Challenges in ageing persons with haemophilia.

As treatments for individuals with inherited bleeding disorders improve, life expectancy increases and is approaching that of the normal population. Concomitant with this we are now seeing the problems of ageing in the bleeding disorder population. Although the clear-cut association between low clotting factor levels and risk of bleeding is well recognised, a relationship between high levels, some non-factor therapies and thrombotic risk also exists. The management of thrombosis in persons with inherited bleeding disorders is complex but manageable with modern treatments and collaboration in decision making between health care professionals and patients. Despite the improvements in treatment and reduction in bleeding, mostly musculoskeletal pain continues to be a major issue with advancing age. The management of pain amongst older people with haemophilia who may have multiple comorbidities should involve a person-centred, holistic, multi-disciplinary approach to support and optimise long-term physical functioning and overall quality of life.

Oral health status and oral habits of children and adolescents with hemophilia: a report from the children's hemophilia comprehensive care center of China.

In recent years, the diagnosis and treatment of hemophilic children in China has significantly improved. However, oral health conditions, which affect quality of life, haven't received attention in this population. To explore the oral health status and oral hygiene of children and adolescents with hemophilia in the Children's Hemophilia Comprehensive Care Center of China. Dental and oral hygiene examinations were performed in children and adolescents with hemophilia who visited Beijing Children's Hospital. DMFT/dmft (decayed, missing, filled teeth in permanent and primary teeth) was assessed according to World Health Organization (WHO) criteria. The simplified oral hygiene index (OHI-S) was used to evaluate the oral hygiene condition of the subjects. Questionnaires were completed by their parents. SPSS 21.0 was used for statistical analysis. A total of 114 children and adolescents were enrolled. The caries prevalence was 57.4%, 72.2% and 41.2% in primary, mixed and permanent dentitions respectively. The filling rates were 14.4%, 13.9%, and 11.4%, respectively, and the OHI-S scores of the three dentition groups were 1.49 ± 0.46, 1.57 ± 0.43, and 1.76 ± 0.46, respectively. A total of 103 valid questionnaires were collected. Sixty-nine children (67%) didn't brushed their teeth 2 times a day. Nearly half of the parents knew little about fluoride toothpaste. Multiple linear regression analysis revealed that brushing teeth with the help of parents had a significant positive impact on OHI-S.  Conclusion: Dental health was unsatisfactory among hemophilic children and adolescents. The caries filling rates were low. Patients and their parents did not give much attention to oral health. What is Known: • Caries and gingivitis are the two main oral diseases that affect children with hemophilia. • However, the oral health conditions of children and adolescents with hemophilia have not received much attention in China. What is New: • This is the first study concentrating on the dental health of children with hemophilia in China. • Dental health was unsatisfactory among children and adolescents with hemophilia in China.

Foam roller-based self-induced myofascial therapy in patients with hemophilic knee arthropathy: a multicenter, single-blind, randomized clinical study.

BACKGROUND: Hemophilia is a congenital coagulopathy characterized by degenerative joint damage. Self-induced myofascial therapy aims to decrease pain and improve tissue mobility, functionality and proprioception. AIM: The aim of this study was to evaluate the safety and efficacy of self-induced myofascial release in patients with hemophilic knee arthropathy. DESIGN: This is a randomized clinical study. SETTING: This study was carried out in different patient associations. POPULATION: Fifty-two patients with hemophilia were included in the study. METHODS: Patients were randomized to the experimental group (daily home protocol of foam roller-based self-induced myofascial therapy for 8 weeks) or the control group (no intervention). The variables were the frequency of hemarthrosis (self-reporting), pain intensity (visual analog scale), range of motion (goniometry) and muscle strength (dynamometry). All variables were evaluated at baseline, post-treatment and after a 10-week follow-up. RESULTS: The patients included in the experimental group showed significant improvements in terms of a decrease in frequency of hemarthrosis (mean difference [MD]=-0.61; 95% confidence interval [CI]: -0.81; -0.41) and pain intensity (MD=-0.33; 95% CI: -0.48, -0.18), increased range of motion (MD=0.88; 95% CI: 0.39; 1.37), strength in quadriceps (MD=0.88; 95% CI: 0.39; 1.37). (MD=12.39; 95% CI: 3.44; 21.34) and hamstrings (MD=7.85; 95% CI: 0.60; 15.11). There were intergroup differences in the frequency of hemarthrosis (F=14.51; P<0.001), pain intensity (F=9.14; P<0.001) and range of motion (F=13.58; P<0.001). CONCLUSIONS: Self-induced myofascial therapy can be an effective complementary technique in the treatment of patients with hemophilic arthropathy. Self-induced myofascial therapy can reduce the frequency of knee hemarthrosis in patients with hemophilia. This technique can improve pain intensity and range of motion in patients with hemophilic knee arthropathy. CLINICAL REHABILITATION IMPACT: Hemophilic knee arthropathy is characterized by chronic pain, decreased range of motion, and periarticular muscle atrophy. Foam roller-based self-induced myofascial therapy can reduce the frequency of hemarthrosis and pain intensity and improve range of motion in patients with hemophilic arthropathy. Foam roller-based self-induced myofascial therapy is safe and effective in the treatment of patients with hemophilia. The inclusion of self-induced myofascial therapy exercises in the approach to degenerative joint pathologies may be an effective and safe treatment option.

Building a haemophilia-specific navigator in Epic® Electronic Health Records: Single-centre preliminary experience.

INTRODUCTION: With the increasing complexity of haemophilia care and the advent of numerous therapeutic innovations, there is an unmet need for documentation and data collection tools tailored to people with haemophilia (PwH). To date, no fully integrated haemophilia-specific electronic health record (EHR) has been described in the literature. AIM: To evaluate the feasibility of integrating a haemophilia-specific navigator into the Epic EHR. METHODS: Based on clinical experience and registry datasets, we identified key variables describing both PwH and carriers of haemophilia. These were then incorporated into a REDCap database, which served as a starting point for the development of a comprehensive haemophilia flowsheet. We built a dedicated haemophilia navigator within Epic that includes a flowsheet featuring up to 212 variables, as well as customised note templates and patient lists integrating data from the haemophilia flowsheet. RESULTS: It was feasible to develop a haemophilia navigator within Epic over the course of 12 months. The navigator's flowsheet enables systematic and comprehensive clinical assessment of PwH and carriers, while customised patient lists provide a quick summary of each patient's profile to the haemophilia treatment centre staff and highlight issues that require an intervention. In our clinical practice, patients actively participated in the new documentation process and responded positively to the navigator. CONCLUSION: Adapting EHRs to the needs of PwH and carriers promotes holistic care for this population and provides an opportunity for patient empowerment. Such haemophilia-specific EHRs are expected to promote standardisation of care and facilitate the collection of registry data on a national and international level.

Age-specific incidence of joint disease in paediatric patients with haemophilia: A single-centre real-world outcome based on consecutive US examination.

INTRODUCTION: Joint health is one of the most important factors contributing to a healthy life in patients with haemophilia. Recent study revealed that starting early prophylaxis was not enough to prevent joint disease in most paediatric patients with haemophilia. AIM: In this study, we aimed to determine the age-specific incidence of acute joint disease during childhood at single haemophilia treatment centre (HTC). METHOD: The joint health in 48 patients was evaluated based on consecutive US testing for 5 years at annual multidisciplinary comprehensive care. RESULTS: During the study period, 23 patients (47.9%) had no joint disease since the initial examination, whereas 13 patients (27.0%) showed development from negative to positive findings. The incidence of joint disease increased with age: 0% in preschool, 5.3% in elementary school, 14.3% in junior high school and 35% beyond high school age. Among the 13 patients who developed joint disease, two experienced acquired synovitis that resolved during the follow-up period. Statistical analysis revealed that the patients who routinely underwent follow-up by the HTC exhibited a significantly lower incidence of joint disease than did those followed up at other institutions (p < .001). CONCLUSION: These results indicated that close check-up, including routine joint examination using US as well as frequent assessment of pharmacokinetic profile at the HTC, might play an important role in avoiding joint disease among paediatric patients with haemophilia.

Quality of life, self-reported outcomes and impact of education among people with moderate and severe hemophilia A: An integrated perspective from a Latin American country.

Collecting and interpreting self-reported outcomes among people with hemophilia A supports the understanding of the burden of the disease and its treatment to improve holistic care. However, in Colombia, this information is limited. Therefore, this study aimed to describe the knowledge, perception and burden of hemophilia A from the patients' perspective. A cross-sectional study was conducted in the context of a hemophilia educational bootcamp held from November 29th to December 1st, 2019, in Medellin, Colombia. The bootcamp was organized by a hemophilia patient association responsible for contacting and inviting patients with hemophilia A (PwHA). Information on patients' health beliefs, treatment experiences, and health-related quality of life (HRQoL) was obtained through focus groups, individual interviews and the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire. A total of 25 moderate or severe PwHA were enrolled in this study and completed the PROBE questionnaire. Acute pain was the most frequently reported symptom, with 88% of the patients reporting the use of pain medication. Difficulty with activities of daily living was reported by 48%. Furthermore, 52% reported having more than 2 spontaneous bleeding events in the last year. Treatment was administered at home for 72% of patients, with regular prophylaxis as the most common treatment regimen. In terms of overall HRQoL, the median EQ-5D VAS score was 80 (IQR: 50-100). PwHA in Colombia still suffer from disease complications related to bleeding events, pain and disability that affect their HRQoL, which highlights the need to develop patient-centered initiatives to improve the wellness of this population.

Effect of low-level laser therapy on post-extraction hemostasis in patients with hemophilia - A prospective cohort study.

Dental extraction in hemophiliacs can be complicated by perilous bleeding. Although developments in local hemostatics and factor replacement have made outpatient extraction feasible, there is no standard protocol for preventing hemorrhagic exigency. Low-level laser therapy (LLLT) has firmly established role in hemostasis due to its ability to seal vessels, but this function has not been conclusively established in hemophiliac patients. The objective of our study was to evaluate the effectiveness of LLLT as compared with the standard protocol alone in achieving post-extraction hemostasis. A prospective interventional cohort study was designed and consisted of 60 patients with hemophilia A or B, who reported to the Maulana Azad Institute of Dental Sciences, New Delhi between October 2021 and March 2022. These were divided equally into test and control groups, both following the standard protocol. In the test group, extraction sockets were exposed to LLLT. The study assessed time required, instance of rebleeding, and additional methods employed for hemostasis in each group. The results showed a 22.42% reduction in average time taken to achieve hemostasis in the test group as compared with the control group. The tranexamic acid pack was replaced in two cases in both groups after 60 min of procedure. Three cases in the control group required suturing, and one case required cauterization. Rebleeding occurred in four cases in the test group and in 13 cases among the controls. Postoperative factor was infused in three and 12 cases in the test and control groups, respectively. The authors believe that perioperative use of LLLT should be encouraged because it demonstrated a significantly reduced time for hemostasis among hemophilia patients.

Hemophilia gene therapy: first, do no harm.

The introduction of adeno-associated virus-mediated, liver-directed gene therapy into the hemophilia treatment landscape brings not only great promise but also considerable uncertainty to a community that has a history punctuated by the devastating effects of HIV and hepatitis C virus. These infections were introduced into people with hemophilia through the innovation of factor concentrates in the 1970s and 1980s. Concentrates, heralded as a major advance in treatment at the time, brought devastation and death to the community already challenged by the complications of bleeding into joints, vital organs, and the brain. Over the past 5 decades, considerable advances in hemophilia treatment have improved the survival, quality of life, and participation of people with hemophilia, although challenges remain and health equity with their unaffected peers has not yet been achieved. The decision to take a gene therapy product is one in which an informed, holistic, and shared decision-making approach must be employed. Bias on the part of health care professionals and people with hemophilia must be addressed and minimized. Here, we review data leading to the regulatory authorization of valoctocogene roxaparvovec, an adeno-associated virus 5 gene therapy, in Europe to treat hemophilia A and etranacogene dezaparvovec-drlb in the United States and Europe to treat hemophilia B. We also provide an overview of the decision-making process and recommend steps that should be taken by the hemophilia community to ensure the safety of and optimal outcomes for people with hemophilia who choose to receive a gene therapy product.

Budget impact of prophylactic treatment of rVIII-SingleChain in moderate and severe hemophilia A in Italy.

INTRODUCTION: rVIII-SingleChain, a recombinant factor VIII (rFVIII), has demonstrated safety and efficacy in patients with hemophilia A in clinical trials and real-world evidence. This analysis aimed to estimate the potential budget impact of increasing the usage of rVIII-SingleChain for the prophylactic treatment of hemophilia A over 3 years in Italy. METHODS: Patients with moderate and severe hemophilia A receiving prophylaxis were included in the analysis. Epidemiological data were obtained from published literature. Mean product consumption and mean annual bleeding rate for rVIII-SingleChain, rFVIIIFc, octocog alfa and BAY 81-8973 were based on pooled real-world data from Italy, Germany and US. A budget impact model has been developed in order to compare two scenarios: a base-case scenario where current rVIII-SingleChain shares are kept constant over 3 years and an alternative scenario where rVIII-SingleChain shares increase by taking from other rFVIII products. Analysis 1 was based on the current Italian list prices and Analysis 2 considered current regional acquisition prices for both scenarios. RESULTS: Annually, adult patients treated with rVIII-SingleChain prophylaxis are expected to consume 324,589 units per patient, resulting in annual costs of €240,196 per patient. In Analysis 1, comparing the base case (constant market share of 9% rVIII-SingleChain over time) with the alternative scenario (higher rVIII-SingleChain market share and increasing from 15% in the first year to 25% in the third year), the total expenditure for prophylaxis using rFVIII products is expected to decrease by €1.4 million in Year 1, by €3.1 million in Year 2 and by €5.4 million in Year 3. In Analysis 2 based on regional prices, the results remained consistent. DISCUSSION/CONCLUSION: This analysis suggests that increasing utilization of rVIII-SingleChain in hemophilia A patients may lead to cost savings as a result of reduced consumption with uncompromised efficacy in bleed protection.

Why was the study done? Hemophilia A is a rare inherited bleeding disorder. People with severe hemophilia are more likely to bleed compared to people without hemophilia and bleeds can occur spontaneously or in response to trauma. Patients are treated with medication to reduce the chance of bleeding. However, the cost of treating patients with hemophilia can be high and place demands on the healthcare system.What did we do and find?This study looked at the cost of treating people with hemophilia in Italy and used a type of economic analysis (called budget impact modelling) to estimate the effect of increasing the use of a particular medication (rVIII-SingleChain), compared to other medications that are available. Different variations of the model were tested to compare a range of scenarios.The results of this analysis suggested that increasing the use of rVIII-SingleChain may lead to cost-savings for the Italian healthcare system, compared to using the other currently available treatments. This analysis suggests that the use of rVIII-SingleChain enables people with hemophilia A to remain protected from bleeds, whilst using less product compared to other available medications.What is the influence of this study on the wider field?This type of analysis can be useful to healthcare systems, to guide the decision-making process regarding which medications to use or when making decisions related to healthcare policy.

Characteristics of BAY 2599023 in the Current Treatment Landscape of Hemophilia A Gene Therapy.

Hemophilia A, a single gene disorder leading to deficient Factor VIII (FVIII), is a suitable candidate for gene therapy. The aspiration is for single administration of a genetic therapy that would allow the production of endogenous FVIII sufficient to restore hemostasis and other biological processes. This would potentially result in reliable protection from bleeding and its associated physical and emotional impacts. Gene therapy offers the possibility of a clinically relevant improvement in disease phenotype and transformational improvement in quality of life, including an opportunity to engage in physical activities more confidently. Gene therapy products for hemophilia A in advanced clinical development use adeno-associated viral (AAV) vectors and a codon-optimized B-domain deleted FVIII transgene. However, the different AAV-based gene therapies have distinct design features, such as choice of vector capsid, enhancer and promoter regions, FVIII transgene sequence and manufacturing processes. These, in turn, impact patient eligibility, safety and efficacy. Ideally, gene therapy technology for hemophilia A should offer bleed protection, durable FVIII expression, broad eligibility and limited response variability between patients, and long-term safety. However, several limitations and challenges must be overcome. Here, we introduce the characteristics of the BAY 2599023 (AAVhu37.hFVIIIco, DTX 201) gene therapy product, including the low prevalence in the general population of anti-AAV-hu37 antibodies, as well as other gene therapy AAV products and approaches. We will examine how these can potentially meet the challenges of gene therapy, with the ultimate aim of improving the lives of patients with hemophilia A.

Humanistic burden of problem joints for children and adults with haemophilia.

INTRODUCTION: The "problem joint" (PJ) concept was developed to address patient-centric needs for a more holistic assessment of joint morbidity for people with haemophilia (PwH). AIM: To quantify the humanistic burden of PJs in PwH to further support validation of the PJ outcome measure. METHODS: Multivariable regression models evaluated the relationship between PJs and health-related quality of life (HRQoL, EQ-5D-5L) and overall work productivity loss (WPL) using data from the 'Cost of HaEmophilia: a Socioeconomic Survey' population studies (adults: CHESS II, CHESS US+; children/adolescents: CHESS-Paeds). Covariates included were haemophilia severity, age, comorbidities and education. RESULTS: The CHESS II sample included 292 and 134 PwH for HRQoL and WPL analyses, mean age 38.6 years (39% ≥1 PJ, 61% none). CHESS US+ included 345 and 239 PwH for HRQoL and WPL, mean age 35 years (43% ≥1 PJ, 57% none). CHESS-Paeds included 198 PwH aged 4-17 (HRQoL only), mean age 11.5 years (19% ≥1 PJ, 81% none). In CHESS II and CHESS US+, presence of PJs was associated with worse HRQoL (Both p < .001). Few CHESS-Paeds participants had PJs, with no significant correlation with HRQoL. In CHESS II, upper body PJs were significantly correlated to WPL (p < .05). In CHESS US+, having ≥1 PJ or upper and lower body PJs were significantly correlated to WPL (vs. none; both p < .05). CONCLUSION: This study has shown a meaningful burden of PJs on PwH, which should be considered in clinical and health policy assessments of joint health.

Multiple criteria decision analysis for therapeutic innovations in a hemophilia care center: A pilot study of the organizational impact of innovation in hemophilia care management.

BACKGROUND: Several innovative drugs liable to lead to changes in healthcare organization are or soon will be available for the management of hemophilia. Analyzing their implementation can shed further light on healthcare decision-making, to anticipate changes and risk of breakdown in the patient's care pathway. METHODS: Multiple criteria decision analysis (MCDA), based on ISPOR recommendations, was used to assess the organizational impact of innovation in hemophilia care management. The MCDA process designed for this specific context involved ten French experts in hemophilia care management (physicians, nurses, pharmacist, physiotherapist and psychologist) in the hemophilia care center of Chambéry, in the Rhône-Alpes Region of France. This pilot study involved seven steps: (i) defining the decision problem; (ii) selecting and structuring criteria; (iii) assessing the relative weight of each criterion with software-assisted simulation based on pairwise comparisons of different organizational change scenarios; (iv) measuring the performance of the selected innovations; (v) scoring alternatives; (vi) calculating aggregate scores; (vii) discussion. The endpoint was to determine the expected overall organizational impact on a 0-100 scale. RESULTS: Seven organizational criteria were selected. "Acceptability for patient/caregiver/association" was the most heavily weighted. Factor VIII by subcutaneous route obtained the highest aggregate score: i.e., low impact on care organization (88.8 out of 100). The innovation with strongest organizational impact was gene therapy (27.3 out of 100). CONCLUSION: This approach provided a useful support for discussion, integrating organizational aspects in the treatment decision-making process, at healthcare team level. The study needs repeating in a few years' time and in other hemophilia centers.

Adding a Clinical Hemophilia Pharmacist to the Hemophilia Comprehensive Care Model Improves Health Care-Related Outcomes and Drug-Related Costs in an Integrated Health Care System.

IntroductionThe National Hemophilia Foundation has advocated for a comprehensive care model in caring for patients with hemophilia. Currently pharmacists are not included as part of the team, and the impact of specific team members on patient outcomes is unknown. The authors designed an intervention to add a clinical pharmacist to this care model. The authors evaluated the impact of this intervention on bleeding outcomes, medication access and adherence, and cost within an integrated health care system. MethodsThe authors performed a multicenter, retrospective analysis of all hemophilia A and B patients enrolled in the hemophilia pharmacy service between March 2017 and February 2019. The authors analyzed data prior to and after this quality improvement project, encompassing the period between March 2016 and February 2020. Primary outcomes included an evaluation of the annualized bleed rates, emergency department visits, and hospitalizations. ResultsIn the cohort of patients with hemophilia A and B, the overall bleed rate was reduced from 40 per 100 patient-years to 37.6 per 100 patient-years. Similarly, emergency department visits were reduced from 22.7 to 18.3 per 100 patient-years, and hospitalizations reduced from 6.4 to 3.0 per 100 patient-years (p values >.05). This was augmented by the use of a unique factor recycling program that saved $900,000 in medication costs over a 12-month period. DiscussionThis study shows that the addition of a clinical pharmacist to the core hemophilia team leads to positive trends toward improved bleeding outcomes for patients, improved medication access and adherence, and substantial cost savings to the health system.

"Haemophilia A" - Presenting with oral squamous cell carcinoma diagnosis and management strategies.

Hemophilia is a hereditary disorder of coagulation that results in deficiency of factor VIII (Hemophilia A) or Factor IX (Hemophilia B) with characteristic X linked mode of inheritance, almost exclusively seen in males while females are asymptomatic carriers.The common clinical manifestation in both is prolonged bleeding on trivial trauma, mainly into larger joints or muscles. Life threatening bleeding episodes can result spontaneously or from trauma to the head or internal organs. Replacement of deficient clotting protein, known as Anti Hemophilic Factor (AHF) is the main stay in the treatment of haemophilia. Any Surgical treatment of these patients is to be planned in Institution hospital where comprehensive care is available. The availability of AHF has enabled surgeons to take up surgeries in patients with haemophilia. We discuss PWH with congenital factor VIII deficiency presented with oral squamous cell carcinoma of left side lower jaw with main aim is to provide insight into surgical management and care protocol of these patients.

Defining the micro and macro roles of a hemophilia treatment center social worker in the United States from an interdisciplinary team perspective.

INTRODUCTION: The social worker (SW) role in the Hemophilia Treatment Center (HTC) is complex and broad, providing direct support, spanning across micro, mezzo and macro levels of care. AIM: Research demonstrates discrepancy between actual and ideal SW roles among the HTC SW community. Soliciting perceptions from HTC staff about the SW role can provide a deeper understanding of this discrepancy and improve collaboration amongst care team members in meeting the psychosocial needs of HTC patients. METHODS: Funded by the National Hemophilia Foundation (NHF), a national online survey was conducted in 2020 to determine the views and attitudes of what the SW role is by HTC staff. Separate surveys were emailed to active HTC SWs and staff to collect anonymous data. Demographics of SWs gathered included age, education, years of practice, full time equivalent (FTE) status, and caseload. All disciplines were asked questions about perceptions, barriers, and potential ways to enhance and strengthen the SW role within HTCs. RESULTS: Results demonstrated that subcategory-oriented questions (40 in total) and qualitative responses highlighted diverse viewpoints and offered clarity about these differences. CONCLUSION: Findings indicated most HTC staff value the multi-faceted role of SW at their centres, and both groups identified time, limited resources, and role confusion as barriers to utilizing SW services. Outcomes will inform the development of a "standards of practice" tool that will provide education for HTC staff, patients, and families, and serve as an empowerment tool for SW to highlight their skillset and define their role.

Eradication of FIX inhibitor in haemophilia B children using low-dose immune tolerance induction with rituximab-based immunosuppressive agent(s) in China.

INTRODUCTION: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications. AIM: To characterize clinical features and outcome of ITI on HBI. METHODS: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low-dose ITI (25-50 FIX IU/kg/three-times-weekly to every-other-day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens. RESULTS: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7-512) BU, and 15 (93.8%) had high-titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen-1), four achieved tolerization in 1.4-43.3 months. Two subsequently relapsed but re-tolerized after a second course of IS Regimen-1. During ITI, the median treated bleed was .39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients received modified 'Beutel' protocol (IS Regimen-2) using multiple-IS-drugs, and two had rapid tolerization (.8 and 1.8 months). CONCLUSIONS: Inhibitor eradication could be achieved by low-dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen-2 is more effective with less complications.

Management and outcomes of mild hemophiliacs and hemophilia carriers during pregnancy and peripartum period: a hemophilia treatment center experience in the United States.

BACKGROUND: Pregnancy, peripartum management, and outcomes of mild hemophiliacs and hemophilia carriers in the United States are not well established. AIM: To describe the management and outcomes of mild hemophiliacs and hemophilia carriers during assisted conception, pregnancy, peripartum and post-partum period at our hemophilia treatment center (HTC). METHODS: Retrospective review of electronic medical records of pregnant women with mild hemophilia A or B (Factor VIII [FVIII] or Factor IX [FIX] level <0.4 IU/mL) and hemophilia A and B carriers followed at our HTC from January 2008 to October 2020. Demographics, the reason for diagnosis, FVIII and FIX levels at baseline and third trimester, bleeding phenotype and genotype were obtained. Method of conception, factor replacement, iron supplementation, mode of delivery, type of anesthesia, peripartum complications, and offspring outcomes was recorded. RESULTS: There was a total of 18 pregnancies in 12 women (2 with mild hemophilia A, 2 mild hemophilia B, 6 hemophilia A carriers, and 2 hemophilia B carriers). Eleven pregnancies (61%) were conceived naturally and 7 (39%) via in-vitro fertilization (IVF). Eight (44.4%) and 10 (55.6%) pregnancies were vaginal and C-section deliveries, respectively. Neuraxial anesthesia was administered in 17 (94.4%) deliveries without complications. Four pregnancies (22.2%) had bleeding complications, 2 of which were post-partum hemorrhages not requiring transfusion. CONCLUSION: In our case series of pregnant hemophilia carriers and mild hemophiliacs, successful outcomes were achieved with a carefully detailed multidisciplinary-driven approach.

Uncontrollable bleeding after tooth extraction from asymptomatic mild hemophilia patients: two case reports.

BACKGROUND: Uncontrollable bleeding after tooth extraction usually occurs in patients with coagulation diseases, including hemophilia, von Willebrand's disease, vitamin K deficiency, platelet deficiency, and taking anticoagulant drugs. Hemophilia A is an X-linked recessive disorder caused by insufficiency of coagulation factor VIII. Mild hemophilia, defined by factor level between 0.05 and 0.40 IU/mL, is characterized by uncontrollable hemorrhage after trauma or invasive operations. Some mild hemophiliacs may remain undiagnosed until late adulthood. Therefore, surgical management of these patients may be relatively neglected. These case reports describe two uncontrollable bleeding patients with unknown mild hemophilia A after tooth extraction. CASE PRESENTATION: This paper reports 2 cases of persistent bleeding after tooth extraction under local anesthesia which could not be completely stopped by routine treatments. Both of them denied prior illness and injury, allergies, anticoagulant medication history, systemic and family illness. The APTT and other coagulation screening tests of the two patients before surgery were normal. Finally, they were diagnosed with mild hemophilia A via coagulation factor assays. The patients acquired complete hemostasis by receiving coagulation factor supplement therapy in hematologic department. CONCLUSION: Mild hemophilia is marked by subclinical, asymptomatic and even normal coagulation test results. The purpose of these case reports is to bring dental professionals' attention that APTT test alone cannot be used to exclude mild hemophilia, and provide reasonable evaluation and treatment procedures of bleeding patients after tooth extraction.

Impact of first COVID-19 lockdown on paediatric and adult haemophilia patients treated in a French Haemophilia Comprehensive Care Centre.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has created an unprecedented global health crisis. AIM: To investigate the impact of the 1st COVID-19 lockdown on haemophilia patients in terms of symptoms, management, medication adherence, mental health and lifestyle behaviours. METHODS: A prospective cross-sectional phone survey using a two-part questionnaire was conducted in haemophilia patients (adults and children) followed-up in a French Haemophilia Comprehensive Care Centre between May 5, 2020 and June 2, 2020 (CLEO CD study: NCT04390126). RESULTS: Among 284 haemophilia A or B patients with FVIII or FIX < 40% contacted for the study, 239 (84%) including 183 adults and 56 children participated to the survey. In 81% of children and 78% of adults, bleeding episodes remained unchanged or decreased. Medication adherence was 82.0% in adults and 98.2% in children. Non-adherence concerned haemostatic agents in six patients and analgesics in three. Overall, 67% of adults and 71% of children felt as good as before lockdown. In both adults and children, the three major changes in lifestyle behaviours were: increase in screen time (49% and 57%), decrease in physical activity (43% and 48%), and weight gain (32% and 27%), respectively. CONCLUSIONS: Encouraging results were observed in terms of haemophilia symptoms, medication adherence, and mental health. Conversely, a negative impact was observed on lifestyle behaviours in a cohort of French haemophilia patients during the 1st lockdown.

Generation of iPSC line from urine cells of hemophilia A with F8 (p. R814X) mutation.

The lack of coagulation factor VIII in patient with nonsense mutation hemophilia A leads to varying degrees of bleeding symptoms, and long-term use of alternative therapies can produce inhibitors that affect the efficacy. In this study, human induced pluripotent stem cells (iPSCs) of hemophilia A were generated by reprogramming of urine cells. Human urine cells (HUCs) were isolated by collecting patients' mid-stream urine, and cultured to good state in urine medium. Then, the HUCs were transfected with PEP4-EO2S-ET2K and pCEP4-M2L, and iPSCs were obtained in the medium without trophoblast cells and the composition was determined. Finally, alkaline phosphatase staining, karyotype analysis, immunofluorescence staining and teratoma were used to verify that we successfully reprogrammed hemophilia A-specific human induced pluripotent stem cells from patients' urine cells, providing a safe and effective cell model for the study of molecular mechanism and related treatment of hemophilia.