Late-Breaking and COVID-19 Abstracts

Late-Breaking and COVID-19 Oral Communication SessionLB/CO01.1 A Novel Adeno Associated Virus (AAV) Gene Therapy (FLT180a) Achieves Normal FIX Activity Levels in Severe Hemophilia B (HB) Patients (B-AMAZE Study): P. Chowdary1,2, S. Shapiro3, M. Makris4, G. Evans5, S. Boyce6, K. Talks7, G. Dolan8, U. Reiss9, M. Phillips1, A. Riddell1, M.R. Peralta1, M. Quaye2, E. Tuddenham1, J. Krop10, G. Short11, S. Kar11, A. Smith11, A. Nathwani1,2 1Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital NHS Foundation Trust, London, United Kingdom2University College London, London, United Kingdom3Oxford Haemophilia & Thrombosis Centre and Oxford NIHR BRC, Oxford, United Kingdom4University of Sheffield, Sheffield, United Kingdom5Kent & Canterbury Hospital, Canterbury, United Kingdom6University Hospital Southampton, Southampton, United Kingdom7Newcastle Haemophilia Comprehensive Care Centre, Newcastle, United Kingdom8Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom9St Jude Children's Research Hospital, Memphis, United States10Freeline, Boston, United States11Freeline, Stevenage, United Kingdom...Copyright © 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

Relationship between Pain, Physical Activity, and Quality of Life in Patients with Haemophilia a and Haemophilia B

Introduction: The extended half-life (EHL) registry was established in 2016 to ascertain the long-term outcomes in patients with HaemophiliaA(HA) and B(HB) receiving replacement therapy. The aim was to quantify disease burden and quality of life at baseline and after switching to EHLs. Method(s): The study is a prospective, observational cohort study that enrolled patients switching EHLs or on standard replacement therapy after informed consent following local ethics approval and was registered at www.clinicaltrials.gov (NCT02938156). The study was paused during the COVID pandemic. Here the baseline results are presented for pain, activity and quality of life and their correlations. Pain evaluation was assessed through the brief pain inventory (BPI) 7-day recall, quality of life by EuroQol-5 Dimension (EQ5D5L) and physical activity through the international physical activity questionnaire (IPAQ). The BPI assess severity of pain and the interference with activities. IPAQ assess physical activity undertaken across a comprehensive set of domains. Three levels of physical activity are used to classify the populations: 'low', 'moderate', and ' high'. Result(s): A total of 231 HA and 97 HB were included in the analysis, of whom 231 had switched to EHL products and 96 were on standard replacement therapy. The levels of Physical Activity were similar between Haemophilia types, with approximately 46%, 32% and 22% of patients reporting high, moderate, and low physical activity, respectively. BPI mean (+/-SD) severity score in HA was 2.86 (+/-2.1), HB 3.24 (+/-2.0);interference score HA 3.22 (+/-2.8), HB 3.09 (+/-2.5), mean EQ5D5L visual analogue scale (VAS) for HA 72.92 (+/-15.5) and HB 71.10 (+/-18.2). Within instruments, IPAQ sub-scores and BPI average scores were highly correlated. Between instruments, the strongest linear correlations were seen between theVAS and the BPI scores (R=-0.59, p< 0.0001, n=206 for the average interference score, R=-0.57, p< 0.0001, n=208 for the average pain severity, v.s. the VAS). Correlations between the IPAQ total score and either VAS or BPI scores were weaker, even when limiting to patients with moderate or high activity and using a log scale given the skewed distribution of the IPAQ summary measure. Discussion/Conclusion: The study demonstrates for the first time a strong correlation between pain and quality of life, and weaker correlation between physical activity and quality of life.

Minor Procedures in Patients with Congenital Bleeding Disorders - One Centre Experience

Introduction: Patients with congenital bleeding disorders (CBD) have an increased bleeding tendency, which varies according to the factor deficiency and severity. In most cases, prolonged bleeding is observed after trauma, surgery and/or invasive procedures. Haemostatic treatment is needed to prevent bleeding complications and allow a good clinical outcome. Our aim is to evaluate the management of patients with CBD in minor procedures. Method(s): Retrospective study of patients with CBD who performed minor procedures over a 7-year period, through review of clinical files. Result(s): Between January 2015 and December 2021, 249 minor procedures were performed in 113 patients with CBD: 42 had diagnosis of Haemophilia A (HA) (15 severe without inhibitors;3 severe with inhibitors;4 moderate and 20 mild);12 had Haemophilia B (HB) (7 severe without inhibitors;2 moderate and 3 mild);5 were carriers of HA and 2 of HB. 35 had von Willebrand disease (VWD);15 had rare bleeding disorders (8 FVII deficiency;6 FXI deficiency;1 FX deficiency) and 2 had diagnosis of inherited platelet glycoprotein deficiencies (1 Glanzmann thrombasthenia and 1 Bernard Soulier syndrome). Most procedures were dental treatments (189);synoviorthesis/ infiltration/mesotherapy (17);endoscopies and colonoscopies (15);skin lesions excision (8);COVID-19 vaccination (5);sebaceous cyst excision (4);cardiac catheterization (3);ureteral stent removal (3);bone marrow biopsy (2);cystoscopy (2) and breast fibroadenoma excision (1). Prophylactic treatment was performed in 237 (95%) of the procedures, respectively FVIII concentrate factor (59);FIX concentrate factor (27);DDAVP (66);von Willebrand factor/factor VIII concentrates (44);bypassing agents (24);platelet (6);inactivated human plasma (9);tranexamic acid (47) and epsilon-aminocaproic acid (161). No side effects were reported. Discussion/Conclusion: Most patients that underwent minor procedures had Haemophilia and VDW(83%). The most common procedure was dental treatment (76%). Patients with CBD require attention and special care in dental practice. The haemostatic prophylactic treatment varies according to the specific haemostatic defect, severity and type of procedure. The treatment performed has been demonstrated safe and effective, with low incidences of haemorrhagic and treatment-related complications. These patients' treatment requires multidisciplinary teams and reference centres.

Prevalence and Course of Covid-19 in Patients with Congenital Bleeding Disorders in Russia

Introduction: Published data on the course of COVID-19 in patients with congenital bleeding disorders (CBDs) is limited. There are questions about howCOVID-19 affects the course of CBDs and, conversely, how CBDs affect the course of coronavirus infection? Some authors suggest that patients with CBDs to be less severely affected by COVID-19. The aim of the study: analysis of the prevalence and course of COVID-19 in patients with CBDs in Russia. Method(s): A web-based questionnaire was developed to collect data. The survey was conducted in the period from 25.06.2022 to 31.07.2022. A cluster of 187 patients from different regions and cities of Russia were interviewed. Result(s): The average age of patients was 37 years. The survey group consisted of 144 patients with hemophilia A, 16 with hemophilia B, 24 with vonWillebrand's disease and 1 patient with factor VII deficiency. COVID-19 affected 115 (61.5%) of 187 surveyed patients and 22 (19%) patients suffered from coronavirus infection twice. Hospitalisation was required for 14 (12.3%) patients. At the beginning of the disease, 82 (71%) patients were on prophylactic treatment with the factor concentrates;11 (10%) received therapy with emicizumab, 20 (17%) received therapy with the factor concentrates on demand and 2 (1.7%) received bypass agents. During COVID-19 different types of bleeding were observed in 9 (7.8%) patients: hemarthrosis, ecchymosis, hematomas, epistaxis, menorrhagia, haemorrhoid bleeding. Due to COVID-19 the blood coagulation parameters were monitored for 15 (13%) of 115 patients who had been ill. The haemostatic therapy regimen was changed in 19 (16.5%) patients. Anticoagulant therapy was received by 8 (7%) patients. There were no thrombotic cases. A change in the course of the underlying disease after COVID-19 was noted by 21 (18%) patients, of which 11 noted an increase in joint pain and 9 reported the appearance of pain in previously intact joints. Discussion/Conclusion: The absence of thrombotic complications in patients with CBDs and COVID-19 suggests that hypocoagulability state may be protective against COVID-19 hypercoagulability-related adverse effects. However, the aggravating condition is an increase in joint pain and the involvement of new joints possible due to both hemostatic disorders and autoimmune reaction.

Hospital and Intensive Care Admissions and Mortality Due to 24 Months of the Covid-19 Pandemic in Adult Patients >=40 Years with Haemophilia in Europe

Introduction: The Age-related DeVelopments ANd Comorbidities in haemophilia (ADVANCE) Working Group is a European collaboration of over 20 Haemophilia Treatment Centres (HTCs) that focuses on the management of PWH aged >=40 years. As it soon became apparent that the risk of severe outcomes from COVID-19 infection was increased in older adults, we aimed to identify the incidence, severity and outcomes of COVID-19 inPWHaged >=40 years treated at ADVANCE centres. Method(s): The number of hospital admissions, ICU admissions and deaths due to COVID-19 was recorded retrospectively via survey for all patients aged >=40 years with haemophilia A or B at ADVANCE HTCs throughout the pandemic over a 24-month period (until 30 April 2022). Patient numbers were recorded for the most serious outcome at month/year of first occurrence. Aggregated data was provided as requested by Ethical Committees. For reported cases, information on age, comorbidities and risk factors for severeCOVID-19 infection were collected where available. Result(s): Of the overall haemophilia A and B population, 36/4166 suffered a serious outcome due to COVID-19 infection;27 required hospital admission, 5 were admitted to the ICU and 4 died (3 with haemophilia A and 1 with haemophilia B). Nearly all patients with haemophilia A who were admitted to the ICU or died had >=1 comorbidity associated with worse outcomes. Most reported cases occurred early in the pandemic with no clear distinction according to haemophilia severity or age. Discussion/Conclusion: This is the first study to evaluate the impact of the pandemic on PWH >=40 years in terms of severe adverse clinical outcomes. Although only limited data were collected, the study provides reassurance that the haemophilia population was not at risk of more serious outcomes due to their haemophilia alone.

COVID-19 vaccination in patients with hemophilia: Experience from a single center

Background: Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), has resulted in an ongoing world-wide pandemic. Vaccination is the key countermeasure of the COVID-19 pandemic. Data on the efficacy, safety and immunogenicity of COVID-19 vaccination in patients with hemophilia -and in particular in those with HIV -are still scarce. Aim(s): The aim of our study was to characterize the immunogenicity and biomarkers of coagulation and endothelial perturbation after mRNA-COVID- 19 vaccination in HIV-positive hemophilic patients. Method(s): We collected blood from 24 adult HIV-positive hemophilic patients followed at our centre (19 with hemophilia A, 5 with hemophilia B) before and two weeks after the administration of the complete vaccination schedule with mRNA-1273 (Moderna Biotech). Most patients had severe hemophilia (n = 21). We measured antibodies to SARS-CoV- 2 spike protein by Elecsys (Roche) to assess immunogenicity and we evaluated protein C, VWF, D-dimer plasma levels as biomarkers of coagulation and endothelial perturbation. Anti-Platelet Factor 4 (PF4) antibodies were also measured. Result(s): Before vaccination, three patients out of 24 showed anti-Spike IgG levels >0.8 U/ml (cut-off value). Two weeks after completing the vaccination schedule, all patients had high values of anti-Spike IgG (min-max 2,387-12,500 U/ml). Mean (standard deviation) basal values of protein C, VWF and D-dimer (106 +/- 21%, 171 +/- 45%, 593 +/- 692 ng/ml respectively) were not significantly different from values measured two weeks after the second dose of vaccine (103 +/- 20%, 162 +/- 43%, 583 +/- 531 ng/ml). Anti-PF4 antibodies were detected in three patients with no associated clinical manifestations. None of the patients reported bleeding in the site of inoculation nor serious adverse events after the vaccination. Conclusion(s): Since immune abnormalities can occur in HIV-positive patients, it is important to collect data on COVID-19 vaccination immunogenicity. We demonstrated that hemophilic HIV-positive patients have a normal antibody response against SARS-CoV- 2 spike protein. In addition, mRNA-1273 had no effect on coagulation and endothelial perturbation.

Safety of Sinopharm Covid-19 vaccine in Iranian patients with congenital bleeding disorders: A preliminary report

Background: There are limited data regarding safety of Sinopharm vaccine in patients with congenital bleeding disorders (CBD). The guidance published by World federation of hemophilia mainly recommends prophylaxis therapy in hemophilia patients with factor activity below 10% before getting vaccinated. Aim(s): To evaluate side effects of Sinopharm vaccine in patients with CBD. Method(s): A total of 93 patients including 75 males and 18 females who filled the consent form, participated in this historical cohort study. A questionnaire was designed to report any experienced side effects. In case of continuing feel of discomfort at the injection site, it was recommended to administration of coagulation factor concentrate. Result(s): The mean age of the patients was 37 +/- 12.8 (18-78) years. The type of bleeding disorders is shown on table 1. The disease severity was mild in 41.9%, moderate in 8.9%, and severe in 41.9% of the patients. About 65% of patients had coagulation factor activity less than 10%. Comorbidities were seen in 7 patients. The most common reported side effects were headache (6.6%), feeling weakness (5.5%) and body pain (4.4%). Two patients (2.1%) experienced hematoma following vaccination in injection site, one severe hemophilia A patient who recovered without any treatment. Another one was a severe hemophilia B who received Factor concentrate resulted in disappearing hematoma. Conclusion(s): No safety concerns were detected in patients who received two doses of Sinopharm vaccine. Moreover, our results showed that it seems vaccination is safe in patients with factor activity less than 10% without giving prophylaxis. This issue is important due to the limited access to coagulation factors in developing countries. (Table Presented).

Safety of intramuscular COVID-19 vaccination in patients with hemophilia

Background: Guidelines recommend that patients with hemophilia should preferably receive vaccination subcutaneously rather than intramuscularly. COVID-19 vaccines, however, are only licensed for intramuscular application. Aim(s): To assess the safety of intramuscular COVID-19 vaccination in patients with hemophilia. Method(s): This observational multicenter study consisted of two parts. Part A enrolled consecutive patients with hemophilia A (HA) and B (HB) of all ages and severities and assessed injection site bleeding and other complications within 30 days of vaccination. Part B enrolled patients providing informed consent for more detailed data collection including medication and prophylaxis around the time of vaccination. Result(s): Four hundred and sixty-one patients were enrolled by six institutions into part A (HA 389 [84%], HB 72 [16%];severe 291 [63%], moderate 61 [13%], mild 109 [24%]). The primary endpoint injection site bleeding occurred in 7 patients (1.5%, 95% confidence interval 0.6-3.1%), including 5 with severe HA, 1 moderate HA, and 1 mild HB. Analysis of 214 patients in part B revealed that 97% of patients with severe hemophilia, who were not on emicizumab, had received factor prophylaxis before vaccination, either as part of their regular regime (60%) or additionally (40%). Only one patient on emicizumab received additional factor. The bleeding patients with severe HA had received factor within 2-17h before vaccination and had no clinical characteristics that could have explained the bleeding. Factor was also given to 26% and 60% of mild and moderate patients not on regular prophylaxis, respectively. The two bleeding patients in this group had not received concentrate before vaccination. Other side effects of vaccination were comparable with studies in the general population. Conclusion(s): This is the first study reporting on the safety of intramuscular COVID-19 vaccination in hemophilia. The rate of injection site bleeding was below 3%, comparable with the general population.

Atypical Presentation of Lance Adams Syndrome in the setting of Clonazepam overdose and SARS-CoV-2 pneumonia

Objective: To report an atypical presentation of Lance-Adams Syndrome presenting from severe respiratory depression rather than cardiac arrest and to highlight the importance of distinguishing it from post hypoxic myoclonic variants. Background: Clinicians often face difficulty distinguishing Lance-Adams Syndrome (LAS) from Myoclonic Status Epilepticus (MSE). Similarities between the two conditions frequently result in confusion when diagnosing, managing and prognosticating for post-hypoxic myoclonus patients. Design/Methods: A 23-year-old male with a history pertinent for Hemophilia B, depression, opiate and alcohol abuse and chronic pain was found down in his home next to an empty bottle of clonazepam. He was hypoxic with oxygen saturation in the 40s and intubated in the field. Upon arrival to the Emergency room, neurological examination revealed intact corneal reflexes but no gag reflex, cough, or purposeful movements of the extremities. The patient exhibited stimulus induced myoclonic jerking which lasted >30 minutes despite being loaded on valproic acid and levetiracetam. Jerking subsequently ceased with propofol drip. Chest X-ray confirmed interstitial opacities and tested positive for SARS-CoV-2. On attempting to wean sedation, patient exhibited full-body myoclonus including face and palate with inability to follow commands and lack of spontaneous movements. As the EEG showed BIPEDS greater than 2.5 HZ, we decided to burst suppress him and treat with targeted temperature management. After 10 days, the patient was successfully weaned from sedation and extubated, but remained on multiple anti-seizure medications. Results: Patient responded well despite his diffuse cerebral anoxic injury. He regained the ability to follow commands upon discharge but had residual moderate expressive aphasia and post-hypoxic action-induced myoclonus, consistent with LAS. Conclusions: The atypical presentation of this case emphasizes the importance of distinguishing LAS from MSE to guide neurologists to aggressively treat LAS to improve outcome, particularly since MSE historically results with a 90-100% mortality rate.

REMOTE COORDINATION of the MULTIDISCIPLINARY HAEMOPHILIA TEAM with SKELETAL IMAGING SUPPORT. beyond the PANDEMIC

Introduction: Regional referral hospital usually receives patients who live far away in neighboring cities. Due to distance or disability, it was difficult to get medical attention during Covid Pandemia. So a multicenter coordination of a specilized multidisciplinary team has been implemented. Specific patient's problems were assessed in a dynamic and quick way, solving concerns and determining therapeutic and surgical decisions. Methods: Between January 2019 and October 2021, 62 medical consultations in patients with Haemophilia A and B were carried out in the multidisciplinary assessment system. Range of age was between 5 and 43 years. Whats App and other telemedicine systems were used, in order to solve patients concerns. This evaluation platform was valued by the hematologyst, orthopedist and radiologyst altogether. Radiographs, MSK Ultrasound, MRI and patient clinical photos were uploaded when necessary in this WhatsApp Platform to be checked by the multidisciplinary group. Results: First Ultrasound study was usually requested in their place of origin. In some cases technical supervision was required. If this imaging method was not available or there was lack of trained personnel, patients were asked to attend the hospital. Sometimes the use of MRI was recommended. Ultrasound follow up evaluation was always carried out in our hospital. In all cases Musculoskeletal Images were reviewed by our specially trained Radiologyst, centralizing interpretation and decision-making in our institution. Orthopedic Surgeon and Hematolgyst also took part remotely with treatment and kinesic indications to be carried out in their living cities. Sport activity gradually reincorporation was also valorated by this way. All patients issues were finally able to be solved through this platform. Discussion/Conclusion: Patient management has always been done in our hospital, but we have learned to adapt to our patient's needs. Previous implementation of this clinical and imaging management modality allowed us to give a quick answer to the requirements during Covid Pandemia, adecuating treatment in order to resolve the hemorragic episodes. This modality has been very useful in MSK commitment reducing the influx and circulation of patients, speeding up and facilitating access to medical care. Dynamic and fused coordination of the multidisciplinary team, highly committed to the patient's problems is the clue.

Efficacy and Safety of Fitusiran Prophylaxis, an siRNA Therapeutic, in a Multicenter Phase 3 Study (ATLAS-INH) in People with Hemophilia A or B, with Inhibitors (PwHI)

Introduction Hemophilia A and B are rare bleeding disorders characterized by ineffective clot formation due to impaired thrombin generation as a result of deficiency of FVIII or FIX, respectively. Fitusiran is a subcutaneously (SC) administered investigational siRNA therapeutic targeting antithrombin to restore thrombin generation and rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. Here, we present the safety and efficacy of fitusiran prophylaxis for PwHI in a phase 3 study (ATLAS-INH;NCT03417102). Methods The ATLAS-INH study is a randomized, open-label Phase 3 study designed to evaluate the efficacy and safety of fitusiran in PwHI. Eligible males ≥12 years receiving on-demand treatment with bypassing agents (BPA) were randomized in a 2:1 ratio to receive once monthly 80 mg SC fitusiran prophylaxis or continue with on-demand BPA. The primary endpoint is annualized bleeding rate (ABR) in PwHI on fitusiran prophylaxis compared to those on BPA on-demand in the efficacy period. The secondary endpoints include spontaneous ABR, joint ABR, and quality of life (QoL) measured by Haem-A-QoL. Results 57 subjects were randomized into the study. Mean (range) age of the study participants at screening was 28.4 (13-63) yrs. Statistical significance was achieved for primary and all secondary endpoints with significant reduction in ABRs of treated bleeds: all, spontaneous and joint bleeds for fitusiran vs on-demand BPA arm (Table 1). A total of 25 patients in fitusiran arm (65.8%) had zero treated bleeding events. Efficacy of fitusiran prophylaxis treatment was seen in both hemophilia A and hemophilia B patients with inhibitors. Statistical significance was also achieved for improvement in physical health domain score, with a difference (95% CI) of -28.72 (-39.07 to -18.37, p-value <0.0001) as well as overall HRQoL and between fitusiran and on-demand BPA arms. Overall, 38 patients (92.7%) in the fitusiran arm and 11 patients (57.9%) in the on-demand BPA arm experienced at least 1 treatment emergent adverse event (TEAE). A total of 13 treatment emergent serious adverse events (TESAEs) were reported in 7 patients (17.1%) in the fitusiran arm and 8 TESAEs were reported in 5 patients (26.3%) in the on-demand BPA arm. All TESAEs were reported in 1 patient each;in the fitusiran prophylaxis arm these included events of device related infection, hematuria, spinal vascular disorder, subclavian vein thrombosis, thrombosis, acute cholecystitis, chronic cholecystitis and asymptomatic COVID-19. One patient (2.4%) in the fitusiran arm experienced TEAEs that resulted in study drug discontinuation (spinal vascular disorder and thrombosis). There were no fatal TEAEs reported. Conclusions This Phase 3 study demonstrated the efficacy of the 80 mg monthly subcutaneous prophylaxis dose of fitusiran in people with hemophilia A or B with inhibitors. Specifically, fitusiran significantly reduced bleeding with a median ABR of zero and significant proportion of people with zero bleeds, resulting in a meaningful improvement in health-related quality of life. Reported TESAEs were generally consistent with what is anticipated in an adult and adolescent population with severe hemophilia A or B with inhibitors, or with the previously identified risks of fitusiran. A revised fitusiran dosing regimen with reduced dose and dose frequency is currently being evaluated in ongoing clinical studies. [Formula presented] Disclosures: Young: Genentech/Roche, Grifols, and Takeda: Research Funding;Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy. Kavakli: Roche: Consultancy, Other: Clinical Trial Support;Novo Nordisk A/S: Consultancy, Other: Clinical Trial Support;Takeda: Consultancy, Other: Clinical Trial Support. Poloskey: Sanofi: Current Employment, Current equity holder in publicly-traded company. Qui: Sanofi: Current Employment, Current equity holder in publicly-traded company. Kichou: Sanofi: Current Employment, Current equity holder in publicly-tr ded company. Andersson: Sanofi: Current Employment, Current equity holder in publicly-traded company;WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees. Mei: Sanofi: Current Employment, Current equity holder in publicly-traded company. Rangarajan: Sanofi: Other: Advisory Board;Pfizer: Other: Advisory Board;Reliance Life Sciences: Consultancy;Takeda: Other: Advisory Board, Conference Support, Speakers Bureau.