Acquired haemophilia A in Finland: A nationwide study of incidence, treatment and outcomes.

INTRODUCTION: Acquired haemophilia A (AHA) is a bleeding disorder caused by autoantibody development against factor VIII (FVIII). Studies on AHA have mainly focused on patients treated at specialist centres. AIM: To determine the incidence, clinical characteristics and outcomes of AHA in an unselected population-based patient cohort from Finland. METHODS: This retrospective observational cohort comprised all cases diagnosed with AHA in Finland between 2006 and 2019. Patients were identified by the two central laboratories performing FVIII antibody testing in Finland, the Finnish Red Cross Blood Service and HUSLAB. Clinical details were collected from all hospitals and healthcare units where patients were treated. This study was performed in conjunction with the AHA in the Nordics study. RESULTS: The median incidence of AHA was 0.65 per million per year (range 0.19-1.27). Fifty-five patients were identified, with a median age of 76 years and an even sex ratio (51% women). When diagnosed, all had bleeding symptoms with severe bleeds in 92%. First-line immunosuppressive treatment regimens included steroid monotherapy in 31% of cases, steroids and a cytotoxic agent in 51% and a rituximab-based regimen in 16%. Clinical remission was achieved in 71% of cases, and 15% had relapses. Mortality was 13% for bleeds and 9% for treatment-related infections. Overall survival was 64% for 1 year and 56% for 2 years after diagnosis. CONCLUSIONS: In a nationwide population-based cohort study, we discovered a lower incidence of AHA than previously reported. Mortality among patients with AHA was high, calling for the consideration of updated treatment strategies.

Development of a Coagulation Disorders Unit.

Our Coagulation Disorders Unit in Helsinki, Finland, provides 24/7 services for local and national hospitals and colleagues upon requests regarding bleeding and thrombosis diagnostics and management, including follow-up. The unit has a tight connection between the clinic and laboratory, and its maintenance and sharing knowledge and observations have been priorities, already for over 20 years and will continue to be of major importance. The consultation service is provided by phone during daytime and on-call hours, and in written form sent electronically to the consulting stakeholders. Thrombosis and hemostasis-targeted outpatient clinics are also available for the patients referred to the center. Writing local guidance and official guidelines, Nordic, European and international collaboration, and educational activities including social communication are critical elements for the Coagulation Disorders Unit. Alertness to acute coagulation abnormalities, such as occurred during COVID-19 and vaccine-induced thrombosis and thrombocytopenia, and development of strategies to manage cross-disciplinary problems are topics which call upon broad networking. The Nordic community has an ongoing historical meeting, which has been circulating among coagulation centers for the past 56 years. At the European level, the European Association of Haemophilia and Allied Disorders focuses on bleeding disorders and their management, including safety surveillance. The International Society of Thrombosis and Haemostasis offers excellent basic and clinical benchmarks for any Coagulation Disorders Unit. We hope that the description of the development and implementation of our Coagulation Disorders Unit in Helsinki achieves international interest and broadens international collaboration. Finally, we congratulate STH on its great contributions around the globe and for providing a vivid forum to foster the discipline of thrombosis and hemostasis.

Infrastructural considerations of implementing gene therapy for hemophilia in the Nordic context.

Background: Despite improvements in hemophilia care, challenges remain, including treatment burden and impaired quality of life. Gene therapy may overcome these. However, its introduction presents a challenge. Objectives: To outline a function-based gene therapy working model describing critical milestones associated with gene therapy handling, administration, and follow-up to facilitate and implement an effective infrastructure for gene therapy introduction. Design: Literature review and consensus discussion among Hemophilia Comprehensive Care centers (HCCCs) in the Nordic region. Methods: Representatives from six HCCCs sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri-, and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, and follow-up. Results: A gene therapy transit map was developed with key stakeholders identified. The approach to prepare the vector will differ between the Nordic centers, but the contracted pharmacy unit will be a key stakeholder. Therefore, a pharmacy checklist for the implementation of gene therapy was developed. For the future, Advanced Therapy Medicinal Product centers will also be implemented. Patients' expectations, commitments, and concerns need to be addressed repeatedly and education of patients and the expanded health-care professionals team will be the key to successful and optimal clinical management. Eligibility testing according to the product's summary of product characteristics and frequent follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. Conclusion: The approach to deliver gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation of this advanced therapy will be applicable to all. The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.

Implementing gene therapy for hemophilia in the Nordic context Why was this study done? • Despite improvements in hemophilia care, challenges remain including treatment burden and impaired quality of life. • Gene therapy may overcome these challenges. • The introduction of gene therapy presents a challenge in many ways. What did the researchers do? • We, as representatives from six Hemophilia Comprehensive Care Centers in the Nordic region, sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri- and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, plus follow-up. What did the researchers find? • We developed a gene therapy transit map and identified key stakeholders. • The approach to prepare the vector will differ between the Nordic centers, but the pharmacy unit will be a key stakeholder. We therefore developed a pharmacy checklist for the implementation of gene therapy. • For the future, Advanced Therapy Medicinal Product centers will be implemented. • Patients' expectations, commitments and concerns need to be addressed repeatedly. • Education of patients and the expanded health care professionals team will be the key to successful and optimal clinical management. • Eligibility testing according to the product's summary of product characteristics and close follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. • Access to both chromogenic and one-stage factor activity assay results from a specialized coagulation laboratory with a short turn-around time is important. What do the findings mean? • The approach to delivering gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation will be applicable to all. • The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.

Acquired Haemophilia A in four north European countries: survey of 181 patients.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5-99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower.

Switching from standard to extended half-life FVIII prophylaxis in haemophilia A: Comparison of factor product use, bleed rates and pharmacokinetics.

INTRODUCTION: Majority of haemophilia A patients in our comprehensive care centre have switched from standard half-life (SHL) to extended half-life (EHL) FVIII products in a short time. AIM: We compared the clinical and laboratory outcomes between SHL and EHL FVIII prophylaxis in product switchers. METHODS: This is a retrospective inception cohort of all adult haemophilia A patients switched to EHL (rFVIIIFc or rFVIII-PEG) prophylaxis in our centre. Dosing, product utilization, annualized bleed rates (ABR), treatment regimen and pharmacokinetics by Web Accessible Population Pharmacokinetic Service (WAPPS)-Hemo were compared between SHL and EHL. RESULTS: We included 38 patients, whose median age was 38 years (range 17-75). Median FVIII dose was 23 IU/kg for SHL versus 25 IU/kg for EHL. After switching, weekly infusions decreased by 29% from median 2.8 (every 2.5 days) to 2.0 (every 3.5 days) (P = <.001) and factor consumption for prophylaxis by 17% from 60 to 50 IU/kg/week (P = <.001). Weekly infusions decreased in 71% and FVIII utilization in 55% of patients. ABR remained low (1.0 for SHL and .5 for EHL, respectively). In pharmacokinetics, the half-life of FVIII increased from median 13 to 21 h after switching. Times above .01 and .03 IU/ml improved from 85 to 131 h and from 65 to 106 h. Half-lives of the SHL products and von Willebrand factor levels predicted half-lives with the EHL products. CONCLUSIONS: Our cohort study confirms the successful experience of switching to EHL FVIII products, with decreased infusion frequency, factor consumption and excellent clinical efficacy.

Surgical outcomes in patients with haemophilia A or B receiving extended half-life recombinant factor VIII and IX Fc fusion proteins: Real-world experience in the Nordic countries.

INTRODUCTION: Perioperative dosing recommendations vary across Nordic haemophilia treatment centres (HTCs) for extended half-life (EHL) factor concentrates in haemophilia A/B (HA/HB) patients. AIM: To summarise Nordic real-world surgical experiences with EHL recombinant factor VIII/IX Fc (rFVIIIFc/rFIXFc) fusion proteins using retrospective data from clinical records at four HTCs in Finland, Sweden and Norway. METHODS: Factor dosing and surgical outcomes were recorded from HA/HB patients who underwent surgery and were treated with rFVIIIFc/rFIXFc. Perioperative factor dosing regimens were clinician-determined based on local practises. RESULTS: Twenty five surgeries were performed on 20 patients, all covered by bolus injections except one minor HA surgery; eight minor surgeries were in paediatric patients. Median preoperative rFVIIIFc dose for major HA surgeries (n = 8) was 48 IU/kg (range: 35-57), with total consumption up to Day 14 of 427 IU/kg (196-568). For the two major HB surgeries (in one patient), preoperative rFIXFc doses were 50 IU/kg and 20 IU/kg; total consumption up to Day 14 was 130 IU/kg and 40 IU/kg. Median preoperative rFVIIIFc/rFIXFc bolus doses for minor HA (n = 10) and HB (n = 4) surgeries were 50 IU/kg (24-79) and 47 IU/kg (40-71), with total consumption up to Day 5 of 138 IU/kg (49-404) and 100 IU/kg (43-125), respectively. Intraoperative and postoperative haemostatic responses were rated as at least good/excellent for 24/25 surgeries, with bleeding episodes reported in only three surgeries. CONCLUSION: Nordic real-world experiences suggest that EHL products can be used safely and effectively for peri-operative haemostasis. Further research is required to develop local dosing guidelines for optimised treatment schedules.

Von Willebrand Factor Multimeric Assay in Acquired von Willebrand Disease Diagnosis: A Report of Experience from North Estonia Medical Centre.

Objectives Acquired von Willebrand syndrome (AVWS) is a rare and frequently underdiagnosed bleeding disorder with an unknown prevalence. The diagnosis of AVWS is made based on laboratory investigations and the presence of clinical symptoms. Evaluation and management of affected patients are complex due to the need for multiple laboratory assays. Materials and Methods Here, we describe the clinical and laboratory data of seven patients with a diagnosis of AVWS. All patients met the criteria for AVWS based on laboratory findings, bleeding symptoms, and the absence of any previous history of a bleeding disorder. Results In all cases, the laboratory findings, lack of bleeding anamnesis, and family history suggested the presence of AVWS. Von Willebrand factor multimeric analysis showed decreased high-molecular weight (HMW) multimers in six cases. Patients with lower HMW multimers experienced more severe bleeding complications. Conclusions The diagnosis of AVWS is complex and requires extensive laboratory evaluation. Interdisciplinary collaboration and complex laboratory evaluations are of paramount importance for the early recognition of AVWS and optimal AVWS diagnosis as well as successful clinical management.