Haemophilia Comprehensive Care Research Articles

Gynecological bleeding in women with congenital bleeding disorders: A comprehensive cohort from Iran

BackgroundGynecological bleeding including menorrhagia and postpartum hemorrhage (PPH) face women's quality of life constantly with difficulties, especially those suffering from inherited bleeding disorders. In this study, we aim to evaluate gynecological bleeding particularly menorrhagia among Iranian women patients with inherited bleeding disorders admitted to the Iranian Comprehensive Hemophilia Care Center (ICHCC). MethodsThis study was conducted on 156 females aged ≥ 12 diagnosed with an inherited bleeding disorder in ICHCC. Demographic and laboratory data were documented for all patients. Bleeding questionnaires (the International Society on Thrombosis and Hemostasis bleeding assessment tool (ISTH-BAT), Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand disease (MCMDM-1), and Pictorial blood loss assessment chart (PBAC)) were filled out for all patients. For comparing metric and categorical parameters, Mann-Whitney was performed. Spearman's rho test was used for analyzing correlation. ResultsThe mean age of patients was 33. Von Willebrand disease (VWD), Factor (F) VII deficiency and combined factor deficiency were the most diagnosed disorders. The median of ISTH-BAT, MCMDM-1, and PBAC was 7,7, and 517, respectively. Menorrhagia was the most common reason for diagnosis. Menorrhagia and PPH domain scores ≥ 2 were recorded in 82 and 34 patients, respectively, and PBAC scores > 100 were seen in 118 patients. Significant positive correlations were observed between bleeding scores and menorrhagia and PPH scores. No significant correlations were recorded for VWF: Ag and VWF: RCo with menorrhagia and PPH scores; however, significant correlations were seen for VWF: Ag and VWF: RCo with bleeding score questionnaires. ConclusionMenorrhagia is the most common problem in females affected by different types of inherited bleeding disorders, particularly VWD. Increased awareness among gynecologists and hematologists about bleeding disorders in cases with unexplained menorrhagia is an essential step for optimal management.

Anxiety and depression among adults with haemophilia A: Patient and physician reported symptoms from the real-world European CHESS II study.

The physical pain and disability affecting many people with haemophilia A (PwHA) are known detractors from psychological wellbeing. While psychosocial support is considered a core tenet of the haemophilia comprehensive care structure, the extent to which mental health challenges are detected and monitored by the individuals treating haematologist remains relatively unexplored. To describe prevalence of anxiety and depression in a real-world cohort of adult PwHA and evaluate the congruence in reporting of anxiety or depression (A/D) between PwHA and their treating physicians. Data for PwHA without inhibitors was drawn from the European 'Cost of Haemophilia: A Socioeconomic Survey II' (CHESS II) study. Haematologist-indicated comorbidities of anxiety and depression were unified into a single A/D indicator. The EQ-5D-5L health status measure was used to characterise self-reported A/D, with individuals stratified into two non-mutually exclusive subgroups based on level of A/D reported (Subgroup A: 'some' or above; Subgroup B: 'moderate' or above). Of 381 PwHA with evaluable EQ-5D-5L responses, 54% (n=206) self-reported at least some A/D (Subgroup A) and 17% (n=66) reported at least moderate A/D (Subgroup B). Patient-physician congruence in A/D reporting was 53% and 76% for Subgroups A and B, respectively. Descriptive analysis suggested that individuals with physician- and/or self-reported A/D experienced worse clinical outcomes (bleeding events, joint disease, chronic pain). While adverse clinical outcomes appear to correlate with A/D, self-reports of moderate-severe symptoms occasionally lacked formal recognition from treating physicians. Cross-disciplinary surveillance of mental health issues could improve both psychological and clinical outcomes among PwHA.

Canadian clinical experience on switching from standard half-life recombinant factor VIII (rFVIII), octocog alfa, to extended half-life rFVIII, damoctocog alfa pegol, in persons with haemophilia A ≥ 12 years followed in a Comprehensive Hemophilia Care Program in Canada.

Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada. To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment. A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization. Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n=9, 50.0%) versus 38.9% (n=7) of patients treated with octocog alfa. Patients' good quality of life was maintained. This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A.

Blood-Induced Arthropathy: A Major Disabling Complication of Haemophilia.

Haemophilic arthropathy (HA) is one of the most serious complications of haemophilia. It starts with joint bleeding, leading to synovitis which, in turn, can cause damage to the cartilage and subchondral bone, eventually inducing degenerative joint disease. Despite significant improvements in haemophilia treatment over the past two decades and recent guidelines from ISTH and WFH recommending FVIII trough levels of at least 3 IU/dL during prophylaxis, patients with haemophilia still develop joint disease. The pathophysiology of HA is complex, involving both inflammatory and degenerative components. Early diagnosis is key for proper management. Imaging can detect joint subclinical changes and influence prophylaxis. Magnetic resonance imagining (MRI) and ultrasound are the most frequently used methods in comprehensive haemophilia care centres. Biomarkers of joint health have been proposed to determine osteochondral joint deterioration, but none of these biomarkers has been validated or used in clinical practice. Early prophylaxis is key in all severe haemophilia patients to prevent arthropathy. Treatment is essentially based on prophylaxis intensification and chronic joint pain management. However, there remain significant gaps in the knowledge of the mechanisms responsible for HA and prognosis-influencing factors. Better understanding in this area could produce more effective interventions likely to ultimately prevent or attenuate the development of HA.

Comparison of one-stage and chromogenic factor VIII assays to tailor the dose of recombinant factor VIII-Fc fusion protein (rFVIIIFc, efmoroctocog alfa) in adult patients with haemophilia A: Single-centre, real-world experience of surgery.

Efmoroctocog alfa (rFVIIIFc) is an extended half-life FVIII used notably in surgery for patients with haemophilia A. More information is needed of its usage in real-life. Adult patients with HA followed at the Lyon Comprehensive Hemophilia Care Center who underwent a surgery with rFVIIIFc were included in this retrospective analysis. The pharmacokinetics of rFVIIIFc was assessed by plasma factor VIII clotting activity (FVIII:C) using both one-stage (OSA) and chromogenic substrate (CSA) assays. A total of 39 major and 31 minor surgeries were performed in 49 patients treated with rFVIIIFc. The median dose of rFVIIIFc infused before major and minor surgeries respectively was 67.5 ((interquartile range [IQR] 52.6-76.9) and 48.0 (38.5-51.8) IU/kg. For major surgeries, during the first postoperative week, the median residual FVIII:C was 78 (64.5-101.5) IU/dL with OSA and 99 (71-118) IU/dL with CSA (p<.0001). After surgery, rFVIIIFc doses were adjusted according to CSA results. This led to a significant decrease of rFVIIIFc consumption compared to what would have been proposed according to the OSA assay, without unusual bleeding or appearance of inhibitor. Considering the high price of the molecule, this was also associated with a significant cost reduction. Dose adjustment of rFVIIIFc according to FVIII: C measured by CSA is effective, safe and well tolerated in patients with haemophilia A undergoing invasive surgery.

Earliest Possible Detection and Intervention for Synovitis in Hemophilia- Results from a Single Center Retrospective Cohort Study

Introduction There is scientific evidence to suggest that the most serious health problems for hemophilic patients arise from joint damage, which in turn results from joint bleeding, which is overlooked and therefore not treated. The ankle joint was affected the earliest in most hemophilic patients. Strategies for detecting and treating bleeding in hemophilic patients need to be further developed and made more widely known by clinicians. Aim of our study The aim of our retrospective, single-center cohort study was to compare the effects of reactive versus preventive joint ultrasound as guidance for adjustments of treatment regimens for patients with severe hemophilia at our Hemophilia Comprehensive Care Center (HCCC) in Duisburg, Germany. Methods Before 2020, we used ultrasound according to the German hemophilia-synovitis guidelines in 2018. This meant that we sonographed the ankle joints and knees of most of our patients when they reported discomfort in the joint or when a joint bleeding had occurred. In these cases, prophylactic hemophilia treatment was immediately adjusted to a level at which the bleeding and/or discomfort stopped. If the factor treatment was not sufficient to accomplish this goal, the joints were treated with radiosynoviorthesis (RSO). In 2020, we changed our diagnostic strategy from reactive to preventive measures. Thus, we used ultrasound on every ankle and knee joint of our severely hemophilic patients at least once a year. If we found so called “silent symptoms,” which means touch-sensitive joints, the joints were sonographed once every three months. In cases of signs of joint degradation, we adjusted the prophylactic factor treatment accordingly. Results From 2020 to 2022, we examined a total of 1193 joints of 688 patients with hemophilia A or B, as well as with vWD disease type 2 or 3 and other severe coagulation disorders (factor VII deficiency, factor XIII deficiency, afibrinogenemia, and Glanzman disease). Of these, 103 had severe hemophilia A or B. In this study, we examined 656 joints sonographically. Of these, we examined 281 ankle joints in 80 patients and 175 knees in 64 patients, and adjusted the therapy regimens accordingly in these patients if necessary. Seven RSOs of the ankle joints and three RSOs of the knees were performed in the cohort up to 2020. After 2020, only two RSOs of the ankle joints were performed in the cohort. Conclusions At least for patients at our HCCC in Duisburg, Germany, we were able to show for the period 2020-2022 that closer ultrasound monitoring of ankle joints and knees in patients with severe hemophilia A or B and appropriate adjustment of prophylactic factor therapy was associated with less severe and less frequent joint degradation.

High Prevalence of a Rare Bleeding Disorder: A Report from Glanzmann Thrombasthenia Registry of Al-Madinah, Saudi Arabia

Introduction Glanzmann thrombasthenia (GT) is a hereditary bleeding disorder caused by a defect or deficiency of platelet glycoprotein IIbIIIa. Though GT is considered a rare bleeding disorder, some countries in the Middle East report a high prevalence of GT. Aim Description of GT patients' prevalence, demographic, clinical, and genetic features in AlMadinah, Saudi Arabia. Methods This is a 20-year report from the AlMadinah GT registry in the Madinah Hemophilia Comprehensive Care Center. The registry has included all patients with a confirmed diagnosis of GT. To label a patient as GT, He must have absence or abnormal response in all agonists except ristocetin plus absence or reduced expression of platelet glycoprotein IIbIIIa on Flowcytometry. Next-generation sequencing is used to target sequencing for Molecular testing. The extracted data underwent an analysis process, where 136 GT patients were identified. Only 125 cases have complete data in records. Statistical analysis made via a statistical package of social sciences (SPSS) version 23. The research and ethical committee approved the study. Results The prevalence of GT among Saudis in AlMadinah, Saudi Arabia, based on the Saudi population in 2022, is 1:10,000. One hundred twenty-five GT patients were studied: 67 (54%) females and 58 (46%) males. The median age at the time of the report was 16.5 (10 days to 56 years). Ninety-nine (79%) patients have type 1 GT. Out of 108 (86%) whose Consanguinity status was recorded, 106 (98%) GT patients are products of consanguineous marriage. Seventy (65%) patients were products of first-degree cousin parents. Family history of GT was reported in 107 (86%) cases. Twenty-five families have more than one sibling (2-5) with GT. A single tripe has 50 members with GT. The median age at presentation is 2 years (7 days to 11 years). The most common symptoms are gum bleeds, Epistaxis, and Bruises. Eighteen (16%) patients suffered from a severe bleeding course (defined as bleeding continued for more than 3 days, drop in hemoglobin for more than 2 g / L from the baseline, or needed admission to the intensive care unit). Forty (35%) patients had a moderate course (bleeding requiring hospital admission and not filling the criteria for severe one). Fifty-seven (50%) patients had a mild clinical course (bleeding can be stopped at home). Eighteen (17%) patients had bleeding episodes more than once a month, 34 (32%) had six or fewer bleeds per year, and 57 (52%) patients had one bleeding episode per year. Menorrhagia affected 35 (86%) ladies and girls. Hormonal therapy has been used at least once in their lives to interfere with the menstrual cycle in 39 (95 %) patients. Twenty-eight pregnancies were reported, producing 24 babies (13 girls and 11 boys). A postpartum hemorrhage took place after 18 deliveries (75%). Mild to moderate pregnancy-related bleeding occurred in 7 pregnancies. Iron deficiency anemia was found in 66 (66%) patients out of 100 whose iron status was reported. Eighteen mutations have been identified: 15 mutations in the ITGA2B gene and 3 mutations in the ITGB3 gene (table 1). The mutation ITGA2B:exon13:c.1210+5G&amp;gt;A is a novel mutation found only in one tripe, where all 12 GT patients in this tripe carry this mutation. The mutation ITGA2B: exon20:c.1879-2A&amp;gt;G is the most frequent mutation affecting one tribe only, and all 42 GT patients who descend from this tribe carry this mutation. The second frequent mutation is ITGB3:exon13:c.2112delC, involving 28 GT patients. Though we could not find a correlation between genotype and phenotype, we noticed GT patients carrying mutations exon13:c.2112delC and exon13:c.1210+5G&amp;gt;A running a more severe clinical course compared to patients affected by the mutation ITGA2B: exon20:c.1879-2A&amp;gt;G. Anti-platelet antibodies have been detected in 11 (9%) patients, 2 of them during pregnancy. Apart from Menorrhagia, 10 out of 15 GT patients running severe clinical courses improved when they reached puberty. Conclusions GT is the commonest bleeding disorder in AlMadinah, Saudi Arabia, with a prevalence of 1:10,000. With a high rate of menorrhagia and IDA. The high rate of consanguineous marriage could be a reason for the high prevalence of GT.

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.

Assessment of Haemophilia Patients' and Other Bleeding Disorders Needs of Psychosocial Support and Health Care Needs and Their Utilization in Haemophilia Treatment Centres (ILLUSTRATE Study)

Background: Psychological support for chronically ill patients as an integral component of medical care could improve health-related quality of life (HRQoL) of patients and contribute to a reduction in treatment costs. A meta-analysis including almost 3,000 patients revealed that persons with hemophilia (PWH) are at increased risk for depression, anxiety, and ADHD compared to the general population (Al-Huniti et al., 2020). Studies have shown that the self-efficacy, coping mechanisms, and HRQoL of parents of hemophilic children were improved by self-help programs, and depression, anxiety, and parenting stress were reduced. Although different psychological interventions have been used to help PWH to cope with their psychological problems, there is a gap between patients' need for psychosocial support from the perspective of health care professionals (HCPs) and their utilization by PWH. The aim of the ILLUSTRATE study was to assess the need for psychosocial support and medical care in patients with inherited bleeding disorders (IBD) and in HCPs and their use in hemophilia centers. Methods: Patients with IBD (PIBD) were invited by different German patient organizations (Deutsche Bluthilfe, DHG, IGH, Hämophilie 2000) to participate in an on-line surevey (from December 2022-June 2023). In addition, HCPs were asked to complete a similar on-line survey via the mailing list of the German Society for Thrombosis and Hemostaseology. A positive ethical approval for the study was obtained by the Local Psychological Ethics Committee at the University Medical Centre in Hamburg, Germany (LPEK-0578). The questionnaire for patients consisted of the following aspects: socio-demographic data, medical background, care services and psycho-social support, dealing with stress and difficult situations, dealing with special situations that may arise or be exacerbated by the bleeding disorder, offer of psycho-social counseling/support, and need for expansion. The questionnaire for HCPs contained the following themes: personal background, need of patients for psycho-social counseling/support (PSCS), supply of PSCS and need for expansion, utilization, and benefits of PSCS. Results: In total, 154 patients and parents of children with an IBD participated (72 PIBD,80 parents, 2 others) with a mean age of 41.06±13.3 years, 60.4% were female. In addition, 65 HCPs completed the respective survey (34 physicians, 27 nurses and 4 others) with a mean age of 48.11 ± 12.7 years, in average they worked since 13.1±10.8 years in haemostaseology, 78.5% worked in a hemophilia comprehensive care center (HCCC), 20% in a hemophilia treatment center (HTC) and 1.5% in a homecare service. In the IBD group (patients, parents) most were married (59.1%), lived with a partner (83.8%) and worked full- or part-time (66%). Most PIBD had hemophilia (74%) with a severe form (81.8%). 28.6% of the IBD group felt little to not at all supported to overcome psycho-social challenges. It was demonstrated that they had an intermediate stress resilience (14.76±3.1), with 1/3 showing a low resilience. When asking what coping strategies they used in stress situations, 26% mentioned that they ignore difficult situations and 16% compensated their stress with drugs and alcohol. 20% often to always felt helpless and overwhelmed due to their IBD and 31% rarely to never received support in these situations. 71% reported to have a need for PSCS, 57% wished more support services (69% mainly at the HTC), 71% felt not to have enough information about these services and 64% would use them more often if they were more accessible. 52% of HCPs found that the IBD group has a need of PSCS, they assumed that parents and adolescent patients would benefit most of these services and expected the highest advantage from psychological counseling. 60% thought that there is a need for information and education. The IBD group and HCPs preferred PSCS in presence, the IBD group would use services as well via phone or digital. Conclusions: Although offered psycho-social support programs are rarely used by patients, a large proportion of the IBD group and HCPs confirmed a need for it. Increased accessibility to PSCS and more information were identified as a factor for increased use of this support programs. Additional digital psycho-social support services were desired and represent a helpful alternative if services are not available on site.

Pregnancy and Delivery Outcome Among Ladies with Glanzmann Thrombasthenia: A Report from Glanzmann Thrombasthenia Registry of Al-Madinah, Saudi Arabia

Introduction Glanzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder due to functional platelet defects impairing platelet aggregation. AlMadinah has reported the highest prevalence of GT globally, with a prevalence of 1:10,000. Pregnancy had been reported among ladies with GT with different outcomes. As a bleeding disorder, Pregnancy among ladies with GT carries a higher risk for bleeding either during pregnancy or intra and postpartum. Neonates have an increased risk for hemorrhage, either due to alloimmunization or they may carry the gene of GT. Many GT ladies got pregnant earlier when GT diagnosis was difficult, and they did not know their diagnosis; even after the diagnosis was possible, ceasing the menstrual cycle was not culturally acceptable. In this study, we are describing the pregnancies among GT ladies and their outcomes. Methods This is a report from the AlMadinah GT registry in the Madinah Hemophilia Comprehensive Care Center. The registry covers a period of 20 years and includes all patients with a confirmed diagnosis of GT. 136 GT patients were identified. 11 patients had no data available. A spreadsheet designed to collect detailed data about pregnancy, delivery, and neonates. Electronic and hard copy medical records have been accessed to collect data. Data was analyzed by the statistical package of social sciences (SPSS) version 23. The research and ethical committee approved the study. Results Twenty-eight pregnancies have been identified. The median age of mothers at the time of pregnancy was 30 ± 5.7 years (20 - 42 years). Mothers' Gravidity was 1-7 (median 2.5 ± 1.6), and parity was 1-6 (median 2 ±1.4). Five miscarriages (18%) identified occurred at the 17 th, 11 th, 13 th and 15 th gestational weeks. In contrast, 5 th one is not on record. Three miscarriages took place after moderate to severe vaginal bleeding. Mild to severe post-abortion bleeding was controlled with platelets transfusion, activated human recombinant factor 7 (rFVIIa), and tranexamic acid. Thirty-two bleeding episodes occurred during 16 pregnancies, with 1-5 bleeding episodes per pregnancy (Median of 2 episodes). Seven (22%) bleeding episodes were vaginal bleeds, while 25 (78%) were GT-related bleeds such as gum bleeding or epistaxis. Two patients must undergo plasma exchange and be on steroids due to alloimmunization development during pregnancy. Delivery occurred at the gestational age of 34-40 weeks (median 38 ± 2 weeks). Sixteen (70%) deliveries were vaginal, and 7(30%) were cesarean sections. The indications for cesarean sections were family request in 4 cases, fetal distress in two instances, and precautional section in one case. Prophylactic platelets transfusion had given pre-delivery on four occasions, rFVIIa on 4, and a combination of rFVIIa and platelets transfusion on six occasions. Tranexamic acid was used in all cases. Ten deliveries were conducted with no prophylaxis. Post-partum hemorrhage (PPH) occurred in 18 (64%) cases, 13 (72%) cases of primary PPH, and 5 (28%) cases of secondary PPH. We could not find a correlation between pre-delivery prophylaxes and PPH (P=0.2). PPH had controlled successfully with platelets transfusion and rFVIIa though red blood cell transfusion was needed on eight occasions. Twenty-eight pregnancies produced 24 babies (13 girls and 11 boys). Four babies had bleeding (2 intracranial hemorrhages, one subdural hematoma, and one gum oozing), and 9 had alloimmunization with mild to severe thrombocytopenia. Of all babies tested for GT, 6 of them were GT. Conclusions Pregnancy among ladies with GT carries a higher risk of bleeding. Management of pregnancy in women with GT has to be in a Multidisciplinary approach. The high rate of PPH among GT ladies makes it essential to treat it promptly. Pregnancy among ladies with GT should be studied in multi-centers sitting to learn more about clinical courses and management.

Accreditation model of European Haemophilia Centres in the era of novel treatments and gene therapy.

The international certification of haemophilia centres in Europe is run by the European Association of Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) since 2013. The centres are designated as European Haemophilia Comprehensive Care Centres (EHCCC) or European Haemophilia Treatment Centres (EHTC), based on the specific requirements which evaluate centres' ability to provide care for patients with haemophilia and allied disorders. To establish the new protocol for accreditation of European Haemophilia Centres. EAHAD, in collaboration with EHC, established Accreditation Working Group with the aim to define necessary measures to safeguard quality and improvement of bleeding disorders care throughout Europe and to build a novel model for accreditation of European Haemophilia Centres. The European guidelines for certification of haemophilia centres have been updated to guidelines for the accreditation and include all the requirements regarding facilities, laboratory and personnel needed for optimal management of novel treatment options, including the introduction of the hub-and-spoke model for delivery of gene therapy. A pilot project for the accreditation of haemophilia centres including on-site audit has been designed. Implementation of the novel accreditation protocol of the haemophilia treatment and haemophilia gene therapy centres has been made to further improve the quality of care for patients with haemophilia and other inherited bleeding disorders.

Evaluation of Functional and Joint Health and Associated Factors in Adults With Hemophilia From a Developing Country With Government-Backed Efforts to Improve Hemophilia Care.

Introduction Hemophilic arthropathy affects people with hemophilia (PwH) and causes joint dysfunction and disability. Brazil has a unique situation and implemented policies to improve health care for PwH. The aim of this study was to evaluate the Functional Independence Score in Hemophilia (FISH), Hemophilia Joint Health Score (HJHS), and associated factors among adult PwH attending a Hemophilia Comprehensive Care Center in Brazil. Methods A post hoc analysis was conducted, including 31 patients who had submitted to a physical evaluation during a previously published cross-sectional study performed from June 2015 to May 2016 at the Brasília Blood Center Foundation, Brazil. Results The mean age was 30.8±9.4 years, and 80.6% had severe hemophilia. FISH was 27.0±3.8, and HJHS 18.0±10.8. The ankle was the most often affected joint (25/31, 80.6%). There were significant correlations between FISH and HJHS scores and the Hemophilia Quality of Life Questionnaire for Adults. Patients with severe hemophilia (P = 0.029) and PwH aged ≥ 30 years (P = 0.049) had lower FISH scores. Monthly household income > 2 Brazilian minimum wages was independently associated with improved HJHS (P = 0.033). The factors simultaneously associated with better HJHS and FISH were age < 30 years (P = 0.021) and monthly household income < 2 minimum wages (P = 0.013). Conclusion FISH and HJHS showed favorable scores despite being performed in a country with unfavorable socioeconomic conditions. In addition to hemophilia severity and age, monthly household income was independently associated with functional and articular state of PwH. The results highlight the importance of the free provision of coagulation factors in Brazil.

Report on 4 cases with decreased recovery due to neutralizing antibodies specific for PEGylated recombinant factor VIII

BackgroundThe immunogenicity, safety, and efficacy of recombinant factor VIII (rFVIII) have gained increasing interest after the introduction of extended half-life products with various modifications of the rFVIII molecule, such as covalent attachment of polyethylene glycol (PEG). Anti-PEG antibodies may be associated with a temporary reduction of FVIII recovery, but according to previous studies, they usually disappear after continuous dosing. Anti-PEG antibodies with an inhibitory capacity have never been demonstrated in patients treated with PEGylated rFVIII products. ObjectivesTo routinely switch from standard half-life to PEGylated extended half-life rFVIII products in patients with hemophilia A. MethodsFrom December 2022 until May 2023, 83 adults with hemophilia A attending Oslo Haemophilia Comprehensive Care Centre received a test dose with a PEGylated rFVIII product to switch treatment. Four patients presented with decreased recovery without the presence of an FVIII inhibitor. Accordingly, we performed a variant inhibitor test utilizing different rFVIII concentrates as a source of FVIII and enzyme-linked immunosorbent assay to search for anti-PEG antibodies. ResultsWe found inhibitory anti-PEG/anti-PEGylated rFVIII antibodies in 4 patients (5%), both persistent and transient, explaining the impaired recovery. The patients had neutralizing anti-PEG antibodies prior to the first dosing of PEGylated rFVIII. We demonstrated neutralizing antibodies (mainly immunoglobuline G) specific for PEG and all 3 commercially available PEGylated rFVIII products. ConclusionThe number of patients with inhibitory anti-PEG antibodies was significant, and the presence of inhibitors against PEGylated rFVIII emphasizes the importance of individual monitoring when switching FVIII concentrates to ensure safety and efficacy of the treatment.

Bleeding disorder of unknown cause: Results from Iranian study

BackgroundDefinite diagnosis of patients with mild to moderate bleeding is challenging. Some studies reported that even more than 50% of their patients remained undiagnosed which is classified as a Bleeding disorder of unknown cause (BDUC). This study aims to document the clinical characteristics and proportion of patients with BDUC in the Iranian Comprehensive Hemophilia Care Center (ICHCC) one of the referral centers for diagnosis of congenital bleeding disorder in Iran. MethodsThis study was conducted on 397 patients who were referred with a bleeding manifestation to ICHCC from 2019 to 2022. Demographic and laboratory data were documented for all patients. Bleeding questionnaires including ISTH-Bleeding Assessment tool (ISTH-BAT) and the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 (MCMDM-1 (ISTH-BAT, MCMDM-1, and the Pictorial Bleeding Assessment Chart (PBLAC) were filled out for all patients. The data were analyzed by the statistical package for social science (SPSS version 22, SPSS, Chicago, Illinois, USA). ResultsBDUC was diagnosed in 200 patients and 197 patients reached the final diagnosis. Hemophilia, von Willebrand disease (VWD), factor (F) VII deficiency, and platelet functional disorders (PFDs) were confirmed in 54, 49, 34, and 15 of the patients, respectively. No significant difference was found in bleeding scores between patients with BDUC and those with confirmed disease. In contrast, after setting cut-off (ISTH-BAT for males ≥ 4 and females ≥ 6 and MCMDM-1 for males ≥ 3 and females ≥ 5) clinically significant difference was found. There was no association between having a positive consanguineous marriage and setting a diagnosis; however, significant associations were seen for having a positive family history of bleeding. Age (OR =0.977, 95% CI.965–0.989), gender (BDUC female, 151/200; final diagnosis female, 95/197) (OR=3.3, 95% CI 2.16–5.06), family history (OR = 3.19, 95% CI 1.99–5.11), and consanguineous marriage (OR=1.59, 95% CI 1.03–2.45) were considered as a risk factor for categorizing the patients with BDUC or final diagnosis. ConclusionThe findings are mainly in line with previous studies about BDUC patients. The large number of patients with BDUC underlines the incompleteness of available routine laboratory tests and shows the necessity of progress in the development of reliable diagnostic tools to identify underlying bleeding disorders.

A first Tunisian pilot study investigating sexual dysfunctions in patients with hemophilia.

Background: Little data is actually available on sexual health problems with sexual activity, and intimacy (sexual difficulty) in patients with hemophilia (PWH). We conducted this study to determine the prevalence of sexual difficulty in PWH and to determine factors associated with erectile dysfunction (ED). Methods: Based on The International Index of Erectile Function 15 (IIEF-15) questionnaire, we evaluated ED and other sexual problems in PWH. Results: Forty-Three (43) PWH were included in our study. The mean age was 33 years. Fourteen (32.6%) respondents were identified as having severe disease. The majority (93%) suffered from erectile dysfunction. Lack of desire and orgasm was observed in 76.7% of cases each. Lack of sexual satisfaction and global satisfaction were noted in 83.7% of cases and 88.4% of cases, respectively. Among PWH, older age was associated with ED. Conclusion: Our study illustrates the need for programs to assess and improve the sexual health of PWH in comprehensive hemophilia care.

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

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. 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. Literature review and consensus discussion among Hemophilia Comprehensive Care centers (HCCCs) in the Nordic region. 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. 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. 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.

Outcomes and management of pregnancy in women with bleeding disorder of unknown cause

BackgroundPatients with a bleeding tendency with normal laboratory tests have been described as having an unclassified bleeding disorder or bleeding disorder of unknown cause (BDUC). There are very little data available on how to manage pregnancy. ObjectivesTo study management and outcomes of these patients at four United Kingdom hemophilia comprehensive care centers. MethodsRetrospective case note review from 2010–2020. ResultsSixty deliveries in 36 patients were recorded. The median International Society on Thrombosis and Haemostasis bleeding assessment tool score was 9. In 54 cases for which data were available, the odds ratio for post partum hemorrhage (PPH) was 6.3 for no primary hemostatic prophylaxis versus prophylaxis (95% confidence interval 1.2–34.2, p < .05); 7/9 (78%) versus 16/45 (36%) PPH incidence for the groups, respectively. Hemostatic prophylaxis was with tranexamic acid but some patients received desmopressin or platelet infusions. Secondary PPH was seen in 5/60 (8%) of cases. No neonatal bleeding complications or maternal thromboembolic complications were noted. Avoidance of regional anesthesia and fetal delivery precautions were commonly advised, but in the small number of cases in which they occurred no complications were noted. ConclusionsDespite hemostatic prophylaxis PPH was commonly seen. Further prospective studies of BDUC patients are required to determine optimal management in pregnancy as well as determine the pathophysiological basis of bleeding.

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.

Seroprevalence to adeno‐associated virus type 6 in people with hemophilia B from a UK adult cohort

BackgroundGene therapy shows promise as a potential “cure” for hemophilia A and B. Adeno‐associated virus (AAV) vectors are the leading platform to deliver modified genetic code of factor VIII or IX to the liver effecting endogenous production. Patient exposure to wild‐type AAV leads to the formation of neutralizing factors, which can prevent successful transduction. It is thus important to establish the seroprevalence of the AAV serotypes in people with hemophilia to aid prediction of successful gene transfer. The seroprevalence of AAV6 in UK people with hemophilia B is not yet reported. ObjectivesWe studied the prevalence of anti‐AAV6 neutralizing factors in UK people with hemophilia B (n = 49). We collected data on people’s hepatitis C exposure and treatment with plasma‐derived factor IX (FIX) to identify if there was correlation with AAV6 exposure. MethodsSerum samples and patient data were collected from 49 people with hemophilia B registered at UK hemophilia comprehensive care centers. The samples were tested for neutralizing factors to AAV6 using a cell‐based transduction inhibition assay. ResultsThirty‐one percent of patients had serum neutralization against AAV6. There was no correlation between AAV6 seropositivity and previous treatment with plasma‐derived FIX products or hepatitis C exposure. ConclusionBased on limited data, there is no evidence of association between the presence of AAV6 neutralizing factors in people with hemophilia B and exposure to contaminated plasma derivatives. The frequency of AAV6 neutralizing factors in our hemophilia B cohort is similar to UK people with hemophilia A and non‐hemophilia populations.

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

IntroductionThe coronavirus disease 2019 (COVID‐19) pandemic has created an unprecedented global health crisis.AimTo investigate the impact of the 1st COVID‐19 lockdown on haemophilia patients in terms of symptoms, management, medication adherence, mental health and lifestyle behaviours.MethodsA 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).ResultsAmong 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.ConclusionsEncouraging 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.