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.

Comparison of thrombotic adverse events in patients treated with factor VIII products and emicizumab using the 2018-2022 US Food and Drug Administration Adverse Event Reporting System data.

BACKGROUND: Relatively little is known about thrombotic adverse events (AEs) of emicizumab in postmarketing real-world settings, particularly in comparison with factor VIII (FVIII) products. A recent European study reported a potentially greater thrombotic risk of emicizumab compared with FVIII products. OBJECTIVES: This drug safety study aims to investigate whether thrombotic AEs are more frequently reported for emicizumab than for FVIII products and if so, whether it is independent of bypassing agents as coreporting drugs using the United States Food and Drug Administration Adverse Event Reporting System data. METHODS: Disproportionality analyses for thrombotic AEs of emicizumab vs FVIII products were conducted. Three signal detection indicators were used: proportional reporting ratio (PRR), reporting odds ratio (ROR), and informational component (IC). RESULTS: During 2018-2022, the proportions of thrombotic AEs among all AEs were 4.07% (97 out of 2383) and 1.44% (134 out of 9324) for emicizumab and FVIII products, respectively: PRR = 2.83 (2.19-3.66), ROR = 2.91 (2.23-3.79), and IC = 1.04 (0.70-1.28). Bypassing agents as coreporting drugs were identified in 36% and 15% of the total thrombotic AE reports associated with emicizumab and FVIII products, respectively. Even after thrombotic AE reports with bypassing agents were excluded, the reporting proportion of thrombotic AEs was still greater for emicizumab than for FVIII products: PRR = 2.19 (1.60-2.99). CONCLUSION: Thrombotic AEs in the United States Food and Drug Administration Adverse Event Reporting System data were about 3 times more frequently reported for emicizumab than for FVIII products. More research and efforts in the future are warranted for monitoring, elucidating, and preventing the potential risk of thrombotic AEs in hemophilia therapy, including emicizumab.

Efficacy and safety of activated prothrombin complex concentrate for the reversal of vitamin K antagonist major bleeding.

Data on the use of activated prothrombin complex concentrate (aPCC) for the management of warfarin associated major bleeding is sparse. The objective of the study was to assess the achievement of effective clinical hemostasis using aPCC in patients presenting with major bleeding while on warfarin. We also assessed the safety of the drug. This retrospective study was conducted at a tertiary care teaching center in the USA where patients with major bleeding while receiving warfarin, and received aPCC were included. Efficacy of aPCC in achieving effective hemostasis was assessed according to the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. Efficacy was also assessed by achieving INR < 1.5 after treatment. The primary safety endpoint was the occurrence of any thromboembolic complications. A total of 67 patients were included in the study. The most common site for bleeding was intracerebral hemorrhage (n = 37, 55.2%), followed by gastrointestinal bleed (n = 26, 38.8%). Clinical hemostasis was achieved in 46 (68.7%) patients and of the 21 (31.3%) patients who did not achieve clinical hemostasis, 16 died. Thirty nine (58.2%) patients achieved INR < 1.5. Five (7.5%) patients developed thromboembolic complications. This study suggests that the use of aPCCs is effective in achieving effective hemostasis in patients on warfarin presenting with major bleeding.

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

Phase 4 Safety and Efficacy Study of Antihemophilic Factor (Recombinant) in Previously Treated Chinese Patients With Severe/Moderately Severe Hemophilia A.

Antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) is indicated for the treatment and prevention of bleeding in patients with hemophilia A. We aimed to assess the safety and efficacy of standard prophylaxis versus on-demand treatment with rAHF in previously treated Chinese patients with severe/moderately severe hemophilia A. This open-label, sequential, interventional, postapproval study (NCT02170402) conducted in China included patients of any age with hemophilia A with factor VIII (FVIII) level ≤2%. Patients received 6 months' on-demand rAHF then 6 months' rAHF prophylaxis (20-40 IU/kg every 48 ± 6 hours). The primary objective was percentage reduction in annualized bleeding rate (ABR) in the per-protocol analysis set (PPAS); secondary objectives included ABR by bleeding subtype, hemostatic efficacy, immunogenicity, and safety. Of 72 patients who received ≥1 rAHF dose, 61 were included in the PPAS. Total ABR was lower during prophylaxis (mean 2.5, 95% CI 1.5-3.7; median 0) versus on-demand treatment (mean 58.3, 95% CI 52.5-64.7; median 53.9), representing a 95.9% risk reduction. Similar findings in favor of prophylaxis were observed for all types of bleeding event by cause and location. rAHF hemostatic efficacy was rated as "excellent"/"good" in 96.1% of treated bleeding events. Transient FVIII inhibitors (0.6-1.7 BU) in 4 patients resolved before study end; no unexpected safety issues were observed. rAHF prophylaxis in this study of previously treated Chinese patients with severe/moderately severe hemophilia A resulted in a clear reduction in bleeding events versus rAHF on-demand treatment, with no change in safety profile.

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 .

Pharmacodynamics of eftrenonacog-alfa (rFIX-Fc) in severe hemophilia B patients: A real-life study.

Eftrenonacog-alfa is a recombinant factor IX-Fc fusion protein increasingly prescribed in hemophilia B patients. We aimed to assess its pharmacodynamics (PD) in real-life setting via FIX activity measurement and thrombin generation assay (TGA). Sixty samples from 15 severe hemophilia B treated patients were collected at different time points. FIX activity was measured using product-specific one-stage clotting assay (reference method) and two chromogenic assays (CSA) (Biophen FIX and Rox FIX). TGA was triggered with 1 pM tissue factor. Five parameters were analyzed: lag time (LT), time to peak (TTP), peak height (PH), endogenous thrombin potential (ETP), and velocity. PD models were built to characterize their relationships with FIX activity, using mixed effects models. Mean trough FIX level was estimated at 4.64 (±1.50) IU/dl with a recovery at 0.78 (±0.16) IU/dl per 1 IU/kg injected dose. FIX activity ranged between 1 and 86 IU/dl with 21.5 IU/dl median value. Biophen FIX and Rox FIX allowed reliable measurements except in samples with FIX <20 IU/dl in which values were underestimated (delta >30%). PD models revealed that velocity was the most sensitive TGA parameter to FIX activity followed by PH, ETP, TTP and finally LT. Following FIX activity peak after eftrenonacog-alfa injection, velocity decreased first, followed by PH then ETP. Both CSA failed to accurately measure FIX in severe hemophilia B patients receiving eftrenonacog-alfa throughout the measuring range. TGA could be an additional valuable tool to evaluate hemostasis balance in treated patients.

Decreased Bleeding Rates in Patients with Hemophilia A Switching from Standard-Half-Life FVIII to BAY 94-9027 Prophylaxis.

BAY 94-9027 (damoctocog alfa pegol, Jivi) is an extended-half-life recombinant factor VIII (rFVIII) shown to be well-tolerated and efficacious in bleeding prevention in previously treated patients with severe hemophilia A. During the PROTECT VIII study, prophylaxis patients received BAY 94-9027 at intervals determined based on their bleeding phenotype, observed during a 10-week run-in treatment period with twice-weekly dosing. Those with ≤ 1 spontaneous joint or muscle bleed were randomized to either 45 to 60 IU/kg every 5 days or 60 IU/kg every 7 days; patients could increase dosing frequency to every 5 days or twice weekly in the case of bleeds. Those enrolled after the randomization arms were full, and those with ≥ 2 bleeds in the run-in period, received 30 to 40 IU/kg twice weekly. Patients completing the main study could receive open-label BAY 94-9027 in the extension phase. Dosing regimen, total, and joint annualized bleeding rates were analyzed over three periods: prestudy, main study, and extension. A total of 80 patients who were on prophylaxis treatment prior to and during the study and had prior bleed data available were evaluated in this post hoc analysis of PROTECT VIII. Most patients (> 80%) required fewer infusions with BAY 94-9027 prophylaxis versus their previous standard-half-life (SHL) rFVIII product. Lower bleeding and joint bleeding rates were observed over time from the prestudy to the extension study period in all treatment regimens. Compared with SHL FVIII, BAY 94-9027 prophylaxis allows patients to reduce infusion frequency with maintained or improved protection from bleeds.

Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study.

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.

Changes in Hemostasis System in Outbred Female Mice with Cisplatin-Induced Procoagulant Status.

Procoagulant status was modeled in outbred female mice by single injection of cisplatin in a maximum tolerated dose and hemostasis parameters monitored over 30 days by methods of coagulogram and low-frequency piezothromboelastography (global test). Monitoring revealed waveform changes in the hemostatic potential: the structural and chronometric hypercoagulation recorded starting from the first day and attaining its maximum on days 5-7 was followed by hypocoagulation and returned to normocoagulation on day 30. This pattern reflects prolonged effect of cisplatin: formation of severe dysfunction of the endothelium providing the main anticoagulant pool of hemostasis (day 1) aggravated by disturbances of the plastic functions of the liver (days 15-20), and recovery (days 20-30).

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.

Reversal strategies and outcomes in patients with atrial fibrillation and warfarin-associated intracranial hemorrhage.

PURPOSE: Evaluate reversal strategies in atrial fibrillation (AF) patients with warfarin-associated intracranial hemorrhage (ICH) in clinical care. MATERIALS AND METHODS: Observational cohort of AF patients with warfarin-associated ICH at two referral hospitals (2007-2010), with patient features, reversal agents, and outcomes collected from medical records. RESULTS: Among 498 ICH patients 403 received fresh frozen plasma (FFP) without 3-factor prothrombin complex concentrates (PCCs) or recombinant factor VIIa (rFVIIa), 65 received PCCs or rFVIIa, mostly with FFP, and 30 received no acute reversal agents. Median time from presentation to reversal agent administration was 3.4 h (IQR 2.3-5.3). INR was reversed to ≤1.4 by 6 h post-presentation in 46% of patients receiving PCCs/rFVIIa versus 15% receiving FFP alone (p<0.0001). Among PCCs/rFVIIa recipients, 31% died in-hospital vs. 24% receiving FFP alone (p=0.27). Adjusted OR for death accounting for age and Glasgow Coma Score was 0.78 (0.36-1.69) for PCCs/rFVIIa vs FFP only and 1.16 (0.59-2.27) comparing those reaching vs. not reaching INR ≤ 1.4 at 6 h. CONCLUSIONS: Treatment with PCCs/rFVIIa led to faster INR reversal than treatment with FFP alone. Neither treatment with PCCs/rFVIIa nor rapid INR reversal was associated with improved survival. Delays receiving PCCs may largely eliminate the benefit of treatment.

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.

Differential response to FEIBA is strongly associated with the prothrombotic microparticles.

BACKGROUND: Treatment of patients with hemophilia with an inhibitor is generally done using bypassing agents (BPA), wherein variability in response is observed. Due to lack of validated laboratory assays, monitoring is being carried out by clinical response only. Emerging biomarkers like procoagulant microparticles (MPs) may prove to be promising. AIM: To analyze whether procoagulant MP levels correlate with clinical response to FEIBA therapy. MATERIALS AND METHODS: Total phosphatidylserine (PS) expressing MPs along with different cell derived MPs were measured in blood samples obtained prior and 2 hour post-FEIBA infusion in 64 bleeding episodes associated with 43 severe hemophilia patients. RESULTS AND DISCUSSION: Patients with excellent response showed statistically significant increase in %MP of PS-MPs (p < 0.0001; 95.0% CI Range: -64.33 to -24.42) when compared to those with moderate response; platelet %MP change was also found significantly associated (p < 0.05) with clinical response. In search of an assay for monitoring FEIBA, results though preliminary seem to be promising with increase in %PS-MP correlating well with the clinical response. Coagulation being multifactorial process involves multiple factors for balanced hemostasis, which needs to be accounted. Larger studies in this line may provide indications for usage of MPs as monitoring and dose adjustment tool of FEIBA therapy.

Coagulopathy reversal in intracerebral haemorrhage.

As intracerebral hemorrahge becomes more frequent as a result of an aging population with greater comorbidities, rapid identification and reversal of precipitators becomes increasingly paramount. The aformentioned population will ever more likely be on some form of anticoagulant therapy. Understanding the mechanisms of these agents and means by which to reverse them early on is critical in managing the acute intracerebral hemorrhage.

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.

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.

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.