Bleeding Episodes In Patients Research Articles

Self-Expanding Metal Stents in the Acute Management of Oesophageal Variceal Bleeding: A Systematic Review.

Acute variceal bleeding (AVB) continues to challenge physicians and healthcare systems. Despite significant advances in our multimodal approach to managing this problem, namely medical, endoscopic, and radiological techniques, the mortality rates for this patient cohort remain as high as 20% on the index admission. This mortality rate has remained unchanged over the past 25 years. A crucial tool in the management of AVB is the balloon tamponade technique. However, this is associated with numerous severe and potentially life-threatening adverse events. Due to the limitations of oesophageal balloon tamponade devices, there has been an increased interest in using self-expanding metal stents (SEMS) to manage refractory variceal bleeding. There is a base of experience in using SEMS derived from their use in managing malignant obstructions. This study aimed to synthesise all available evidence, for the first time, on using SEMS to manage refractory oesophageal AVB. This study was a systematic review of published papers, which is reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We identified 16 suitable studies for review. These comprised one randomised controlled trial comparing SEMS to balloon tamponade, one prospective cohort study, nine retrospective cohort studies, four case reports, and one case series. In total, 246 patients were included. An average survival rate of 49% was seen among the 11 studies that reported a six-week survival rate; this included a cohort of 225 patients. The SEMS were left in situ for an average of 7.5 days, with a maximum average of 18 days in one study. The average rate for controlling the acute bleeding episode in patients receiving a SEMS was 96%. The re-bleeding rate on the removal of SEMS was 5%, far superior to the widely reported 50% re-bleeding rate for the balloon tamponade technique. The adverse event profile for the SEMS appears superior to the balloon tamponade technique overall. The rate of stent-related adverse events in patients receiving a SEMS was 25%. The most common adverse events were technical issues related to stent functioning, namely stent migration. The most severe stent-related adverse event was compression of the left main bronchus in two cases, which required the removal of the stent. Our study has several limitations, which we have alluded to throughout the paper. The studies on this issue are of poor quality, with only one randomised controlled trial performed. As a result, we must interpret the results of our research with caution. Our study supports the use of SEMS in managing AVB as a promising area of research. We have highlighted that further well-designed randomised controlled trials are needed to assess the efficacy of this technique, ideally compared directly to the balloon tamponade technique. However, based on this systematic review, the current body of evidence would suggest that the SEMS is superior to the balloon tamponade technique in terms of adverse event profile, re-bleeding rate, and length of time the device can safely be left in situ. Current evidence suggests that SEMS are as effective at controlling acute bleeding episodes as the balloon tamponade technique.

The comparative study between treatment with Cryoprecipitate and recombinant Factor VIII in Hemophilia in children

Introduction: Hemophilia A is a genetic disorder caused by a deficiency or absence of coagulation Factor VIII, leading to impaired blood clotting and prolonged bleeding, especially into joints and muscles. Without appropriate treatment, recurrent bleeding can result in chronic joint damage and disability. Traditionally, Cryoprecipitate, a blood product containing concentrated clotting factors, has been used to manage bleeding episodes in patients with Hemophilia A. However, with advancements in biotechnology, recombinant Factor VIII, a synthetic product, has become an alternative. Recombinant Factor VIII eliminates the risks associated with blood-derived products, such as viral transmission, and offers more consistent dosing and availability. Despite these advantages, recombinant therapies are significantly more expensive. This study seeks to compare the clinical efficacy, safety of Cryoprecipitate versus recombinant Factor VIII in pediatric patients with Hemophilia A, providing critical insights for optimal management strategies. Purpose: The purpose of this study is to compare the clinical outcomes, safety of Cryoprecipitate versus recombinant Factor VIII in the management of children diagnosed with Hemophilia A. Materials and methods: This retrospective study included 32 pediatric patients diagnosed with Hemophilia A, treated either with Cryoprecipitate or recombinant Factor VIII. Clinical data were collected on bleeding frequency, Factor VIII recovery. Statistical analyses were conducted to determine significant differences between the two groups. Results: The study demonstrated that treatment with recombinant Factor VIII resulted in significantly improved clinical outcomes compared to Cryoprecipitate. In the group treated with recombinant Factor VIII, patients required scheduled hospitalizations for routine follow-up and management, with no reports of acute bleeding episodes during these admissions. This contrasts sharply with the Cryoprecipitate group, where all hospitalizations were precipitated by acute bleeding events, necessitating urgent intervention. Conclusions: Recombinant Factor VIII demonstrates superior efficacy in managing Hemophilia A in children compared to Cryoprecipitate. Recombinant therapy provides better clinical outcomes, justifying its use in modern treatment protocols.

Assessing the uterine bleeding profile in women using a subcutaneous contraceptive implant containing etonogestrel: Real-life clinical practice

Introduction. Pregnancy planning is one of the leading areas in the population reproductive health care, in particular preventing and reducing the number of abortions.Aim. To evaluate the uterine bleeding profile and other adverse events associated with the use of an etonogestrel subcutaneous contraceptive implant (Implanon NXT®). Materials and methods. We analysed medical records of female patients (n = 153) who used Implanon NXT® in the period from 2013 to 2023, records of adverse events, uterine bleeding, bleeding management techniques and reasons given by women for discontinuing the use of implants.Results. The median duration of uterine bleeding episodes ranged from 7 to 13 days within a three-year period of use of Implanon NXT®. During the first 3 months, the proportion of women with prolonged bleeding was higher as compared to all other observation periods and gradually decreased during the first year of use of the drug from 41.2 to 15.8%. 40 patients with complaints of unsatisfactory uterine bleeding patterns required adjustment of drug dosages; 14 women continued to use Implanon NXT® after adjustment of drug dosages and repeated visits. 17.0% (n = 26) of patients required early removal of the implant. Due to pregnancy planning, the implant was removed early in 13% (n = 20) of patients. The most common adverse events included functional ovarian cysts, mastalgia, increased appetite, decreased libido, dizziness, acne; most of them were transient and did not require any management, and were not considered the reason for implant removal.Conclusion. The number of uterine bleeding episodes in patients using the etonogestrel implant was comparable to the normal menstrual cycle. Some women had changes in the uterine bleeding patterns, such as amenorrhea, frequent and prolonged bleeding, which reduced the duration of use of this contraception method. At the same time, combined oral contraceptives were the most effective as compared to other drugs used in correction regimens.

Health-related quality of life in children with severe hemophilia A on emicizumab prophylaxis

Background Emicizumab is a novel nonreplacement therapy for patients with hemophilia A. It is intended to reduce the frequency and severity of serious bleeding episodes in patients with hemophilia A. Aim To assess how emicizumab affected quality of life and physical activity in children with severe hemophilia A. Patients and methods Thirty-seven children with severe hemophilia A received emicizumab prophylaxis. We used EQ-5D-Y and pedHAL activity list questionnaires to assess quality of life and physical activity, respectively, at baseline (before receiving emicizumab prophylaxis) and after 1 year of regular emicizumab prophylaxis. Results The mean age of the children included in the study was 9.32 ± 3.75 years. Of them, 19 patients were with FVIII inhibitors (51.35%), and 18 patients were negative for FVIII inhibitors (48.65%). The median (interquartile range) PedHAL sum score was 57.6 (48.8–62) at baseline, then reached 76 (70–81.5) after a year of emicizumab prophylaxis; this change was found to be statistically significant (P<0.001). Also, there was a significant increase in the proportion of patients with no problem in all EQ-5d-Y dimensions after a year of emicizumab prophylaxis (P<0.05). The median (interquartile range) value of the visual analog scale score at baseline was 67 (54–75) and became 76 (70–81.5) after a year of receiving emicizumab prophylaxis. This improvement was statistically significant (P<0.001). Conclusion Emicizumab prophylaxis improves quality of life and physical activity in children with severe hemophilia A.

A Post-Authorization Safety Surveillance Study to Report Clinical Experience with Purified Factor IX Concentrate in Pediatric Patients with Hemophilia B.

Purified factor IX (FIX) concentrate (IMMUNINE®, Takeda Manufacturing Austria AG, Vienna, Austria) is indicated for the treatment and prophylaxis of bleeding episodes in patients with congenital hemophilia B. Data on the use of purified FIX concentrate in patients ≤6 years old with congenital hemophilia B are limited. Document real-world clinical experience with purified FIX concentrate in routine practice for pediatric patients with hemophilia B. This prospective post-authorization safety surveillance study enrolled patients ≤6 years old with moderate or severe hemophilia B (baseline FIX ≤5%) who were prescribed purified FIX concentrate, as determined by the treating physician. The planned observation period for each patient was either 12 months or ≥50 exposure days, whichever occurred first. The primary endpoints were the occurrence of treatment-related adverse events (AEs) and serious AEs (SAEs), and inhibitor development. Thirteen male patients (mean ± standard deviation age, 3.80 ± 1.76 years) enrolled and received ≥1 treatment with purified FIX concentrate. Thirty-two AEs were reported in 6 patients; 4 were SAEs. No AEs were considered related to purified FIX concentrate. No patients developed inhibitory antibodies. Inhibitor testing was not conducted in 2 patients. Eighteen bleeding episodes were treated with purified FIX concentrate in 6 patients. Hemostatic efficacy was rated as either "excellent" or "good" in all patients with an available rating. No treatment-related AEs were reported, and purified FIX concentrate was shown to be effective in treating and preventing bleeding episodes in pediatric patients ≤6 years old with hemophilia B.

Safety of recombinant activated factor VII for treatment of breakthrough bleeds in patients with congenital haemophilia A and inhibitors receiving emicizumab prophylaxis: Review of the real-world evidence.

Emicizumab is used as a subcutaneous prophylaxis for prevention of bleeding episodes in patients with haemophilia A (HA) with and without inhibitors. While low bleeding rates were observed in clinical trials, patients still experience breakthrough bleeds (BTBs) with emicizumab in the real-world. Current guidelines recommend use of recombinant activated factor VII (rFVIIa) for treatment of BTBs in patients with inhibitors. Due to thrombotic events observed in the HAVEN 1 study, activated prothrombin complex concentrate (aPCC) should be used with caution. The objective of this review is to identify and discuss real-world data on the frequency of BTBs and the safety of concomitant rFVIIa use in patients with inhibitors on emicizumab prophylaxis. A search of the following databases was conducted on 15 July 2022: BIOSIS Previews® , Current Contents Search® , Embase® , MEDLINE® . Search terms included 'real world', 'haemophilia A', and 'emicizumab'. Eleven relevant publications were identified (seven original research articles and four congress abstracts). The frequency of BTBs specifically for HA patients with inhibitors was described in three publications with 5%-56% patients on emicizumab reporting ≥1 bleeding episode. Treatment of these BTBs appeared to be managed according to relevant guidelines. Importantly, no thrombotic complications occurred during concomitant rFVIIa use. Due to the nature of real-world studies, direct comparison of the results between studies is limited. However, real-world data show that BTBs in inhibitor patients during emicizumab prophylaxis can be safely treated with rFVIIa.

Effectiveness of emicizumab in preventing bleeding events in severe and moderate hemophilia A: A single-center experience in Bangladesh.

Emicizumab is a monoclonal antibody that bridges activated factor IX (FIX) and factor X (FX) to replace the function of missing activated factor VIII (FVIII) in hemophilia A patients irrespective of FVIII inhibitor status. This study assessed the effectiveness of emicizumab in preventing bleeding episodes in patients with hemophilia A. This observational study included patients with moderate to severe hemophilia A who were undergoing episodic FVIII replacement therapy. The primary endpoint was the difference in annualized bleeding rates (ABR) and the secondary endpoint was the difference in Hemophilia Joint Health Score (HJHS) before and after emicizumab prophylaxis. A total of 30 male hemophilia patients were included, the mean age was 16.7 (SD: ±8.1) years, and most of them had moderate hemophilia A [63.3%]. Before prophylaxis, the median ABR was 48 (interquartile range [IQR]: 35-60), and 93.3% of patients had ABR greater than eight, whereas after prophylaxis the median ABR decreased significantly (median [IQR]: 0 [0.0-0.4], p<0.001), and 56.7% had zero bleeds. ABR was not significantly different in patient with and without FVIII inhibitors. The HJHS scores significantly improved after prophylaxis (10 vs. 2.5, p<0.001). The bleeding events were reduced significantly (23 vs. 0.0, p<0.001), and zero new target joints were reported after prophylaxis. Most of the patients [93.3%] did not face any serious adverse events after prophylaxis. Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events among participants with hemophilia A, regardless of inhibitor status.

Hemorragia digestiva como primeira manifestação na síndrome de Alagille - Relato de caso

Introduction: The aim of this report is to describe a case of gastrointestinal bleeding that started at 1 month of age in a patient with Alagille Syndrome. Case report: Patient started recurrent gastrointestinal bleeding, leading to hypovolemic shock in the second month of life. During the investigation, cholestasis and incoagulable INR were evidenced. The facial stigmata, associated with the posterior embryotoxon in the ophthalmologic examination and transthoracic echocardiogram with stenosis of the pulmonary branches and patent foramen ovale, suggested the hypothesis of Alagille Syndrome, later confirmed by compatible liver biopsy and genetic testing with a mutation in the JAGGED1 gene. After administration of vitamin K, the patient evolved with normalization of the coagulogram, without new episodes of gastrointestinal bleeding. At follow-up, replacement of fat-soluble vitamins and treatment with ursodeoxycholic acid were initiated. Discussion: Reports in the literature describe bleeding episodes in patients with Alagille Syndrome, however, the main site of bleeding is the central nervous system. There is no description of bleeding in the gastrointestinal tract as the initial and neonatal manifestation of the syndrome. The case reported is an uncommon form of presentation and shows the importance of diagnostic suspicion in cases of neonatal cholestasis with gastrointestinal bleeding, allowing for adequate treatment and improved prognosis.

Joint Dysfunction as a Cause of Spontaneous Subclinical Bleeding in Infants with Hemophilia.

Hemophilia is an inherited hemorrhagic disorder; its main clinical manifestations being bleeding in muscles and joints. Ankles, knees, and elbows are the most frequently affected joints, followed by shoulders and hips. The clinical signs of joint involvement are reduced mobility, swelling and walking difficulties. Bleeding episodes in patients with hemophilia are usually divided into traumatic and spontaneous, but we believe that the latter are not truly spontaneous but rather the result of joint stresses owing to motion actions that create dysfunctions starting from infancy. Pharmacological prophylaxis with factor replacement therapies or non-replacement drugs markedly reduces musculoskeletal hemorrhages. However, the onset of subclinical joint stress can be reduced only by associating this therapeutic approach with the accurate observation of the child motion patterns and restoring them if dysfunctional, thereby primarily preventing subclinical bleeding and ultimately the onset or progression of hemophilic arthropathy.

Neurological Complications Associated with Hereditary Bleeding Disorders.

Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies. ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient's pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD. Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications-intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.

Cases of less-than-expected FVIII activity in previously treated patients during post-marketing surveillance of N8-GP.

Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019,>800 patients have been treated worldwide. To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP. The post-marketing safety database was searched using keywords such as 'coagulation FVIII level decreased'. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded. Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product. In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues.

Evolution of Antidrug Antibody Assays During the Development of Anti-Tissue Factor Pathway Inhibitor Monoclonal Antibody Marstacimab.

Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic coagulation pathway. In patients with hemophilia A or B, inhibition of TFPI is an alternative therapeutic approach that augments the extrinsic coagulation pathway. Marstacimab is an investigational fully human monoclonal antibody that binds and neutralizes TFPI and is being evaluated as a prophylactic treatment to prevent or reduce the frequency of bleeding episodes in patients with severe hemophilia A or B, with or without inhibitors (antibodies against coagulation factors). However, the efficacy, safety, and pharmacokinetics of marstacimab may be affected by the induction of antidrug antibody (ADA) responses. Here, we describe the evolution and validation of three quasi-quantitative electrochemiluminescence-based methods to detect marstacimab ADAs, starting from their use in a first-in-human phase 1 study to their use in phase 2 and 3 clinical studies of patients with severe hemophilia. For all three methods, validation criteria evaluated the performance of the assays in screening and confirmatory cut points, precision, selectivity, drug tolerance, target interference, and stability. Additional criteria for validation were dilution linearity (Methods 1 and 2) and low positive control concentration, prozone effect, plate homogeneity, and robustness (Method 3). The three methods met validation criteria and are a potentially valuable tool in detecting the induction of marstacimab ADAs during treatment in patients with hemophilia.

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Recombinant von Willebrand factor (rVWF, vonicog alfa, Vonvendi/Veyvondi, Takeda Pharmaceuticals USA, Lexington, MA) and several plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrates are available for treating bleeding episodes in patients with von Willebrand disease (VWD). To develop population pharmacokinetic (PK)/pharmacodynamic (PD) models that describe VWF:ristocetin cofactor (VWF:RCo) activity and its relationship with FVIII activity (FVIII:C) over time following intravenous administration of either rVWF or a pdVWF/FVIII concentrate (VWF:RCo/FVIII:C 2.4:1) in patients with VWD; to use the final PK/PD models for an in silico comparison of rVWF and pdVWF/FVIII. The population PK model for rVWF was based on data from four clinical studies in which rVWF was administered to adult patients with VWD type 1, 2 or 3 (phase 1: NCT00816660; phase 3: NCT01410227 and NCT02283268) or severe hemophilia A (phase 1: EudraCT 2011-004314-42). The PK and PK/PD models for pdVWF/FVIII were based on data from the phase 1 study (NCT00816660) in patients with type 3 VWD who received either rVWF plus recombinant FVIII (rFVIII, octocog alfa, ADVATE®, Takeda Pharmaceuticals USA, Lexington, MA, USA) or pdVWF/FVIII. There was a marked difference in clearance following rVWF administration compared with pdVWF/FVIII in type 3 VWD, leading to a ~1.75 longer mean residence time (ie, persistence of VWF:RCo activity in the body) and half-life for rVWF versus pdVWF/FVIII. Simulations showed that following repeated administration of rVWF (50 IU/kg), a FVIII:C activity of >40 IU/dL can be maintained for the full 72 h dosing interval. The slower elimination of VWF:RCo following rVWF administration results in a prolonged effect on FVIII turnover compared with pdVWF/FVIII administration.

A French Real-World Evidence Study Evaluating the Efficacy, Safety, and Pharmacokinetic Parameters of rVIII-SingleChain in Patients with Hemophilia A Receiving Prophylaxis.

rVIII-SingleChain is a recombinant factor VIII (FVIII) with increased binding affinity to von Willebrand factor compared with other FVIII products. rVIII-SingleChain is indicated for the treatment and prevention of bleeding episodes in patients with hemophilia A. To collect real-world evidence data from patients treated with rVIII-SingleChain to confirm the efficacy and safety established in the clinical trial program and carry out a population pharmacokinetic (PK) analysis. This interim analysis includes data, collected between January 2018 - September 2021, from patients treated with rVIII-SingleChain prophylaxis at French Hemophilia Treatment centers. Data on annualized bleeding rates, dosing frequency, and consumption before and after switching to rVIII-SingleChain were recorded. A population PK analysis was also conducted to estimate PK parameters. Overall, 43 patients switched to prophylaxis with rVIII-SingleChain either from a previous prophylaxis regimen or from on-demand treatment. Following the switch to rVIII-SingleChain, patients maintained excellent bleed control. After switching to rVIII-SingleChain, most patients maintained or reduced their regimen. Interestingly, a majority of patients treated >2 ×/weekly with a standard half-life FVIII reduced both injection frequency and FVIII consumption with rVIII-SingleChain. A PK analysis revealed a lower clearance of rVIII-SingleChain (1.9 vs. 2.1 dL/h) and a longer half-life both in adolescents/adults (n = 28) and pediatric (n = 6) patients (15.5 and 11.9 hours, respectively vs. 14.5 and 10.3 hours) than previously reported. Patients who switched to rVIII-SingleChain prophylaxis demonstrated excellent bleed control and a reduction in infusion frequency. A population PK analysis revealed improved PK parameters compared with those reported in the clinical trial.

POSTER ABSTRACTS

POSTER ABSTRACTS

Perioperative Monitoring with Global Coagulation Test in Severe Hemophilia a without Inhibitor on Emicizumab Prophylaxis Undergoing Orthopedic Surgery

INTRODUCTION Emicizumab is a bispecific antibody used to prevent bleeding episodes in patients with severe hemophilia A (PwHA) without inhibitor. However, using FVIII to manage breakthrough bleeding or invasive procedures in patients without inhibitors remains necessary. Current guidelines recommend using chromogenic FVIII (FVIII:C) levels based on bovine reagents to monitor the hemostatic response to the combination of both drugs. However, the perioperative hemostatic management of PwHA undergoing prophylaxis with emicizumab and FVIII remains challenging. Here we describe the hemostatic management and monitoring using global coagulation test of two PwHA without inhibitor on emicizumab prophylaxis undergoing orthopaedic surgery with FVIII. METHODS Perioperative monitoring for two patients was performed, measuring FVIII:C levels using bovine-derived reagents. Samples for global coagulation test were collected in tubes with Corn Trypsin Inhibitor to prevent activation of the contact pathway. Clotting time (CT) was evaluated by Rotational Thromboelastometry (ROTEM®) using whole blood activated by a low concentration of tissue factor (TF) solution (final dilution 1:50,000 of EXTEM reagent) plus recalcification. Thrombin Peak (TP) was assessed by thrombin generation test (TGT) in plasma, also using a low amount of TF and phospholipids (PPP-LOW, Stago). ROTEM and TGT were performed in samples collected before and after FVIII administration during the perioperative process. Samples obtained before FVIII dosing were also spiked in vitro with equivalent therapeutic amounts of FVIII products. RESULTS Patient 1 is a 55-year-old male with severe HA under EMI prophylaxis (1.5 mg/week). He underwent an ankle arthrodesis with osteosynthesis due to severe hemophilic arthropathy. Plasma-derived FVIII/FVW concentrate (pdFVIII/FVW) was used to provide effective hemostatic coverage during the procedure. He received the first dose before surgery and the last dose on day +7 after surgery. The postoperative course was uneventful, and he was discharged on day +4. Patient 2 is a 52-year-old male with a medical history of HIV infection, lymphoma in complete remission and severe HA on EMI prophylaxis (6 mg every four weeks). He was referred to an orthopaedic surgeon due to cubital tunnel syndrome secondary to hemophilic arthropathy that required surgery. A single dose (50 Ul/kg) of extended half-life recombinant FVIII (rFVIII EHL) concentrate was administered before intervention. He was discharged on day +2 in the absence of bleeding complications. He received an additional dose of rFVIII EHL on day +3 after the surgery. Table 1 shows FVIII:C levels in both patients. Both global coagulation tests showed that treatment with emicizumab was insufficient for complete normalization of hemostatic parameters. Clotting time was longer, and thrombin generation was reduced in emicizumab-treated patients compared to healthy controls before the intervention (Figure 1). We observed an improvement and normalization of CT and TP values after administering both FVIII products (plasma-derived or recombinant with EHL) during the perioperative period. This improvement was similar to that obtained with in vitro spiking of equivalent doses of FVIII (Figure 1). Additionally, a correlation between FVIII:C levels and CT and TP values was also observed. CONCLUSIONS The global coagulation test were used to evaluate the hemostatic response to FVIII treatment in PwHA on emicizumab prophylaxis during invasive procedures. Considering that both tests provide a more comprehensive assessment of the hemostatic state of the interaction of emicizumab and FVIII, these tests may complement FVIII levels in complex cases of bleeding or surgery. Funding: ISCIII-FEDER PI19/00631; Catedra UAM-Roche Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Two pediatric cases of severe hemophilia A in which emicizumab prophylaxis failed to prevent traumatic extra-articular hemorrhage.

Emicizumab reduces bleeding episodes in patients with severe hemophilia A (PwHA). Little information is available on hemostatic management of severe traumatic hemorrhages in emicizumab-treated pediatric PwHA. We assessed therapeutic efficacy and global coagulation potentials in two pediatric cases of emicizumab-treated pediatric PwHA with intracranial or retroperitoneal/iliopsoas hemorrhage. A modified clot waveform analysis (CWA) triggered by mixtures of tissue factor and ellagic acid was used to assess coagulant potentials, and maximum coagulant velocity (Ad|min1|) was calculated. One patient with intracranial hemorrhage was treated with continuous infusions of recombinant factor VIII (rFVIII) at a dose of 4-4.6IU/kg/hr for 9days, followed by bolus infusion at 66IU/kg/day for 2days and 33IU/kg/day for an additional 2days. The Ad|min1| was increased from 5.5 (at baseline) to 7.0-8.1 under concomitant treatment and maintained within or near normal range (IQR; 6.9-7.7). The other patient with retroperitoneal/iliopsoas hemorrhage received bolus infusions of rFVIII at 50IU/kg/day for 20days and every-other-day infusion of rFVIII for 8days. The Ad|min1| was increased from 5.2 (at baseline) to 5.8-6.8 under concomitant treatment and maintained within the normal range. We successfully managed a treatment plan for severe traumatic bleeding in emicizumab-treated pediatric PwHA using modified CWA.

Phase III dose selection of marzeptacog alfa (activated) informed by population pharmacokinetic modeling: Anovel hemostatic drug.

Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human FVII (rFVIIa) variant developed as subcutaneous (s.c.) administration for the treatment or prevention of bleeding episodes in patients with hemophilia A (HA) or hemophilia B (HB) with inhibitors and other rare bleeding disorders. Population pharmacokinetic (PK) modeling was applied for dose selection for a pivotal phase III clinical trial evaluating s.c. MarzAA for episodic treatment of spontaneous or traumatic bleeding episodes. The population PK model used MarzAA intravenous and s.c. data from previously completed clinical trials in patients with HA/HB with or without inhibitors. Based on the model, clinical trial simulations were performed to predict MarzAA exposure after different dosing regimens. The exposure target was identified using an exposure-matching strategy with a wild-type rFVIIa but adjusting for the difference in potency between the two compounds. Simulations demonstrated a sufficient absorption rate and prolonged exposure following a single 60 μg/kg dose leading to 51% and 70% of the population reaching levels above the target after 3 and 6 h, respectively. According to the phase III protocol, if a second dose was required after 3 h because of a lack of efficacy, 90% of the population was observed to be above target 6 h after the initial dose. The model-informed drug development approach integrated information from several trials and guided dose selection in the pivotal phase III clinical trial for episodic treatment of an acute bleeding event in individuals with HA or HB with inhibitors without the execution of a phase II trial for that indication.

Desmopressin for bleeding in non‐severe hemophilia A: Suboptimal use in a real‐world setting

BackgroundDesmopressin is an important treatment option in nonsevere hemophilia A because it has several benefits compared with factor (F) concentrates, including no inhibitor risk and much lower costs. Despite these advantages, data are limited on the real‐world use of desmopressin in the treatment of bleeds. ObjectiveTo describe the clinical use of desmopressin in relation to other therapeutic modalities in the treatment of bleeding episodes in patients with nonsevere hemophilia A. MethodsPatients with nonsevere hemophilia A aged 12–55 years were included from the DYNAMO cohort study. Data on the desmopressin test response and treated bleeding events in the period January 2009 to July 2020 were retrospectively collected from medical files. An adequate desmopressin test response was defined based on a peak FVIII level of ≥30 IU/dl. ResultsA total of 248 patients with a median age of 38 years (interquartile range 25–49) were included. An adequate desmopressin test response was documented in 25% and 73% of patients with moderate and mild hemophilia, respectively. In adequate responders, 51% of bleeds were exclusively treated with FVIII concentrates, 24% exclusively with desmopressin, 21% with a combination of both and 4% with other treatments. In 54% of bleeds treated with a single dose of factor concentrates, the expected FVIII level after desmopressin exceeded the level targeted. ConclusionMost bleeds in patients with an adequate response to desmopressin are treated with factor concentrates. These findings may indicate a suboptimal use of desmopressin and that barriers to the use of desmopressin should be explored.

Current and future therapies for haemophilia-Beyond factor replacement therapies.

Some non-factor products that work by facilitating the coagulation pathway (emicizumab) and blocking the anticoagulant pathway (fitusiran, concizumab and marstacimab) for patients with haemophilia (H) have been developed, and clinical trials using these products are currently ongoing. Prophylaxis using non-factor products by subcutaneous administration provides marked reductions of bleeding episodes in patients with HA or HB, regardless of the presence of inhibitor. Emicizumab has already been approved globally. Emicizumab alters the phenotype of patients with HA from severe to mild by maintaining trough levels of equivalent factor VIII activity (15-20iu/dl). Phase 3 clinical trials and long-term observations assessing emicizumab revealed tolerable safety and efficacy. However, thrombotic events have occurred in patients receiving these non-factor products. Furthermore, monitoring of the haemostatic function of these products with concomitant therapy is also required in clinical practice. These products have promising haemostatic efficiency, but wider clinical experience is needed to provide optimal therapeutic strategies in the future.