagulopathy. To replenish coagulation factors and enhance thrombin generation in bleeding surgical patients, frozen plasma (FP) and four-factor prothrombin complex concentrate (4F-PCC) are used. However, the efficacy–safety balance of 4F-PCC relative to FP in cardiac surgery is unconfirmed.Methods and analysisLEX-211 (FARES-II) is an active-control, randomised, phase 3 study comparing two coagulation factor replacement therapies in bleeding adult cardiac surgical patients at 12 hospitals in Canada and the USA. The primary objective is to determine whether 4F-PCC (Octaplex/Balfaxar, Octapharma) is clinically non-inferior to FP for haemostatic effectiveness. Inclusion criteria are any index (elective or non-elective) cardiac surgery employing CPB and coagulation factor replacement with 4F-PCC or FP ordered in the operating room for bleeding management. Patients will be randomised to receive 1500 or 2000 international units of 4F-PCC or 3 or 4 units of FP, depending on body weight. The primary endpoint of haemostatic treatment response is ‘effective’ if no additional haemostatic intervention is required from 60 min to 24 hours after the first initiation of 4F-PCC or FP; or ‘ineffective’ if any other haemostatic intervention (including a second dose of study drug) is required. An estimated 410 evaluable patients will be required to demonstrate non-inferiority (one-sided α of 0.025, power ≥90%, non-inferiority margin 0.10). Secondary outcomes include transfusions, bleeding-related clinical endpoints, coagulation parameters and safety.Ethics and disseminationThe trial has been approved by the institutional review boards of all participating centres. Trial completion is anticipated at the end of 2024, and results will be disseminated via publications in peer-reviewed journals and conference presentations in 2025. The results will advance our understanding of coagulation management in bleeding surgical patients, potentially reducing the need for allogeneic blood products and improving outcomes in surgical patients.Trial registration numberNCT05523297.

ObjectiveTo explore whether prothrombin complex concentrate (PCC) is not inferior to fresh frozen plasma (FFP) with regard to reducing perioperative blood loss in patients undergoing cardiac surgery under cardiopulmonary bypass (CPB).SettingFu Wai Hospital, and Peking Union Medical College Hospital in China.ParticipantsPatients undergoing elective coronary artery bypass grafting, valve replacement or valvuloplasty under CPB, between 18 and 80 years old, will be included.DesignThis study is a non-inferiority, randomised controlled clinical trial. A total of 594 subjects will be randomly assigned to two groups (group PCC and group FFP) and given corresponding interventions when at least one of the following criteria is met: (1) international normalised ratio >1.7 measured 20 min after CPB, (2) prolonged prothrombin time or activated partial thromboplastin time (>1.5 times baseline) measured 20 min after CPB and (3) excessive bleeding observed. 4-factor PCC (15 IU/kg) and FFP (10 mL/kg) will be given to group PCC and group FFP, respectively. Preoperative management, anaesthetic and surgical techniques will be standardised for both groups.Primary and secondary outcome measuresThe primary outcome is the volume of blood loss during and within 24 hours after surgery. The secondary outcomes include (1) the total units of allogeneic red blood cells transfused during and within 7 days after surgery, (2) re-exploration due to postoperative bleeding within 7 days after surgery, (3) adverse events and serious adverse events within 30 days after surgery and (4) length of intensive care unit stay and hospital stay.Trial registration numberRegistered under NCT04244981 at ClinicalTrials.gov on 28 January 2020, https://clinicaltrials.gov/ct2/show/NCT04244981?cond=NCT04244981&draw=2&rank=1.Ethics and disseminationThis study has been approved by the Institutional Review Board of Peking Union Medical College Hospital (ZS-2242).

Background Fresh frozen plasma (FFP) is the accepted standard treatment for clotting factor replacement in bleeding patients during or immediately after cardiac surgery. In the United Kingdom prothrombin complex concentrate (PCC) is not licensed in this setting, although it is being used in Europe because it has a higher concentration of clotting factor levels, and it can be administered rapidly and in small volume, resulting in less volume overload during cardiac surgery. Methods PROPHESY is a pragmatic, single-centre, open-label, randomised, controlled pilot trial that will assess whether it is feasible to perform a large trial in the future that will compare PCC versus FFP in patients who are bleeding (not on warfarin) and who require blood transfusion. Over a 15-month period, 50 patients will be randomised to PCC versus FFP if they develop active bleeding within 24 h of cardiac surgery and for whom the clinician has decided to administer FFP for treatment of bleeding. Standard laboratory and point-of-care assessments will be performed as per routine practice, and additional research blood samples will be taken at three time points to assess haemostasis. Subjects will be assessed daily up to hospital discharge or 30 days or death (whichever occurs first) and will be seen in follow-up for 90 days after surgery to assess for thromboembolic complications and hospital re-admission since discharge. Quality-of-life assessment will be performed pre-surgery and at 90 days post-surgery. We will also perform qualitative research with clinical experts and patients to explore the understanding of and experience with the interventions, as well as adherence to study procedures and protocol. Discussion There have been no randomised controlled trials that have compared the safety and efficacy of FFP versus PCC in cardiac surgery patients who are bleeding. This pilot study will assess if individual components of a large trial are deliverable to assess the safety and efficacy of the two blood products in the future. Trial registration EudraCT, 2018-003041-41; ClinicalTrials.gov, NCT03715348 . Registered on 29 July 2018.

Background In patients with cirrhosis, the synthesis of coagulation factors can fall short, reflected by a prolonged prothrombin time. Although anticoagulants factors are decreased as well, blood loss during orthotopic liver transplantation can still be excessive. Blood loss during orthotopic liver transplantation is currently managed by transfusion of red blood cell concentrates, platelet concentrates, fresh frozen plasma, and fibrinogen concentrate. Transfusion of these products may paradoxically result in an increased bleeding tendency due to aggravated portal hypertension. The hemostatic effect of these products may therefore be overshadowed by bleeding complications due to volume overload. In contrast to these transfusion products, prothrombin complex concentrate is a low-volume highly purified concentrate, containing the four vitamin K dependent coagulation factors. Previous studies have suggested that administration of prothrombin complex concentrate is an effective method to normalize a prolonged prothrombin time in patients with liver cirrhosis. We aim to investigate whether the pre-operative administration of prothrombin complex concentrate in patients undergoing liver transplantation for end-stage liver cirrhosis, is a safe and effective method to reduce perioperative blood loss and transfusion requirements. Methods/Design This is a double blind, multicenter, placebo-controlled randomized trial. Cirrhotic patients with a prolonged INR (≥1.5) undergoing liver transplantation will be randomized between placebo or prothrombin complex concentrate administration prior to surgery. Demographic, surgical and transfusion data will be recorded. The primary outcome of this study is RBC transfusion requirements. Discussion Patients with advanced cirrhosis have reduced plasma levels of both pro- and anticoagulant coagulation proteins. Prothrombin complex concentrate is a low-volume plasma product that contains both procoagulant and anticoagulant proteins and transfusion will not affect the volume status prior to the surgical procedure. We hypothesize that administration of prothrombin complex concentrate will result in a reduction of perioperative blood loss and transfusion requirements. Theoretically, the administration of prothrombin complex concentrate may be associated with a higher risk of thromboembolic complications. Therefore, thromboembolic complications are an important secondary endpoint and the occurrence of this type of complication will be closely monitored during the study. Trial registration The trial is registered at http://www.trialregister.nl with number NTR3174 . This registry is accepted by the ICMJE.

OBJECTIVELymphoceles are among the most common postoperative complications of pelvic lymphadenectomy (PL), with a reported incidence of 1% to 50%. Symptoms are pelvic pain, leg edema, gastrointestinal obstruction, obstructive uropathy, and deep vein thrombosis, and severe complications such as sepsis and lymphatic fistula formation. After laparoscopic PL, we tested the prevention of lymphoceles using collagen patch coated with the human coagulation factors (TachoSil, Nycomed International Management GmbH, Zurich, Switzerland) on 55 patients with endometrial cancer stages IB to II who had undergone laparoscopy. MATERIALS AND METHODSThe authors divided the patients into 2 laparoscopy groupsPL plus TachoSil (group 126 patients) and PL without TachoSil in a control group (group 229 patients), as historical cohort of patients who underwent PL between 2010 and 2012. We collected surgical parameters, and the patients underwent ultrasound examination on postoperative days 7, 14, and 28. The main outcome measures were the development of symptomatic or asymptomatic lymphoceles, the need for further surgical intervention, as adverse effect of surgery, and the drainage volume and duration. RESULTSThe same number of lymph nodes in both groups was removed; group 1 showed a lower drainage volume. Lymphoceles developed in 5 patients in group 1 and in 15 patients in group 2; of these, only 2 patients were symptomatic in group 1 and 5 patients were symptomatic in group 2, without statistical difference and no percutaneous drainage request. CONCLUSIONSIn this preliminary investigation, the intraoperative laparoscopy application of TachoSil seems to reduce the rate of postoperative lymphoceles after PL, providing a useful additional treatment option for reducing drainage volume and preventing lymphocele development after PL.

Acute blood loss in trauma requires quick identification and action to restore circulating volume and save the patient. Massive transfusion protocols (MTPs) have become standard at Trauma Centers, in order to rapidly deliver blood products to bleeding patients. This literature review presents current standards of transfusion ratios, as well as insights into adjuncts during massive transfusions. PubMED was searched for articles from 2005 to 2020 on MTPs, the article were assessed for single vs. multi-institutional, mechanism of injury, type of MTP, timing in which blood products should be administered, timing of delivery of blood products to trauma bay, pre-hospital treatment and adjuncts, and outcomes. Eleven studies addressed transfusion ratios. Seven studies looked at timing of blood products. Nine studies addressed MTP pre-hospital treatment and adjuncts. Prior to 2015, studies supported the benefits of a balanced transfusion ratio, which was then confirmed by the PROPPR randomized controlled trial. The shorter the time to blood product delivery the better the outcomes. New advances in technology have allowed us to measure different patterns of coagulation, allowing more individualized approaches to the bleeding patient. Current massive transfusion protocols should utilize between 1:1:1 and 1:1:2 ratios of the 3 main products; plasma, platelets, and red blood cells. Massive transfusion protocols are effective in decreasing mortality. Better resuscitation efforts were seen when blood products were readily available in the trauma bay when the patient arrived and the faster the replacement of blood, the better the outcomes.