Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection. OBJECTIVES: To present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial. METHODS: GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs). RESULTS: At week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment. CONCLUSION: Hemostatic efficacy was maintained, and safety remained unchanged from previous years.

Venenos de serpentes do gênero Bothrops: impacto da glicosilação na complexidade dos proteomas e função de toxinas / Bothrops snake venoms: impact of glycosylation on the complexity of proteomes and toxins function

A variabilidade estrutural é uma característica das proteínas de venenos de serpentes, e a glicosilação é uma das principais modificações pós-traducionais que contribui para a diversificação de seus proteomas. Recentes estudos de nosso grupo demonstraram que venenos do gênero Bothrops são marcadamente definidos pelo seu conteúdo de glicoproteínas, e que a maioria das estruturas de N-glicanos dos tipos híbrido e complexo identificados em oito venenos deste gênero contêm unidades de ácido siálico. Em paralelo, em glicoproteínas do veneno de B. cotiara foi identificada a presença de uma estrutura de N-acetilglicosamina bissecada. Assim, com o objetivo de investigar a variação do conteúdo de glicoproteínas, assim como os mecanismos envolvidos na geração dos diferentes venenos de Bothrops, neste estudo foram analisados comparativamente os glicoproteomas de nove venenos do gênero Bothrops (B. atrox, B. cotiara, B. erythromelas, B. fonsecai, B. insularis, B. jararaca, B. jararacussu, B. moojeni e B. neuwiedi). As abordagens glicoproteômicas envolveram cromatografia de afinidade e ensaio de pull-down utilizando, respectivamente, as lectinas SNA (aglutinina de Sambucus nigra) e MAL I (lectina de Maackia amurensis), que mostram afinidade por unidades de ácido siálico nas posições, respectivamente, α2,6 e α2,3; e cromatografia de afinidade com a lectina PHA-E (eritroaglutinina de Phaseolus vulgaris), que reconhece N-acetilglicosamina bissecada. Ainda, eletroforese de proteínas, blot de lectina, e identificação de proteínas por espectrometria de massas foram empregadas para caracterizar os glicoproteomas. As lectinas geraram frações dos venenos enriquecidas de diferentes componentes, onde as principais classes de glicoproteínas identificadas foram metaloprotease, serinoprotease, e L-amino ácido oxidase, além de outras enzimas pouco abundantes nos venenos. Os diferentes conteúdos de proteínas reconhecidas por essas lectinas, com especificidades distintas, ressaltaram novos aspectos da variabilidade dos subproteomas de glicoproteínas desses venenos, dependendo da espécie. Ainda, considerando que metaloproteases e serinoproteases são componentes abundantes nesses venenos e fundamentais no quadro de envenenamento botrópico, e que estas enzimas contêm diversos sítios de glicosilação, o papel das unidades de ácido siálico na atividade proteolítica das mesmas foi avaliado. Assim, a remoção enzimática de ácido siálico (i) alterou o padrão de gelatinólise em zimografia da maioria dos venenos, (ii) diminuiu a atividade proteolítica de alguns venenos sobre o fibrinogênio e a atividade coagulante do plasma humano de todos os venenos, e (iii) alterou o perfil de hidrólise de proteínas plasmáticas pelo veneno de B. jararaca, indicando que este carboidrato pode desempenhar um papel na interação das proteases com seus substratos proteicos. Em contraste, o perfil da atividade amidolítica dos venenos não se alterou após a remoção de ácido siálico e incubação com o substrato Bz-Arg-pNA, indicando que ácido siálico não é essencial em N-glicanos de serinoproteases atuando sobre substratos não proteicos. Em conjunto, esses resultados expandem o conhecimento sobre a variabilidade de proteomas de venenos do gênero Bothrops e apontam a importância das cadeias de carboidratos contendo ácido siálico nas atividades enzimáticas das proteases desses venenos

Structural variability is a feature of snake venom proteins, and glycosylation is one of the main post-translational modifications that contributes to the diversification of venom proteomes. Recent studies by our group have shown that Bothrops venoms are markedly defined by their glycoprotein content, and that most hybrid and complex N-glycan structures identified in eight venoms of this genus contain sialic acid units. In parallel, the presence of a bisected N-acetylglucosamine structure was identified in B. cotiara venom glycoproteins. Thus, with the aim of investigating the variation in the content of glycoproteins, as well as the mechanisms involved in the generation of different Bothrops venoms, in this study the glycoproteomes of nine Bothrops venoms (B. atrox, B. cotiara, B. erythromelas, B. fonsecai, B. insularis, B. jararaca, B. jararacussu, B. moojeni e B. neuwiedi) were comparatively analyzed. The glycoproteomic approaches involved affinity chromatography and pulldown using, respectively, the lectins SNA (Sambucus nigra agglutinin) and MAL I (Maackia amurensis lectin), which show affinity for sialic acid units at positions, respectively, α2,6 and α2,3, and affinity chromatography with PHA-E (Phaseolus vulgaris erythroagglutinin), which recognizes bisected N-acetylglucosamine. In addition, protein electrophoresis, lectin blot, and protein identification by mass spectrometry were employed for glycoproteome characterization. The lectins generated venom fractions enriched with different components, where the main classes of glycoproteins identified were metalloprotease, serine protease, and L-amino acid oxidase, in addition to other low abundant enzymes. The different contents of proteins recognized by these lectins of distinct specificities highlighted new aspects of the variability of the glycoprotein subproteomes of these venoms, depending on the species. Furthermore, considering that metalloproteases and serine proteases are abundant components of these venoms and essential in Bothrops envenomation, and that these enzymes contain several glycosylation sites, the role of sialic acid units in their proteolytic activities was evaluated. Thus, enzymatic removal of sialic acid (i) altered the pattern of gelatinolysis in zymography of most venoms, (ii) decreased the proteolytic activity of some venoms on fibrinogen and the clotting activity of human plasma of all venoms, and (iii) altered the hydrolysis profile of plasma proteins by B. jararaca venom, indicating that this carbohydrate may play a role in the interaction of proteases with their protein substrates. In contrast, the profile of amidolytic activity of the venoms did not change after removal of sialic acid and incubation with the substrate Bz-Arg-pNA, indicating that sialic acid is not essential in N-glycans of serine proteases acting on small substrates. Together, these results expand the knowledge about the variability of proteomes of Bothrops venoms and point to the importance of carbohydrate chains containing sialic acid in the enzymatic activities of venom proteases

Management of Intracranial Hemorrhage in Patients with a Left Ventricular Assist Device: A Systematic Review and Meta-Analysis.

BACKGROUND: Intracranial hemorrhage (ICH) has been reported to occur in up to 23% of patients with left ventricular assist devices (LVADs). Currently, limited data exists to guide neurosurgical management strategies to optimize outcomes in patients with an LVAD who develop ICH. METHODS: A systematic review and meta-analysis of the literature was performed to evaluate the mortality rate in these patients following medical and/or surgical management and to evaluate antithrombotic reversal and resumption strategies after hemorrhage. RESULTS: 17 studies reporting on 3869 LVAD patients and 545 intracranial hemorrhages spanning investigative periods from 1996 to 2019 were included. The rate of ICH in LVAD patients was 10.6% (411/3869) with 58.6% (231/394) being intraparenchymal hemorrhage (IPH), 23.6% (93/394) subarachnoid hemorrhage (SAH), and 15.5% (61/394) subdural hemorrhage (SDH). Total mortality rates for surgical management 65.6% (40/61) differed from medical management at 45.2% (109/241). There was an increased relative risk of mortality (RR=1.45, 95% CI: 1.10-1.91, p = 0.01) for ICH patients undergoing surgical intervention. The hemorrhage subtype most frequently managed with anticoagulation reversal was IPH 81.8% (63/77), followed by SDH 52.2% (12/23), and SAH 39.1% (18/46). Mean number of days until antithrombotic resumption ranged from 6 to 10.5 days. CONCLUSION: Outcomes remain poor, specifically for those undergoing surgery. As experience with this population increases, prospective studies are warranted to contribute to management and prognostication .

Computer-based simulation to reduce EHR-related chemotherapy ordering errors.

BACKGROUND: The electronic health record (EHR) is a contributor to serious patient harm occurring within a sociotechnical system. Chemotherapy ordering is a high-risk task due to the complex nature of ordering workflows and potential detrimental effects if wrong chemotherapeutic doses are administered. Many chemotherapy ordering errors cannot be mitigated through systems-based changes due to the limited extent to which individual institutions are able to customize proprietary EHR software. We hypothesized that simulation-based training could improve providers' ability to identify and mitigate common chemotherapy ordering errors. METHODS: Pediatric hematology/oncology providers voluntarily participated in simulations using an EHR testing ("Playground") environment. The number of safety risks identified and mitigated by each provider at baseline was recorded. Risks were reviewed one-on-one after initial simulations and at a group "lunch-and-learn" session. At three-month follow-up, repeat simulations assessed for improvements in error identification and mitigation, and providers were surveyed about prevention of real-life safety events. RESULTS: The 8 participating providers identified and mitigated an average of 5.5 out of 10 safety risks during the initial simulation, compared 7.4 safety risks at the follow up simulation (p=0.030). Two of the providers (25%) reported preventing at least one real-world patient safety event in the clinical setting as a result of the initial training session. CONCLUSIONS: Simulation-based training may reduce providers' susceptibility to chemotherapy ordering safety vulnerabilities within the EHR. This approach may be used when systems-based EHR improvements are not feasible due to limited ability to customize local instances of proprietary EHR software.

Current perspective on fibrinogen concentrate in critical bleeding.

INTRODUCTION: . Massive hemorrhage continues to be a treatable cause of death. Its management varies from prefixed ratio-driven administration of blood components to goal-directed therapy based on point-of-care testing and administration of coagulation factor concentrates. AREAS COVERED: . We review the current role of fibrinogen concentrate (FC) for the management of massive hemorrhage, either administered without coagulation testing in life-threatening hemorrhage, or within an algorithm based on viscoelastic hemostatic assays and plasma fibrinogen level. We identified relevant guidelines, meta-analyzes, randomized controlled trials, and observational studies that included indications, dosage, and adverse effects of FC, especially thromboembolic events. EXPERT OPINION: . Moderate- to high-grade evidence supports the use of FC for the treatment of severe hemorrhage in trauma and cardiac surgery; a lower grade of evidence is available for its use in postpartum hemorrhage and end-stage liver disease. Pre-emptive FC administration in non-bleeding patients is not recommended. FC should be administered early, in a goal-directed manner, guided by early amplitude of clot firmness parameters (A5- or A10-FIBTEM) or hypofibrinogenemia. Further investigation is required into the early use of FC, as well as its potential advantages over cryoprecipitate, and whether or not its administration at high doses leads to a greater risk of adverse events.

Fibrinogen Concentrate as an Alternative to Cryoprecipitate in a Postcardiopulmonary Transfusion Algorithm in Infants Undergoing Cardiac Surgery: A Prospective Randomized Controlled Trial.

BACKGROUND: Infants undergoing cardiac surgery are at risk for bleeding and massive transfusion due to an immature coagulation system, complex surgeries, and cardiopulmonary bypass (CPB) effects. Hemodilution from CPB promotes an acquired hypofibrinogenemia that results in impaired fibrin formation, inadequate clot formation, and increased bleeding. In North America, the current standard of care to supplement fibrinogen is cryoprecipitate. An alternative option is the off-label use of fibrinogen concentrate (FC; RiaSTAP; CSL Behring, Marburg, Germany), a purified fibrinogen. Because perioperative allogenic transfusions are associated with increased morbidity and mortality, we sought to determine whether FC would be an acceptable alternative to cryoprecipitate in a post-CPB transfusion algorithm in infants undergoing open-heart surgery. METHODS: We randomized 60 infants (<12 months) undergoing nonemergent cardiac surgery with CPB at 2 tertiary care children's hospitals to receive either cryoprecipitate or FC in a post-CPB transfusion algorithm. Infants underwent a stratified randomization based on institution and surgical complexity. The primary outcome was the difference in number of intraoperative allogenic blood product transfusions. Secondary outcomes included 24-hour chest tube output (CTO), mechanical ventilation time, adverse events (AEs), intensive care unit (ICU) length of stay (LOS), hospital LOS, postoperative thrombosis, and death within 30 days of surgery. The primary analysis followed the intent-to-treat (ITT) principle and was performed using linear regression adjusted for institution and complexity of surgery. A per-protocol (PP) analysis was also performed. RESULTS: Between June 2016 and January 2018, we enrolled 60 patients with complete data available for 25 patients who received cryoprecipitate and 29 patients who received FC. Patients in the cryoprecipitate group (median age: 4 months [2-6 months]) received 5.5 (4.0-7.0) allogeneic blood units in the ITT analysis and 6.0 units (5.0-7.0 units) in the PP analysis. Patients in the FC group (median age: 4 months [2-5]) received 4 units (3.0-5.0 units) in the ITT analysis and 4.0 units (3.0-5.0 units) in the PP analysis. In the adjusted ITT analysis, the FC group received 1.79 units (95% confidence interval [CI], 0.64-2.93; P = .003) less than the cryoprecipitate group. In the adjusted PP analysis, the FC group received 2.67 units (95% CI, 1.75-3.59; P < .001) less than the cryoprecipitate group. There were no significant differences in secondary outcomes or AEs. CONCLUSIONS: Our findings suggest that FC may be considered as an alternative to cryoprecipitate for the treatment of hypofibrinogenemia in infants with bleeding after CPB. Although we found no significant differences between secondary outcomes or AEs, further studies are needed to assess safety.

A review of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery.

Oral anticoagulants, old and new, are effective therapies for prevention and treatment of venous thromboembolism and reduction of stroke risk in patients with atrial fibrillation. However, blocking elements of the clotting cascade carries an inherent risk of bleeding. Also, anticoagulated patients sometimes require urgent surgery or invasive procedures. This has led to the emergence of a body of scientific literature on the reversal of anticoagulation in these two settings. Traditionally, vitamin K antagonists (VKAs), which indirectly inactivate clotting factors II, VII, IX and X (and natural anticoagulant proteins C and S), had been the mainstay of oral anticoagulation for half a century. Only a few years ago, the US Food and Drug Administration (FDA) approved a specific VKA reversal agent, 4-Factor Prothrombin Complex Concentrate (4F-PCC). The last decade has seen the rise of non-Vitamin K oral anticoagulants (NOACs), which target specific factors, i.e. Factors IIa and Xa. Investigators have rapidly developed reversal agents for these agents as well, idarucizumab for the Factor IIa inhibitor dabigatran (Pradaxa) and andexanet alfa for the entire class of Factor Xa inhibitors (FXaIs), currently four drugs: rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) and betrixaban (Bevyxxa). Clinicians still use off-label PCC for reversing FXaIs in some settings, and a universal reversal agent, ciraparantag, remains in development. This review summarizes the safety and efficacy of these reversal agents in the setting of anticoagulant-associated major bleeding and the need for urgent surgery.

Efficacy of emicizumab prophylaxis versus factor VIII prophylaxis for treatment of hemophilia A without inhibitors: network meta-analysis and sub-group analyses of the intra-patient comparison of the HAVEN 3 trial.

Objectives: To compare the efficacy of emicizumab prophylaxis with that of factor VIII (FVIII) prophylaxis in patients with hemophilia A without inhibitors using two approaches: network meta-analyses (NMA) and additional sub-group analyses from the HAVEN 3 trial.Methods: The NMA used data from trials identified using a systematic literature review and compared bleed rates in patients receiving emicizumab prophylaxis and patients receiving FVIII prophylaxis using a Bayesian, random effects generalized linear model with log link Poisson likelihood. Additional sub-groups of the HAVEN 3 trial included here were defined as patients whose dose-taking behavior met either European label or World Federation of Hemophilia guidelines. A negative binomial regression model was used to conduct an intra-patient comparison of bleed rates within the sub-groups, during treatment with FVIII prophylaxis before entering HAVEN 3 and treatment with emicizumab prophylaxis during HAVEN 3.Results: Four studies were included in the base-case NMA. Evidence showed that the total treated bleed rate was lower with emicizumab prophylaxis compared with FVIII prophylaxis (rate ratio [RR] = 0.36 [95% credible interval (CrI) = 0.13-0.95]). Similar associations were observed in sensitivity analyses. The additional HAVEN 3 analyses also showed lower rates of treated bleeds with emicizumab prophylaxis than with FVIII prophylaxis (RRs [95% confidence interval (CI)] = 0.380 [0.186-0.790] and 0.472 [0.258-0.866] in two sub-groups). These results confirm the original HAVEN 3 intra-patient comparison findings.Conclusions: Combined findings from NMA and additional sub-group analyses of HAVEN 3 support the superiority of emicizumab prophylaxis over FVIII prophylaxis in patients with hemophilia A without inhibitors.

Practical considerations on anticoagulation reversal: spotlight on the reversal of dabigatran.

Idarucizumab (Praxbind) is a humanized antibody fragment, that reversibly and with high affinityties up dabigatran (Pradaxa). Anticoagulation reversal is achieved immediately, and with no procoagulant effect. It is administered intravenously and clearance is renal. The main clinical application of idarucizumab is to antagonize bleeding related to dabigatran, especially if it occurs at critical sites, such as nervous system (central or peripheral), intraocular, pericardial, retroperitoneal or pulmonary. Other indications are: i) dabigatran-induced anticoagulation reversal in the need for emergency surgery or procedures at high risk of bleeding; and ii) second-line treatment in bleedings that persist despite local hemostasis procedures. In this narrative review, we comprehensively address clinical indications for idarucizumab, summing up evidence derived from a systematic literature review, but also from case reports.

Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery.

Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. SUMMARY: Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40-60 IU kg-1 , VWF ristocetin cofactor activity was measured 12-24 h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3 h before surgery, rVWF was administered alone 1 h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n = 10), minor (n = 4) and oral (n = 1) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6 h, which were sustained for 72-96 h; 70% (n = 7/10) of major surgeries were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery.

New technologies in gene therapy for inducing immune tolerance in hemophilia A.

INTRODUCTION: Conventional hemophilia treatment is based on repeated infusion of the missing clotting factor. This therapy is lifelong, expensive and can result in the formation of neutralizing antibodies, thus causing failure of the treatment and requiring higher doses of the replacement drug. Areas covered: Gene and cell therapies offer the advantage of providing a definitive and long-lasting correction of the mutated gene, promoting its physiological expression and preventing neutralizing antibody development. This review focuses on the most recent approaches that have been shown to prevent and even eradicate immune response toward the replaced factor. Expert commentary: Despite the encouraging data demonstrated by ongoing clinical trials and pre-clinical studies, more extensive investigations are necessary to establish the long-term safety and efficacy of gene therapy treatments in maintaining immune tolerance.

A role for very low-dose recombinant activated factor VII in refractory bleeding after cardiac surgery: Lessons from an observational study.

OBJECTIVES: Although off-label use of recombinant activated factor VII against refractory bleeding is incorporated in current guideline recommendations, safety concerns persist predominantly with respect to thromboembolic complications. We analyzed the safety and efficacy of recombinant activated factor VII at a very low dose in cardiosurgical patients with refractory bleeding. METHODS: This prospective study includes 1180 cardiosurgical patients at risk of bleeding. Goal-directed substitution was based on real-time laboratory testing and clinical scoring of the bleeding intensity. All patients who fulfilled the criteria for enhanced risk of bleeding (n = 281) were consequently included in the present analysis. Patients in whom refractory bleeding developed despite substitution with specific hemostatic compounds (n = 167) received a single shot of very low-dose recombinant activated factor VII (≤20 µg/kg). Mortality and risk of thromboembolic complications, and freedom from stroke and acute myocardial infarction in particular, were analyzed (vs patients without recombinant activated factor VII) by multivariable logistic and Cox regression analyses, as well as Kaplan-Meier estimates. RESULTS: There was no increase in rates of mortality (30-day mortality 4.2% vs 7.0% with P = .418; follow-up survival 85.6% at 13.0 [interquartile range, 8.4-15.7] months vs 80.7% at 10.2 [interquartile range, 7.2-16.1] months with P = .151), thromboembolic complications (6.6% vs 9.6% with P = .637), renal insufficiency, need for percutaneous coronary intervention, duration of ventilation, duration of hospital stay, or rehospitalization in patients receiving very low-dose recombinant activated factor VII compared with patients not receiving recombinant activated factor VII. Complete hemostasis without any need for further hemostatic treatment was achieved after very low-dose recombinant activated factor VII administration in the majority of patients (up to 88.6% vs 0% with P < .001). The key results were confirmed after adjustment by propensity score-based analyses. CONCLUSIONS: When combined with early and specific restoration of hemostatic reserves after cardiac surgery, very low-dose recombinant activated factor VII treatment of refractory bleeding is effective and not associated with any apparent increase in adverse events.

Mechanisms of action and clinical use of specific reversal agents for non-vitamin K antagonist oral anticoagulants.

OBJECTIVES: With a steadily growing number of patients with non-valvular atrial fibrillation, anticoagulation use increases. Anticoagulation therapy is associated with increased risk of serious bleeding and an increased complexity in management of patients in need for urgent surgery. We wanted to assess the magnitude of this challenge as well as review current and potential future clinical management strategies. DESIGN: A review of the literature on the magnitude of patients using antigoaculants in potential need for acute restoration of hemostasis was conducted, as well as current status of reversal agents for non-vitamin K antagonist oral anticoagulants (NOACs). Additionally, a case illustration of its use is presented. RESULTS: Two main groups of patients may need acute restoration of hemostasis, those in need of acute surgery or acute invasive procedures, ∼ 2% of patients annually, and those with serious and critical hemorrhage, ∼1.5% annually. One specific reversal agent is available on the market (idarucizumab) and two (andexanet alfa, ciraparantag) are in clinical development. Idarucizumab is a specific antidote for the thrombin inhibitor dabigatran while andexanet alfa is factor Xa inhibitor class-specific currently in late-stage development. Ciraparantag is a universal reversal agent in early-phase development. These agents can facilitate effective management of bleeding or bleeding risk, as illustrated in a patient on dabigatran in urgent need for a pacemaker. CONCLUSIONS: Amongst patients using anticoagulants, around 3.5%, could be in need of immediate restoration of hemostasis annually. The availability and use of specific reversal agents for NOACs could be crucial for the clinical outcomes.

Reversal agents for non-vitamin K antagonist oral anticoagulants.

The non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban, and rivaroxaban, which inhibit coagulation factor Xa. Although clinical studies of NOACs were conducted without antidotes, patient outcomes with major bleeding when receiving NOACs were no worse than those in patients treated with a vitamin K antagonist. Nonetheless, in patients with life-threatening bleeding or requiring urgent surgery, the capacity for rapid NOAC reversal is likely to increase patient safety. Three NOAC reversal agents are in various stages of development: idarucizumab, a specific reversal agent for dabigatran; andexanet alfa, which reverses factor Xa inhibitors; and ciraparantag, which is purported to reverse all NOACs. Idarucizumab is licensed in many countries, andexanet is under consideration by regulatory agencies, and ciraparantag is undergoing phase III evaluation. In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are often used in patients taking these agents who present with life-threatening bleeding. In this Review, we summarize the approved indications for the NOACs, outline how to measure their anticoagulant effects, describe the mechanism of action of the reversal strategies, assess the preclinical and clinical data supporting their use, provide guidance on potential indications for reversal, and offer a management approach for patients treated with NOACs who present with serious bleeding or require urgent surgery.

Recombinant factor VIIa use in acute type A aortic dissection repair: A multicenter propensity-score-matched report from the Nordic Consortium for Acute Type A Aortic Dissection.

BACKGROUND: Surgery for acute type A aortic dissection (ATAAD) is often complicated by excessive bleeding. Recombinant factor VIIa (rFVIIa) effectively treats refractory bleeding associated with ATAAD surgery; however, adverse effects of rFVIIa in these patients have not been fully assessed. Here we evaluated rFVIIa treatment in ATAAD surgery using the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) database. METHODS: This was a multicenter, propensity score-matched, retrospective study. Information about rFVIIa use was available for 761 patients, of whom 171 were treated with rFVIIa. We successfully matched 120 patients treated with rFVIIa with 120 controls. Primary endpoints were in-hospital mortality, postoperative stroke, and renal replacement therapy (RRT). Survival data were presented using Kaplan-Meier estimates. RESULTS: Compared with controls, patients treated with rFVIIa received more transfusions of packed red blood cells (median, 9.0 U [4.0-17.0 U] vs 5.0 U [2.0-11.0 U]; P = .008), platelets (4.0 U [2.0-8.0 U] vs 2.0 U [1.0-4.4 U]; P <.001), and fresh frozen plasma (8.0 U [4.0-18.0 U] vs 5.5 U [2.0-10.3 U]; P = .01) underwent reexploration for bleeding more often (31.0% vs 16.8%; P = .014); and had greater 24-hour chest tube output (1500 L [835-2500 mL] vs 990 mL [520-1720 mL]). Treatment with rFVIIa was not associated with significantly increased rates of in-hospital mortality (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.34-1.55; P = .487), postoperative stroke (OR, 1.75; 95% CI, 0.82-3.91; P = .163), or RRT (OR, 1.18; 95% CI, 0.48-2.92; P = .839). CONCLUSIONS: In this propensity-matched cohort study of patients undergoing ATAAD surgery, treatment with rFVIIa for major bleeding was not associated with a significantly increased risk of stroke, RRT, or mortality.

Plasma-derived human factor X concentrate for on-demand and perioperative treatment in factor X-deficient patients: pharmacology, pharmacokinetics, efficacy, and safety.

INTRODUCTION: Hereditary factor X (FX) deficiency is a rare autosomal recessive bleeding disorder characterized mainly by mild-to-severe bleeding into the mucous membranes, muscles or joints. Previously, treatment options for hereditary FX deficiency were limited mostly to products that may not specify FX content (i.e. fresh frozen plasma and prothrombin complex concentrates) and that have associated safety concerns. To meet the need for a single-factor replacement therapy specifically for use in FX-deficient patients, a high-purity, high-potency, human plasma-derived FX concentrate (pdFX; Coagadex®; Bio Products Laboratory, Elstree, UK) has been developed and approved for treatment of perioperative bleeding and on-demand treatment in FX-deficient patients. Areas covered: The pharmacology, efficacy, and safety of pdFX are discussed, with a review of preclinical studies and clinical trial data that led to regulatory approval of pdFX in the United States and Europe. Expert opinion: As the first single-factor replacement therapy indicated for hereditary FX deficiency, pdFX is a safe and efficacious treatment option in patients aged ≥12 years with hereditary FX deficiency. Clinical studies of pdFX provide a dosing regimen for use in cases of bleeding episodes, surgery, and prophylaxis. Further studies are ongoing regarding use of pdFX long term and in patients aged ≤12 years.

Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial.

INTRODUCTION: BAY 81-8973 (Kovaltry(®) ) is a full-length, unmodified recombinant human factor VIII (FVIII) with the same amino acid sequence as sucrose-formulated recombinant FVIII and is produced using additional advanced manufacturing technologies. AIM: To demonstrate efficacy and safety of BAY 81-8973 for treatment of bleeds and as prophylaxis based on two different potency assignments. METHODS: In LEOPOLD I (ClinicalTrials.gov identifier, NCT01029340), males aged 12-65 years with severe haemophilia A and ≥150 exposure days received BAY 81-8973 20-50 IU kg(-1) two or three times per week for 12 months. Potency was based on chromogenic substrate assay per European Pharmacopoeia and label adjusted to mimic one-stage assay potency. Patients were randomized for potency sequence and crossed over potency groups after 6 months, followed by an optional 12-month extension. Primary efficacy endpoint was annualized bleeding rate (ABR). Patients also received BAY 81-8973 during major surgeries. RESULTS: Sixty-two patients received BAY 81-8973 prophylaxis and were included in the analysis. Median ABR was 1.0 (quartile 1, 0; quartile 3, 5.1) without clinically relevant differences between potency periods. Median ABR was similar for twice-weekly vs. three times-weekly dosing (1.0 vs. 2.0). Haemostasis was maintained during 12 major surgeries. Treatment-related adverse event (AE) incidence was ≤7% overall; no patient developed inhibitors. One patient with risk factors for cardiovascular disease developed a myocardial infarction. CONCLUSIONS: BAY 81-8973 was efficacious in preventing and treating bleeding episodes, irrespective of the potency assignment method, with few treatment-related AEs. Caution should be used when treating older patients with cardiovascular risk factors.

Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme.

INTRODUCTION: BAY 81-8973 is a recombinant factor VIII (rFVIII) with the same amino acid sequence as Bayer's sucrose-formulated rFVIII (rFVIII-FS) but manufactured with certain more advanced technologies. AIM: To describe surgery outcomes with BAY 81-8973 in the LEOPOLD trials. METHODS: Male patients with severe haemophilia A and no inhibitors aged 12-65 years with ≥150 exposure days (EDs) to FVIII (LEOPOLD I and II), or aged ≤12 years with ≥50 EDs to FVIII (LEOPOLD Kids), received BAY 81-8973 based on dosing recommendations for rFVIII-FS according to surgical requirements. Haemostasis-related complications, investigator/surgeon assessment of haemostasis, blood loss, need for transfusion and use of BAY 81-8973 were determined. RESULTS: In LEOPOLD I and II, 11 patients (mean age, 35.3 years) underwent 13 major surgeries. In LEOPOLD Kids, one patient (aged 6 years) underwent one major surgery. Thirty-two adult and paediatric patients underwent 46 minor surgeries. Haemostasis was rated good or excellent in all major and minor surgeries. Blood loss during surgery did not exceed expected amounts; blood transfusions were required in three of the 14 major surgeries. For major surgeries in LEOPOLD I and II, patients received a presurgical 50-IU kg(-1) dose of BAY 81-8973; median nominal dose on day of surgery was 7000 IU (107.5 IU kg(-1) ). Total BAY 81-8973 dose was 2500 IU (108.7 IU kg(-1) ) on the day of the only major surgery in LEOPOLD Kids. No haemostasis-related complications were reported. CONCLUSIONS: Haemostatic control with BAY 81-8973 during all surgeries in the LEOPOLD trials was good or excellent, with no haemostasis-related complications.

Hypercoagulant Abdominal Swabs in Cardiac Surgery: Potential Problems and Background.

Background During cardiac surgery with heart-lung-machine support, abdominal swabs are routinely used to adsorb blood from the operation field. In part, abdominal swabs exhibit procoagulant activity, which is usually considered harmless. However, coagulation induction and abnormal clot formation on the surface of abdominal swabs in the operation field may, if the blood is retransfused into the extracorporeal circuit, lead to severe thromboembolic complications. The aim of the present study was to elucidate the origin of the unexpected blood clotting upon contact with hypercoagulant swabs. Methods The coagulant properties of three abdominal swabs were characterized using a simple clotting test and human whole blood, which was anticoagulated with different heparin concentrations. Eluates prepared from the abdominal swabs and the color stabilizer polydiallyamine (PDAA) were incubated with blood and blood clotting was investigated. Furthermore, the effects of the abdominal swabs on blood clotting time and on heparin were investigated. Results Our data show that the three abdominal swabs as well as the respective eluates exhibit distinctive coagulant properties. The abdominal swab with the highest hypercoagulant effect significantly reduced blood clotting time and also led to a reduction in free heparin. PDAA does not induce activation of the coagulation system. Conclusion The data indicate that the hypercoagulant swab reduces the clotting time and the concentration of free heparin. Abdominal swabs used during complex cardiac surgery with heart-lung-machine support should definitely be tested for their coagulant properties using appropriate tests before clinical applications, as it cannot be specified what leads to their hypercoagulant property.

Periprocedural warfarin reversal with prothrombin complex concentrate.

INTRODUCTION: Approximately 10% of chronically anticoagulated patients require an invasive procedure annually. One in 10 procedures is emergent and requires prompt anticoagulation reversal. The study objective is to determine the safety and efficacy of a 3 factor prothrombin complex concentrate (PCC) for periprocedural anticoagulation reversal. MATERIALS AND METHODS: Consecutive patients receiving 3 factor PCC for warfarin reversal for either urgent/emergent invasive procedures or major bleeding were analyzed. Primary endpoints included percent achieving INR <1.5, peri-operative major hemorrhage, thromboembolism and death during the 40day post-infusion period. RESULTS: Between January 1, 2010-December 31, 2012, 52 patients were treated with PCC for pre-procedural warfarin reversal and 113 patients for major bleeding. Within the peri-procedure group, there were 24 intra-abdominal surgeries, 12 percutaneous interventions, 6 cardiothoracic surgeries, 5 orthopedic and 3 endoscopic procedures. INR values <1.5 were achieved in 51% at 2.5h post-infusion. Major bleeding (13%), thromboembolism (13%) and mortality rates (15%) were high. Within the major bleeding group, PCC therapy reversed INR values (<1.5) in 75% of patients within 4h. For this group, thromboembolism (21%) and mortality rates (16%) were likewise high. Post-PCC anticoagulation, reinitiated in 37%, had no impact on bleeding or thrombotic complications. Mortality rates were threefold higher for those patients not restarting warfarin therapy. CONCLUSIONS: Although PCC therapy promptly and effectively reverses INR values for patients requiring urgent/emergent invasive procedure both thromboembolic and fatal complications are soberingly high and call for judicious use of these agents in these high risk populations.