High-titer Inhibitors Research Articles

Application of peripherally inserted central catheter in immune tolerance induction treatment of children with hemophilia A and accompanying inhibitors in China

ABSTRACTObjective:To explore the feasibility, safety and cost effectiveness of the use of peripherally inserted central catheter (PICC) in children with hemophilia A and inhibitors who underwent ITI treatment.Method:This retrospective cohort study evaluated the effect of PICC placement and ITI on bleeding rates, costs, and parents’ satisfaction before and within 6 months after PICC placement in children with hemophilia A and inhibitors.Results:A total of 20 children with hemophilia A and high-titer inhibitors were included, with a success rate for PICC placement of 100%, at a cost of ¥6730.50. Parents’ satisfaction with PICC was 100%, and the total length of catheter indwelling was 6055 days. In terms of curative effect, the success rate of ITI treatment was 75%, and the annualized bleeding rate was decreased from 10.90 ± 12.16 times before placement to 2.10 ± 3.32 times (p < 0.05). The transportation expense for children and their parents to the clinic decreased from ¥20,920 ± 32,274.57 before catheter placement to ¥2915 ± 2195.99 (p < 0.05). Time of children missed school and their parents missed work decreased from 10.85 ± 22.36 days to 1.90 ± 3.58 (p < 0.05) days and 40.33 ± 46.11 days to 3.83 ± 7.11 days (p < 0.05), respectively.Conclusion:The use of PICC for ITI treatment in children with hemophilia A and accompanying inhibitors in developing countries (e.g. China) can ensure the effect of ITI, reducing expense and improving the quality of life without obvious side effects.

Acquired Hemophilia A after SARS-CoV-2 Infection: A Case Report and an Updated Systematic Review.

The role of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been implicated in the pathogenesis of acquired hemophilia A (AHA). The aim of this study is to report our case and to summarize clinical studies on de novo AHA after SARS-CoV-2 infection. We performed a systematic search on the association of SARS-CoV-2 with AHA in four medical databases up to 28 May 2023. Eligible studies should include de novo AHA patients who had SARS-CoV-2 infection before or concomitant with the diagnosis of AHA. Findings were synthesized narratively. In addition, we report the case of a 62-year-old female patient, who presented to our clinic with left flank pain 2 weeks after SARS-CoV-2 infection. Clinical investigations confirmed AHA and imaging studies revealed retroperitoneal bleeding. Her hemostasis was successfully secured with bypassing agents; however, despite immunosuppressive therapy, high inhibitor titer persisted. In the systematic review, we identified only 12 relevant cases with a questionable cause-effect relationship between SARS-CoV-2 infection and AHA. Based on the qualitative analysis of the relevant publications, current clinical evidence is insufficient to support a cause-effect relationship. The analysis of data from ongoing AHA registries can serve further evidence.

Successful treatment of lupus anticoagulant hypoprothrombinemia syndrome with rituximab

Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare acquired bleeding disorder secondary to development of antibodies against prothrombin protein, in the presence of antiphospholipid antibodies. We describe the case of a 13-year-old girl who presented with severe menorrhagia and symptomatic anemia. Labs indicated anemia, thrombocytopenia, elevated PT and aPTT, high-titer inhibitor on mixing studies, positive ANA and anti-dsDNA antibodies, along with a triple-positive antiphospholipid antibody panel. Given additional systemic manifestations, systemic lupus erythematosus was diagnosed. High dose steroids and hydroxychloroquine subsequently started. Her clinical course was complicated by femoral deep venous thrombosis and post renal biopsy retroperitoneal hematoma. Further workup revealed low prothrombin level and the diagnosis of lupus anticoagulant hypoprothrombinemia syndrome. In view of suboptimal response to initial immunosuppressive therapy, rituximab was added to her regimen, leading to an improvement in clinical symptoms and resolution of hypoprothrombinemia. She remains recurrence free 5 years from the event.

Simoctocog alfa (Nuwiq®) in previously untreated patients with severe haemophilia A-Final efficacy and safety results from the NuProtect study.

Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. To report the efficacy and safety results from the NuProtect study. PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

The spleen is the major site for the development and expansion of inhibitor producing-cells in hemophilia A mice upon FVIII infusion developing high-titer inhibitor

BackgroundHemophilia A (HA) is a hereditary bleeding disorder caused by defects in endogenous factor (F)VIII. Approximately 30 % of patients with severe HA treated with FVIII develop neutralizing antibodies (inhibitors) against FVIII, which render the therapy ineffective. The managements of HA patients with high-titter inhibitors are especially challenging. Therefore, it is important to understand the mechanism(s) of high-titer inhibitor development and dynamics of FVIII-specific plasma cells (FVIII-PCs). AimsTo identify the dynamics of FVIII-PCs and the lymphoid organs in which FVIII-PCs are localized during high-titer inhibitor formation. Methods and resultsWhen FVIII-KO mice were intravenously injected with recombinant (r)FVIII in combination with lipopolysaccharide (LPS), a marked enhancement of anti-FVIII antibody induction was observed with increasing FVIII-PCs, especially in the spleen. When splenectomized or congenitally asplenic FVIII-KO mice were treated with LPS + rFVIII, the serum inhibitor levels decreased by approximately 80 %. Furthermore, when splenocytes or bone marrow (BM) cells from inhibitor+ FVIII-KO mice treated with LPS + rFVIII were grafted into immune-deficient mice, anti-FVIII IgG was detected only in the serum of splenocyte-administered mice and FVIII-PCs were detected in the spleen but not in the BM. In addition, when splenocytes from inhibitor+ FVIII-KO mice were grafted into splenectomized immuno-deficient mice, inhibitor levels were significantly reduced in the serum. ConclusionThe spleen is the major site responsible for the expansion and retention of FVIII-PCs in the presence of high-titer inhibitors.

Safe and Successful Surgical Outcome in Persons with Hemophilia A with and without Inhibitors Treated with Emicizumab: A Large, Single Center, Real-World Experience.

Emicizumab is a humanized recombinant bispecific antibody, bridging together activated factor IX (FIXa) and factor X (FX), thus mimicking the activity of FVIII in vivo. Emicizumab is designed for long-term prophylaxis in patients with severe hemophilia A with and without inhibitors. This approach provides constant protection, with significant reduction in bleeding rate and improved quality of life. However, protection provided by emicizumab is not absolute, and clotting factor concentrates (FVIII, rFVIIa, aPCC) may be necessary for post-traumatic bleeding or surgery, with a potential thrombotic risk or difficulty in preventing bleeding. Real world evidence is still scanty, especially for managing major surgery. In this study, 75 surgeries were managed in 28 patients (27 major procedures in 15 patients and 48 minor procedures in 20 patients. In 17 patients without inhibitors, 30 minor surgeries were carried out by using FVIII in 5, with only a bleeding event, which was successfully treated with FVIII concentrate. Six major surgeries were uneventfully performed with FVIII concentrate. Eleven PWHA and high-titer inhibitors underwent 39 surgical procedures (18 minor and 21 major surgeries). Minor surgeries were mostly performed without prophylaxis with rFVIIa, with only a single bleeding complication. All 21 major surgeries were covered with a homogeneous protocol using rFVIIa. In four instances, bleeding complications occurred, treated with rFVIIa. Of them, a single patient only failed to respond and died because of an uncontrollable bleeding from a large ruptured retroperitoneal pseudotumor. Surgery in patients with emicizumab can be safely carried out with the use of appropriate replacement therapy protocols.

Cerebellar hematoma in severe hemophilia with inhibitor on emicizumab prophylaxis: a case report

BackgroundEmicizumab is a novel prophylactic medication used to treat patients with hemophilia A. It is indicated to minimize the frequency of bleeding episodes and the severity of serious bleeding in patients with hemophilia A utilizing inhibitors. However, some cases of bleeding episodes have been reported, and more data are needed regarding their management and expected outcomes.Case presentationWe report a case of a 4-year-old Saudi Arabian boy with severe hemophilia A who presented with a post-traumatic cerebral hemorrhage. The patient, with high titer inhibitors, was on emicizumab prophylaxis therapy. On hospital admission, he received tranexamic acid (10 mg intravenously, every 6 hours), and recombinant activated factor VII 120 µg/kg every 2 hours for 2 days then every 4 hours for 4 days. On follow-up, the patient showed no signs of neurological deficit. There was no need for emergency neurosurgical intervention since the bleeding had been controlled throughout the first 2 days. There were no recorded thrombotic sequelae or neurological complications, with complete resolution within 10 days.ConclusionsThis case implies that low-dose recombinant activated factor VII might be used safely and effectively with patients with hemophilia A on emicizumab prophylaxis, to reduce the risk of cerebral hemorrhage or another episode of serious bleeding along with its long-term complications.

Central venous access devices implantation in children with severe hemophilia a: data from the children comprehensive care center of China

ObjectivesTo report the perioperative management experience of central venous access devices (CVAD) in Chinese children with severe hemophilia A (SHA) in China. MethodsThis retrospective study included SHA children who underwent Port-A-Cath or peripherally inserted central catheter (PICC) implantation between 2020/01 and 2021/07. Collected data included baseline characteristics, factor replacement regimen and CVAD-related complications. ResultsNine patients had nine ports placed, and eight patients underwent 10 PICCs placement. Patients without or with low-titer inhibitor (<5 BU) received a port. The median preoperative and postoperative plasma-derived factor VIII (pd-FVIII) doses were 53.0 (44.4–61.1) and 315.9 (88.2–577.8) IU/kg. The median port duration was 189 (15–512) days, with infection incidence of 0.06 per 1000 CVAD days. Patients with high-titer inhibitors (>10 BU) received PICC. The median recombinant factor VIIa (rFVIIa) dose was 87.47 μg/kg before and for 5–7 doses after implantation over 2–3 days. The median PICC duration was 226.5 days, with infection incidence of 0.12 per 1000 catheter-days. ConclusionsCVADs can be safely implanted in China. PICC implantation is a practical and safe option for SHA children with high-titer inhibitors.

Recombinant factor VIII Fc fusion protein for first-time immune tolerance induction: final results of the verITI-8 study

AbstractInhibitor development remains a major challenge in factor VIII (FVIII) replacement therapy. verITI-8 is the first prospective study of a recombinant FVIII Fc fusion protein (rFVIIIFc; efmoroctocog alfa) for first-time immune tolerance induction (ITI) in males with severe hemophilia A and high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL). In this single-arm, open-label, multicenter study, screening was followed by ITI (rFVIIIFc 200 IU/kg per day until tolerization or maximum of 48 weeks). Those who achieved ITI success entered a tapering period, returning to standard prophylaxis, and then entered follow-up. Primary end point was time to tolerization with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg), and half-life (t½) ≥7 hours within 48 weeks. Sixteen patients received ≥1 rFVIIIFc dose. Twelve (75%), 11 (69%), and 10 patients (63%), respectively, achieved negative inhibitor titers, an IR ≥66%, and a t½ ≥7 hours (ie, tolerance) within 48 weeks. Median times in weeks to achieve these markers of success were 7.4 (interquartile range [IQR], 2.2-17.8), 6.8 (IQR, 5.4-22.4), and 11.7 (IQR, 9.8-26.2), respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE), and 1 reported ≥1 related TEAE (injection site pain). Nine patients experienced ≥1 treatment-emergent serious AE. No thrombotic events, discontinuations because of AEs, or deaths were reported during the study. As the first extended half-life rFVIII with prospective data in ITI, rFVIIIFc offered short time to tolerization with durable responses in almost two-thirds of patients and was well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT03093480.

A creative approach to managing a case of haemophilia A with inhibitors in a low-resource country: case report

Abstract The development of antibodies to therapeutic factor VIII, known as inhibitors, is a leading cause of morbidity and mortality in people with haemophilia. This is particularly challenging in areas where access to novel treatment options is limited. This case report presents a clinical scenario in South Western India involving a 16-year-old male with severe haemophilia A with high titre inhibitors, who sustained a tibia-fibula shaft fracture necessitating emergency surgical intervention. The successful management of this patient required a multidisciplinary approach, encompassing haemostasis optimisation, innovative factor replacement strategies to work around financial constraints, and a comprehensive rehabilitation plan. The patient’s history of multiple factor VIII concentrate transfusions contributed to inhibitor development. Limited funds for bypassing agents prompted the utilisation of fresh frozen plasma to achieve haemostasis before access to FEIBA and recombinant factor VII. Emicizumab, a subcutaneously administered bispecific antibody, was used to assist perioperative haemostasis. A comprehensive rehabilitation plan with regular physiotherapy was followed. Emicizumab prophylaxis was initiated and the patient now shows improvement. This case emphasises the importance of novel treatment options such as FEIBA and emicizumab in dealing with complications in haemophilia such as inhibitors. In resource-limited settings, there is still a need to improve the availability of these life-saving interventions to optimise surgical outcomes in such cases.

FVIII inhibitor surveillance in children with hemophilia A in Indonesia: a report from the Indonesian Pediatric Hematology-Oncology Working Group.

Factor VIII (FVIII) inhibitor diagnosis and surveillance in Indonesia are challenging owing to geographic conditions and the lack of laboratory facilities nationwide for inhibitor assays. This study aimed to determine the prevalence of FVIII inhibitors in children diagnosed with hemophilia A (HA) in Indonesia. A cross-sectional study was conducted in 12 hospitals in eight provinces of Indonesia between 2020 and 2021. Factor VIII inhibitor screening was performed in a central hemostasis laboratory for all children with HA (≤18 yr) who had received a minimum of 10 exposure days to clotting factor concentrates. The FVIII inhibitor titer was determined using the Bethesda assay. Children (388) were enrolled in this study, including 219 (56.4%), 131 (33.8%), and 38 (9.4%) with severe, moderate, and mild HA, respectively. The prevalence of children who developed FVIII inhibitors was 37 out of 388 (9.6%). Factor VIII inhibitors were found in 25/219 (11.4%) severe, 11/131 (8.3%) moderate, and 1/38 (2.6%) children with mild HA. Thirteen children had low-titer inhibitors and 24 had high-titer inhibitors, with a median of 9.44 (1.48‒412.0) Bethesda Units. Among 13 children with low-titer inhibitors, eight underwent a confirmation test, of which five tested negative and were classified as transient. A significant difference in annual joint bleeding rate was found between patients with low and high inhibitor titers and those without inhibitors (P＜0.001). Factor VIII inhibitor prevalence in Indonesia was relatively low. However, the risk factors that may contribute to FVIII inhibitor development among Indonesian patients require further study.

Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications.

The development of coagulation factor VIII (FVIII) inhibitory antibodies is a serious complication in hemophilia A (HA) patients after FVIII replacement therapy. Inhibitors render regular prophylaxis ineffective and increase the risk of morbidity and mortality. Immune tolerance induction (ITI) regimens have become the only clinically proven therapy for eradicating these inhibitors. However, this is a lengthy and costly strategy. For HA patients with high titer inhibitors, bypassing or new hemostatic agents must be used in clinical prophylaxis due to the ineffective ITI regimens. Since multiple genetic and environmental factors are involved in the pathogenesis of inhibitor generation, understanding the mechanisms by which inhibitors develop could help identify critical targets that can be exploited to prevent or eradicate inhibitors. In this review, we provide a comprehensive overview of the recent advances related to mechanistic insights into anti-FVIII antibody development and discuss novel therapeutic approaches for HA patients with inhibitors.

Shorter Time Interval from Inhibitor Detection to Starting Low-Dose Immune Tolerance Induction Therapy Is Associated with Better Inhibitor Eradication Outcomes in Severe Hemophilia a Children with High-Titer Inhibitors in China

Background Shorter time from inhibitor detection to immune tolerance induction (ITI) start (interval-time) might play a critical role in ITI outcomes for severe Hemophilia A (SHA) children with high-titer inhibitors. However, the acceptable interval-time hasn't well been confirmed yet, especially for treatment-delay patients undergoing low-dose ITI therapy in China. Aim To explore the interval-time in Chinese SHA children with high-titer inhibitors, undergoing low-dose ITI strategy with outcomes. Methods A retrospective study in single center, 47 Chinese SHA children with high-titer inhibitors [> 10 Bethesda Unite (BU)/ml] undergoing low-dose ITI strategy with more than 24 months follow-up period. ITI outcomes were evaluated at the 24th month of treatment. The association between interval-time and outcomes was analyzed. Success was defined as negative inhibitor titer and FVIII recovery ≥ 66% of expected. The predictive ability of interval-time to identify ITI success was determined using receiver operating characteristic (ROC) curve. Results Forty-seven cases enrolled in this study, the median age of inhibitor detection was 2.4 (range, 0.6, 10.4) years and the interval-time was 5.8 (0, 61.1) months with the peak inhibitor titer of 55.8 (10.1, 512.0) BU/ml, 42.6% (20/47) using ITI-alone and 57.4% using ITI combined with Rituximab based immunosuppression (IS). Over a follow-up time of 31.3 (24.0, 69.5) months, 34 patients (72.3%) achieved success with the time to success of 11.0 (3.1, 23.0) months. (Table 1) The interval-time in ITI success group was shorter than in non-success group significantly [2.8 (0. 59.1) vs 28.1 (0, 61.1) months, p = 0.04]. Multivariate logistic regression model demonstrated the peak inhibitor titer and the interval-time were two independent predictors of ITI success (P < 0.05). The area under ROC curve (AUC) was 0.701 (95%CI: 0.507 - 0.896, p = 0.034) and reliable cut-off value of 22.3 months could be calculated in the prediction of ITI outcomes with the sensitivity of 0.853 and the specificity of 0.615. (Figure 1) Univariable linear regression demonstrated the relationship between the time to success and the interval-time, the equation y=0.1552*x+9.285 (R2 = 0.2252, p = 0.005). ROC curve describing the accuracy of the predictor of early-success (ITI time < 12 months); the AUC was 0.704 (95%CI: 0.521 - 0.887, p = 0.049); the cut-off value was 9.4 months with the sensitivity of 0.824 and the specificity of 0.533. (Figure 1) Conclusions Our study shows that shorter interval-time was associated with better inhibitor eradication outcomes in terms of ITI success rate and time to success in our SHA children with high-titer inhibitors (> 10BU/ml) undergoing low-dose ITI strategy. We showed that an interval-time of ≤ 22.3 months was associated with higher ITI success rate. And an interval-time of ≤ 9.4 months was related to shorter time to success. Our study on low-dose ITI in a developing country setting support the findings using higher dose ITI in developed countries setting that ITI should be started as soon as possible after inhibitor development. However, stronger evidence is needed from further clinical studies with better study design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence of Inhibitors in Previously Untreated Patients with Severe Hemophilia a Treated with Plasma-Derived Vs. Recombinant Factor VIII Concentrates: A Systematic Review and Meta-Analyses

Introduction: The most important treatment complication of hemophilia A is the development of neutralizing antibodies anti-factor VIII (inhibitors). Among the non-genetic risk factors for inhibitors development, the influence of the type of factor concentrate used in replacement therapy remains controversial. Objective: The aim of this study was to systematically review the incidence of inhibitor development after treatment with recombinant factor FVIII (rFVIII) compared with plasma factor FVIII (pdFVIII) in previously untreated patients (PUPs) with severe hemophilia A. Methods: A computer-assisted search of MEDLINE, Cochrane Library, EMBASE, Scopus, Google Scholar and Web of Science, without language restriction, between January 2010 and May 2022, was conducted using different combinations keywords. Other publications were selected from presentations from the largest conferences in the area, to identify relevant studies not detected in the electronic search. Additional studies were identified by contacting experienced researchers in the field and searching the reference list of primary studies. The articles were analyzed by two independent reviewers using pre-established eligibility criteria and in case of disagreement, a third independent reviewer was responsible for the final decision. To avoid double counting of the same cohort of patients, study periods were observed, and patients in duplicates were excluded. Data extraction form was made using the RedCap Platform. If some study data were missing or incomplete, an email was sent to the corresponding author to obtain the information. Quality assessment was performed on all included studies using The Newcastle-Ottawa Scale for Observational Cohort and Case Control Studies (NOS) and The Cochrane RoB 2.0 scale. Results: Of the 974 potentially relevant publications initially selected, 34 were included in the final analysis, published between January 2010 to May 2022. Data from 4,244 patients enrolled in these studies were included in this analysis. Of these, 1,047 received pdFVIII, and 3,324 received rFVIII. The total number of patients who developed inhibitors was 1,136, of which 204 (19.5%) were treated with pdFVIII and 929 (28.8%) with rFVIII. High-titer inhibitors were found in 730/4,271 (17.1%) patients, 144/1,047 (13.8%) for pdFVIII and 585/3,224 (18.1%) for rFVIII. The pooled analysis of all studies showed inhibitor incidence rate of 17% for pdFVIII vs. 28% for rFVIII. Regarding high-titer inhibitors, the pooled incidence rate was 11% for pdFVIII studies compared to 17% for rFVIII (figure 1). Analyzing the different generations of rFVIII, it was observed the inhibitor incidence rate of 19% for first-generation rFVIII, 31% for the second-generation, 26% for third-generation and 27% for fourth-generation. Considering only the pooled incidence rate of high-titer inhibitors, it was observed 15%, 23%, 15% and 16 %, respectively. The inhibitor incidence rate in patients who received extended half-life (EHL) rFVIII was 28%, with 14% of high-titer inhibitor. Comparing pdFVIII concentrates to standard rFVIII, there was a statistically significant difference (p = 0.004). Regarding the two EHL-rFVIII concentrates with data available in the literature on PUPs (rFVIII-Fc [Elocta®] and N8-PEG [Esperoct®]) it was demonstrated also a statistical difference in inhibitor development compared to pdFVIII (p = 0.003). However, when compared inhibitor incidence rate of third-generation rFVIII and EHL-rFVIII, no statistical difference was observed. Nevertheless, the incidence rate of high-titer inhibitors among patients using pdFVIII and rFVIII, was statistically different only with second-generation rFVIII concentrates (p = 0.001). Conclusions: In our systematic review and meta-analysis, which included 34 studies, an increase in the incidence of inhibitors was demonstrated in patients who used rFVIII when compared to pdFVIII. However, when analyzing only high-titer inhibitors, there was statistical difference only with second-generation rFVIII, which are not commonly used nowadays. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Usefulness of Emicizumab Associated with Immune Tolerance Induction in Patient with Hemophilia a and Inhibitors: Experience in Cuenca-Ecuador

Background: Referring to the World Federation of Hemophilia (WFH) 2020 Annual Global Survey Report published in October 2021: In Ecuador, with a population of 17,643,060 inhabitants, there are 1,708 cases of hemophilia, 99 cases of Von Willebrand disease, and 7 cases of other coagulation disorders. Within the hemophilia A group, 21 patients have active inhibitors, and there is a record of 2 new cases of inhibitors in relation to the previous notification. Emicizumab is a bispecific, humanized monoclonal antibody that binds activated FIX and factor X (FX) resulting in the generation of activated FX (FXa) which then catalyzes the formation of thrombin from prothrombin. Based on the HAVEN 1-4 clinical trials, the FDA and EMA approved the use of Emicizumab as prophylaxis in Hemophilia A (with and without inhibitors) in both adults/adolescents (>12 years) and pediatrics (<12 years). In both the primary analyzes and long-term follow-up, emicizumab produced statistically and clinically significant reductions in annual bleeding rates compared with Factor VIII prophylaxis (in patients without inhibitors); and with bypassing agents (in patients with inhibitors). These trials excluded patients in immune tolerance (ITI). Keywords: emicizumab, immune tolerance, hemophilia. Objectives: -Assess the usefulness of Emicizumab in immune tolerance in terms of bleeding control, osteoarticular health and functional activity Materials and Methods: 1) The evaluation was carried out in a 9-year-old patient (boy) with severe Hemophilia A and high titer inhibitors who, prior to the start of ITI, had predictive factors of high risk and poor prognosis (historical peak 234 UB, 5 years since inhibitor screening) with 4-8 joint bleeds per year. The ITI scheme used was with plasmatic Factor VIII 100 IU/Kg 3 times a week with management with bypass agents on demand (ITI duration: 3 years) and inclusion of emicizumab 2 years after starting the strategy 2) The analysis was determined based on periodic clinical evaluations, osteoarticular status was assessed through the Hemophilia Joint Health Score 2.1 (HJHS), Disease Activity Score (DAS28); and functional activity through Functional Independence Score in Hemophilia (FISH), and Health Assessment Questionnaire (HAQ). An analysis was made prior to the start of immune tolerance and after reaching immunological tolerance. Results: 1) This strategy contributed to better control of joint bleeding, and therefore to the inhibitor eradication process. 2) Improved the evolutionary course of his osteoarticular state: - Prior to ITI: DAS28: 4.26 (moderate activity), HJHS 33. Target joints: left knee and ankle. - After immunological tolerance: DAS28: 1.87 (clinical remission), HJHS 12. 3) Favorable progression of his functional status, despite slight limitation of his left knee in flexion (sequel to recurrent episodes of hemarthrosis): - Prior to the start of ITI: FISH 14, HAQ: 1.50 (severely affected functional capacity), functional scale IV (use of a wheelchair). - After immunological tolerance: FISH 27, HAQ: 1.00, functional scale II (able to carry out activities of daily living with slight difficulty). Conclusions: 1) Larger-scale studies and accumulated evidence are needed that allow us to establish the usefulness of Emicizumab in ITI and therefore corroborate these results. 2) We must establish the best clinical application profile and the economic impact of these therapies; especially in health systems like ours, in which accessibility to drugs is complex and optimization of resources is the norm. Bibliography: 1. Alvarez Roman M: Guías Españolas para el manejo de la hemophilia. 2022, 1-190. 2. Callaghan M, Negrier C, Paz-Priel I, Chang T, Chebon S y col: Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. 2021;137(16):2231-2242 3. Carcao M, Escurriola C, Santagostina E, Oldenburg J, Liesner R y col: The changing face of immune tolerance induction 3. Hematology Am Soc Hematol Educ Program. 2021, Dec 10;2021(1):219-225. 4. Young G: Management of children with hemophilia A: How emicizumab has changed the landscape. Journal of Thrombosis and Haemostasis. 2021 Jul;19(7):1629-1637 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics Associated with Receipt of Immune Tolerance Induction Among Patients with Severe Hemophilia a in the United States in the Pre-Emicizumab Era

Introduction: Immune tolerance induction (ITI) has long been the standard of care for treatment of patients with hemophilia A complicated by an inhibitor. Although the approval of emicizumab to treat hemophilia has led to new debate as to the role of ITI, many continue to advocate for its use to restore the effectiveness of factor VIII for treatment of bleeding events and major surgery. Unfortunately, ITI is cumbersome to undertake, and providers may perceive that some families are unable to complete the complex treatment. This opens the door for bias and health inequities. To better understand potential health inequities in hemophilia care, we sought to explore the association of race and ethnicity, as well as patient and facility characteristics, on the receipt of ITI among patients with hemophilia A in the United States (US). Methods: This cross-sectional study used data from the Community Counts (CC) Registry, which is a collaboration of the American Thrombosis & Hemostasis Network (ATHN), Centers for Disease Control and Prevention (CDC), and the Hemophilia Center Network (HTCN) using the ATHN study manager. The Registry collects data from patients that received care from more than 135 hemophilia treatment centers (HTC) across the US. Included in this analysis were patients with severe hemophilia A who entered the CC Registry between 2013-2017, were ≥5 years of age at the study entry, and had a history of an inhibitor (n=614). Data from 2013-2017 were selected to represent the pre-emicizumab era. The primary outcome was ever receiving ITI treatment, which was ascertained in the initial CC Registry visit form. The proportion receiving ITI was examined according to race/ethnicity, the age and year that an inhibitor was detected, age at study entry, current health insurance, pre-ITI peak inhibitor titer, and HTC size, dichotomized into having <40 or ≥40 patients with severe hemophilia A in the CC registry. Unadjusted prevalence ratios (PR) and corresponding 95% exact confidence intervals (CI) were computed with contingency tables. Results: Among 614 patients included in the study, slightly over half (56.4%) were White, 19.7% were Black, 18.4% were Hispanic, and 4.9% were Asian (Table 1). The average age at the study entry was 22.2 [standard deviation (SD =14.3)] years and the average age at inhibitor detection was 5.6 (SD=9.9) years. Most patients had a high titer inhibitor (≥5 BU/mL). Approximately 85.2% of patients in the study received ITI; results were not statistically different by race-ethnicity. However, in an analysis restricted to patients whose inhibitors were detected ≤5 years of age, Black (PR=0.94, 95%CI 0.86, 1.02) and Hispanic (PR=0.91, 95%CI 0.83, 1.00) patients were non-significantly less likely to receive ITI compared to White patients (Table 2). Receipt of ITI was also significantly lower among people currently receiving care from HTCs with <40 vs ≥40 patients (PR=0.92, 95%CI 0.86,0.99). Patients who were older when their inhibitor was detected (ages 5-19 years and ≥20 years vs. ≤5 years), were older during the study (ages ≥40 years vs. 5-19 years), had their inhibitor detected in 1995 or earlier vs 2006 or later, or had Medicare insurance vs commercial insurance were less likely to receive ITI. Additionally, those who had an inhibitor titer ≥5 BU/ml vs < 5 BU/ml were less likely to be treated with ITI (Table 2). Conclusion: Most patients with severe hemophilia A with history of an inhibitor were treated with ITI. However, larger HTCs were more likely to implement ITI and those receiving Medicare were less likely to receive ITI. Additionally, among patients whose inhibitors were detected at ≤5 years of age, Black and Hispanic patients with severe hemophilia A had non-significantly lower rates of ITI for the treatment of inhibitors compared to White patients. Although the role of ITI may evolve with growing use of emicizumab and the introduction of new products, understanding characteristics that influence care will be relevant going forward and potentially applicable to other complex therapies such as gene therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Guiding Pups with Severe Hemophilia a and Their Parents from Diagnosis to a Full Prophylactic Schedule Mitigating the Risk of Bleed and the Risk for Inhibitor Formation - a Single Centre Approach

Introduction Pediatricians treating newly diagnosed severe hemophilia A patients are confronted with the challenge to protect the children against bleeds that are potentially life-threatening or have long-term damaging effects on joints. A well-established protective effect has early prophylaxis with coagulation factor VIII (FVIII). However, higher doses and "peak treatment moments” have been associated with a rate of inhibitor formation against factor VIII in up to 40%1,2. Another still controversial topic is the impact of the product choice on inhibitor risk. There is some evidence that plasma-derived factor VIII, or certain concentrates, are less immunogenic3,4. We report our experience with an individualized approach to managing PUPs at a single hemophilia treatment center (HTC) in Germany. Methods PUPs with severe hemophilia A (FVIII:C <1%) treated at the Gerinnungszentrum Rhein-Ruhr (GZRR), Germany, between January 2013 and July 2022 were followed prospectively. Our treatment approach includes a thorough training of parents to early detect signs of bleeds and avoid injuries with special focus on the first 50 exposure days (EDs). Patients are treated with a human plasma-derived FVIII (pdFVIII/VWF) concentrate for at least the first 50 EDs with an individually tailored treatment schedule that leads to a full prophylactic schedule. Initial doses are chosen low, given weekly or every 10 days and escalated according to bleeding tendency. In case of more severe bleeds, high doses of 60-80 IU/kg are chosen to avoid treatment for more than 2 days. Minor bleeds or hematomas are not always treated. The parents stay in close contact with the center so that the decision to treat with pdFVIII/VWF can be done on a case-by-case basis. We monitor joint health by prophylactic physiotherapy and regular ultrasound every 3-6 months. Non-urgent surgical procedures are postponed, and venous access system implants are avoided within the first 100 EDs. Inhibitor levels are measured using the modified Bethesda assay every 3-4 EDs until ED 100, and every 3 months thereafter for 2 years. Results Data from 38 consecutive PUPs with severe hemophilia A were collected, of which 35 (92.1%) have been treated with FVIII. Of the 38 patients, 34 started regular treatments within the first 10 EDs. The schedule was tailored individually ranging from 21 IU/kg every 10 days up to 40 IU/kg twice per week. One patient was treated on-demand for an intracranial bleed from ED 1-100. Only 3 spontaneous bleeds in 3 patients were treated; those bleeds had led to diagnosis. All other patients remained free of spontaneous bleeds requiring treatment. One patient developed a high titer inhibitor that was diagnosed at ED 4. He had received 35 IU/kg for treatment of a hematoma and 2 further equal doses in 2 separate weeks. The mother had reported unusual hematoma formation with a dark and more extended middle part following a slow resolution already before the Bethesda assay was positive. Discussion Our approach to managing PUPs includes treatment with human pdFVIII/VWF for at least the first 50 EDs. During this time, we treat bleeds only when considered necessary but then with high doses to minimize further infusions. We report 1 inhibitor development in a prospective cohort of 38 patients. In contrast, between 2003 and 2012, four of nine (44%) PUPs treated at our center developed inhibitors during the first 20 EDs (2 low-, 2 high-titer inhibitors). At that time, we used recombinant FVIII (rFVIII) for prophylaxis in most patients and were less selective about which and how to treat bleeds with FVIII. After at least 50 EDs we usually discuss the option to switch patients from pdFVIII/VWF to rFVIII as the injection volume is generally lower. Conclusion With a rate of 1/30 (3.3%) patients with more than 20 EDs developing an inhibitor, these data support the use of our individualized management approach allowing for a tolerization phase with FVIII on the way to a full prophylactic schedule. We consider the close contact and thorough training of the parents/guardians crucial in order to closely monitor the patients and assure adequate protection from bleeds. 1. Gouw SC et al. J Thromb Haemost 2007; 5(7): 1383-90. 2. Gouw SC et al. Blood 2013; 121(20): 4046-55. 3. Klukowska A, et al. Haemophilia 2018; 24(2): 221-8. 4. Peyvandi F et al. A. New Engl J Med 2016; 374(21): 2054-64. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Titer Inhibitor-Acquired Hemophilia A Treated With Human FVIII Concentrate in Limited Resource: A Case Report

Acquired hemophilia A (AHA) is a rare condition that affects one in a million people each year, and there are not many diagnostics or therapeutic agents available for treatment due to its rarity. This is a case report of a 61-year-old woman who presented with a spontaneous subcutaneous hematoma and multiple extensive bruises in her extremities. There was no prior history of bleeding disorders, and the laboratory results showed an isolated aPTT prolongation with no correction after mixing studies, and a reduction in FVIII activity level along with a high FVIII inhibitor titer (928BU). Furthermore, the diagnosis of idiopathic AHA was made after other secondary causes had been ruled out, and the patient received human FVIII concentrate instead of bypassing agents due to its availability. The patient still experienced clinical improvement despite using this alternative. AHA is currently managed using both hemostasis agents and inhibitor eradication, and they come with several limitations. Human FVIII concentrate therapy is still an option in situations with limited resources, even though it is not recommended in patients with high inhibitor titer levels.

Acquired Haemophilia A: A Review of What We Know.

Autoantibodies against plasma coagulation factors could be developed by some individuals inducing severe and sometimes fatal bleedings. This clinical entity is called acquired haemophilia. It should be suspected in subjects with acute abnormal bleedings, without personal or familiar history of congenital bleeding disorders with an unexplained prolonged aPTT. It is rare disease, although its incidence may be underestimated due to the low knowledge about it by many specialists, the frequent use of anticoagulant or antiplatelet therapies in the affected population that can mask the diagnosis and, sometimes, a so withering effect that avoid its confirmation. Mortality ranges between 9% and 33% depending on the series in the first 2 months after diagnosis. This mortality is attributed in up to 40% of the cases to infections in the context of immunosuppressive treatments used to eliminate the inhibitor. Factor VIII levels below 1% and high inhibitor titers are conditions of worse response rates. Advanced age, patient's ECOG, and underlying conditions are key prognostic factors for response to treatment and patient survival. To reduce morbidity and mortality in these patients, it is important to have clinical knowledge and access to guidelines to achieve an early diagnosis and to optimize the haemostatic and immunosuppressive treatment. This review aims to contribute to the dissemination of basic concepts on the epidemiology etiopathogenesis, diagnosis, treatment and management of these patients, as well as risk factors to get remission and the longest overall survival to allow individualized care. Especial awareness will be proposed in patients with some underlying conditions like cancer, autoimmune diseases, children, pregnancy or drugs.

Factor IX inhibitors in haemophilia B: A report of National Haemophilia Registry in China.

The development of inhibitors against factor FIX (FIX) is the most serious complication of FIX replacement therapy in haemophilia B (HB) patients. Currently, only few cohorts of HB inhibitor patients have been reported worldwide. This Chinese nationwide study of HB inhibitor patients explored their risk factors for FIX inhibitor development and experience on their management. We retrospectively analysed patient characteristics, F9 genotypes, treatment strategies and outcomes of HB inhibitor patients registered to the Chinese National Registry and Patient Organization Registry. Forty-four unique HB inhibitor patients were identified in 4485 unique HB patients registered by year 2021 to the two Registries. Inhibitor diagnosis were usually delayed and the low prevalence (.98%) may suggest some inhibitor patients were not identified. Their median age at inhibitor diagnosis was 7.5 (IQR, 3.0-14.8) years. Most patients (95.5%) had high-titre inhibitors. Allergic/Anaphylactic reactions occurred in 59.1% patients. Large deletions and nonsense mutations were the most common F9 mutation types in our FIX inhibitor patients. Patients with large F9 gene deletions were more likely to develop inhibitors (p =.0002), while those with missense mutations had a low risk (p <.0001). Thirteen (29.5%) patients received immune tolerance induction (ITI) therapy using low-dose prothrombin complex concentrate regimens. Twelve completed ITI with three (25.0%) achieving success. Nephrotic syndrome developed in two (16.7%) patients during ITI. This study reports the largest Chinese cohort of HB inhibitor patients. Large deletions were most significantly associated with inhibitor development. Low-dose ITI might be feasible for FIX inhibitor eradication.