Use of antidepressant and antipsychotic drugs in subjects with hemophilia of the Umbria Region in the period 2011-2022.

INTRODUCTION: Chronic diseases, such as hemophilia, can evoke psychological sequelae and be associated with a higher risk of mental health disorders. The utilization of antidepressant and antipsychotic drugs in subjects with hemophilia is not completely understood and few data are available. OBJECTIVES: The aim of this analysis is to describe use of antidepressant and antipsychotic drugs in subjects with hemophilia of the Umbria Region in the period 2011-2022. METHODS: A descriptive, cross-sectional, and retrospective analysis based on data on filled prescriptions for antidepressants and antipsychotics has been carried out. The overall and annual prevalence of drugs use and consumption were calculated based on pharmaceutical prescriptions charged to the National Health Service in subjects with hemophilia and matched controls from general population. RESULTS: In the study period 170 subjects with hemophilia were identified; about 80% were male. About 20% and 8.2% received antidepressants and antipsychotics, respectively. A higher percentage of users and consumption were found in subjects with hemophilia compared to matched controls, although no statistically significant differences were observed. CONCLUSIONS: Our analysis suggests that depression and psychosis are important comorbidities in subjects with hemophilia. Further larger studies are needed in order to confirm these data and better define the burden of mental health disorders in subjects with hemophilia.

Treatment of Chronic Haemophilic Synovitis with PRP: Clinical and In Vitro Studies.

Intra-articular blood, iron and hemosiderin, hydroxyl radical cytokines, and neo-angiogenesis cause synovial inflammation, which leads to cartilage and joint damage. Platelet-rich plasma (PRP) inhibits most of the mediators that produce and maintain synovitis. We compile here our work showing the clinical effectiveness of intra-articular PRP injections and their potential role in stopping articular cartilage damage due to bleeding and its possible repair. A total of 116 joints, including knees (63%), elbows (19.8%), and ankles (17.2%), were treated with intra-articular injections of PRP. Moreover, we also show here the number of extracellular DNA traps (ETs) and the PRP effect in the synovial fluid of patients at the time of treatment and six months after. Clinically, it is demonstrated that PRP is effective in reducing bleeding episodes (p < 0.001) and pain (p < 0.0001) and improving the hemophilia joint health score (HJHS) (p < 0.001) at one year of follow-up. Furthermore, our results demonstrate that PRP inhibits ET formation in vitro and reconstitutes the immune system's cellular components in the synovial fluid of patients after treatment. We conclude that PRP can be considered an effective, safe, and easy treatment for hemophilic synovitis.

Switching hemophilia A patients to rVIII-SingleChain: The Iberian experience.

The real-world outcomes of lonoctocog alfa (rVIII-SingleChain), a long-acting factor VIII (FVIII) with a favorable safety and efficacy profile in trials, were assessed in patients with hemophilia A in Iberian (Spain and Portugal). This was a retrospective study involving patients switching to rVIII-SingleChain from other FVIIIs in 7 Spanish and Portuguese hospitals. The efficacy and safety of replacement therapies were compared between 12 months before switching and the period from switching to the end of the study. Twenty-nine patients (median age 25 years; severe hemophilia A, 37.9%) were recruited. Before switching, 12 were on prophylaxis and were followed-up for a median of 12 months. After switching, 17 received prophylaxis with rVIII-SingleChain and were followed-up for a median of 41 months. Those with ≤2 weekly infusions increased from 37.5% before switching to 60.7% after switching to rVIII-SingleChain. The median monthly consumption was 312 IU/kg with prior FVIIIs and 273 IU/kg with rVII-SingleChain. Six spontaneous bleeds were reported in each period in the prophylaxis patients. In the entire cohort, 50 bleeds were reported with prior FVIIIs and 33 were reported after switching to rVIII-SingleChain. Patients requiring ≤1 dose for hemostasis increased from 44.0% with prior FVIIIs to 60.6% with rVIII-SingleChain. Responses were rated good/excellent in 95.4% of cases. No safety concerns were reported. Patients who switched to rVIII-SingleChain prophylaxis had excellent bleeding control and reduced infusion frequency in regular clinical practice, with the subsequent increase in quality-of-life.

Assessment of joint health in patients receiving prophylaxis for haemophilia A: a cross-sectional survey in five European countries.

OBJECTIVES: To evaluate joint health, pain and health-related quality of life (HRQoL) in patients with moderate/severe haemophilia A in Europe. DESIGN: Multinational, cross-sectional survey, with retrospective data collection. Data were taken from the Adelphi Real World Haemophilia Disease Specific Programme Wave II, using surveys completed by physicians and patients between February 2020 and May 2021. SETTING: Haematologists/haemato-oncologists and their patients in France, Germany, Italy, Spain and the UK. PARTICIPANTS: Males aged ≥18 years with moderate or severe haemophilia A (baseline clotting factor level ≤5%), without existing inhibitors and currently receiving prophylaxis. Patients were grouped into those with or without haemophilia-affected joints (HAJs) based on bleeding, radiographic, surgical, mobility and joint pain data. PRIMARY OUTCOME MEASURE: Characterisation of humanistic and clinical outcomes in patients with or without HAJs. RESULTS: A total of 120 physicians provided data for 351 eligible patients; 209 (59.5%) patients had HAJs and 142 (40.5%) had no HAJs. Pain/discomfort was significantly different (p=0.01) and reported more frequently in the HAJ (85.7%) vs non-HAJ group (53.3%). Pain medication use was significantly higher in the HAJ versus non-HAJ group (73.2% vs 60.6%; p=0.01). Up to half of the patients with HAJs had synovitis (49.8%) or arthropathy (48.4%), and one-third had undergone joint surgery (35.4%). Overall health status was significantly worse in the HAJ versus non-HAJ group (mean (SD) EuroQol Visual Analogue Scale score: 65.5 (19.3) vs 81.1 (14.6); p=0.01). CONCLUSIONS: In this multinational real-world study, nearly two-thirds of adults with moderate/severe haemophilia A without inhibitors experienced HAJs despite prophylaxis. Individuals with HAJs had higher rates of pain and pain medication use, and lower HRQoL compared with those without HAJs. These data indicate that HAJs represent a clinically relevant burden and early identification/monitoring and management of affected joints should be an important consideration to help prevent long-term joint morbidity.

Toward Personalized Care and Patient Empowerment and Perspectives on a Personal Health Record in Hemophilia Care: Qualitative Interview Study.

BACKGROUND: To enable personalized treatment and shared decision-making in chronic care, relevant health information is collected. However, health information is often fragmented across hospital information systems, digital health apps, and questionnaire portals. This also pertains to hemophilia care, in which scattered information hampers integrated care. We intend to co-design a nationwide digital personal health record (PHR) for patients to help manage their health information. For this, user perspectives are crucial. OBJECTIVE: This study aims to assess patients' and health care providers' perspectives regarding the use of a PHR in hemophilia care in the Netherlands, required functionalities, and expectations and concerns. METHODS: In this semistructured interview study, 19 pediatric and adult persons with hemophilia, parents, and women with other inherited bleeding disorders, as well as 18 health care providers working within and outside of hemophilia treatment centers, participated. Perspectives of patients and providers were explored separately. To explore requirements, participants were asked to prioritize functionalities. RESULTS: Participants expected a PHR would increase the transparency of health information, improve patients' understanding of their illness, and help the coordination of care between health care providers and institutions. Prioritized functionalities included the integration of relevant health information and patient-entered data. Formulated expectations and concerns focused on 4 themes: usability, safety, inclusiveness, and implementation. While patients expressed worries over medicalization (ie, more confrontational reminders of their illness), providers were concerned about an increased workload. CONCLUSIONS: People with hemophilia, their parents, and health care providers welcomed the development of a PHR, as they expected it would result in better coordinated care. Formulated expectations and concerns will contribute to the successful development of a PHR for persons with hemophilia, and ultimately, for all persons with a chronic condition.

Association of bullous pemphigoid with acquired hemophilia A: a case report.

Acquired hemophilia A, a rare condition resulting in spontaneous bleeding without prior bleeding disorders, arises due to autoantibody-mediated inhibition of coagulation factor VIII and is typically associated with autoimmune, neoplastic, drug, or obstetric factors. We present the case of a 31-year-old woman with bullous pemphigoid, managed with corticosteroids since 2013, who presented spontaneous hemorrhagic manifestations. Upon admission, laboratory tests revealed hypochromic microcytic anemia, prolonged activated partial thromboplastin time, and a factor VIII level < 1%, indicative of acquired hemophilia A. Further assessments showed elevated Ristocetin cofactor activity, von Willebrand factor antigen, and a factor VIII inhibitor level of 665 BU. This underscores the importance of considering acquired hemophilia A in autoimmune dermatological conditions like bullous pemphigoid, highlighting the association between autoimmune disorders and coagulation abnormalities, particularly in cases of spontaneous hemorrhagic events.

[Clinical Significance of the Levels of Peripheral Blood Tregs and Cytokines IL-35, TGF-ß and IL-10 in Hemophilia A Patients with Fâ § Inhibitor].

OBJECTIVE: To explore the levels of regulatory T cells (Tregs) and cytokines IL-35, TGF-ß and IL-10 in peripheral blood of hemophilia A(HA) patients with FⅧ inhibitor and their clinical significance. METHODS: 43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected, including 6 cases with FⅧ inhibitor and 37 cases without FⅧ inhibitor. In addition, 20 healthy males who underwent physical examinations were selected as healthy controls. Flow cytometry was used to detect the levels of CD4 + CD25 + CD127 - Tregs in peripheral blood of the HA patients and healthy controls, and ELISA assay was used to detect the expression levels of IL-35, TGF-ß and IL-10 in serum, and their differences between different groups were compared. RESULTS: Compared with the healthy control group, the level of Tregs in HA patients was decreased, and the level of Tregs in the FⅧ inhibitor positive group was the lowest, the difference was statistically significant (P <0.05). There was no significant difference in the expression level of Tregs in HA patients of different severity levels. The serum IL-35, TGF-ß, and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group, and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group (all P <0.05). CONCLUSION: The decrease of Tregs, IL-35, TGF-ß, and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.

Pre-clinical evaluation of an enhanced-function factor VIII variant for durable hemophilia A gene therapy in male mice.

Durable factor VIII expression that normalizes hemostasis is an unrealized goal of hemophilia A adeno-associated virus-mediated gene therapy. Trials with initially normal factor VIII activity observed unexplained year-over-year declines in expression while others reported low-level, stable expression inadequate to restore normal hemostasis. Here we demonstrate that male mice recapitulate expression-level-dependent loss of factor VIII levels due to declines in vector copy number. We show that an enhanced function factor VIII variant (factor VIII-R336Q/R562Q), resistant to activated protein C-mediated inactivation, normalizes hemostasis at below-normal expression without evidence of prothrombotic risk in male hemophilia A mice. These data support that factor VIII-R336Q/R562Q may restore normal factor VIII function at low levels of expression to permit durability using low vector doses to minimize dose-dependent adeno-associated virus toxicities. This work informs the mechanism of factor VIII durability after gene transfer and supports that factor VIII-R336Q/R562Q may safely overcome current hemophilia A gene therapy limitations.

Acute Abdominal Crisis in Type A Hemophilia: Unraveling Retroperitoneal Hematoma: A Case Report.

BACKGROUND Classical hemophilia A, an X-linked recessive disorder, is characterized by an inability to produce factor VIII in normal quantities. This condition, also leading to factor IX deficiency, underpins the bleeding disorder known as hemophilia A. Among the complications of this illness, spontaneous retroperitoneal hematoma is rare but can be associated with congenital coagulopathies such as von Willebrand disease or hemophilia A. This type of spontaneous internal bleeding has been the subject of a limited number of studies. CASE REPORT A 38-year-old man with a known diagnosis of hemophilia A presented to the Emergency Department exhibiting acute pain in the right lower abdomen. A computed tomography scan of the abdomen identified a right-sided retroperitoneal mass, suspected to be a hematoma. Within 7 h after admission, the patient experienced significant drops in the hemoglobin level and platelet count. He was administered packed red blood cells, fresh frozen plasma, and platelet transfusions prior to transfer to the Intensive Care Unit. There, he was treated with factor VIII and recombinant factor VIIa, coupled with stringent monitoring. Following clinical and laboratory findings and stabilization, he was discharged with specific medications, and a follow-up appointment was scheduled. CONCLUSIONS Spontaneous retroperitoneal hematoma in patients with hemophilia A is a rare and grave emergency. This case underscores the need for precise diagnostic approaches, tailored management strategies, and vigilant surveillance to prevent and mitigate the potentially life-threatening complications associated with spontaneous hemorrhage in this population.

A long term outcomes analysis of severe haemophilia A boys receiving 4 years prophylaxis on the Chinese Haemophilia Individualized escalating low dose Prophylaxis (CHIPS).

BACKGROUND: The Chinese Haemophilia Individualized Prophylaxis Study (CHIPS), which was launched in 2016, reported a significant reduction in haemarthrosis over a one-year study. However, its long-term efficacy requires verification. This paper summarizes the clinical outcomes of 18 severe haemophilia A (SHA) patients who completed one year on the CHIPS and 3 more years of follow-up. METHODS: Clinical follow-up was based on the CHIPS protocol (from July 2018 to July 2021). Escalation was based on index joint bleeding, and serial ultrasound (greyscale and colour Doppler) examinations of the index joints (both sides of the ankles, knees and elbows) were conducted every 6 months via a scoring system. RESULTS: A total of 18 SHA patients completed the 3-year study. Fifteen patients dropped out due to the financial crisis during the COVID-19 pandemic in China. The median age was 5.4 (range 4.3-6.9) years. A significant reduction in haemarthrosis was achieved, with mean annual bleeding rates reduced from 18.9 ± 2.8 to 1.7 ± 0.4 (p < 0.001), annual joint bleeding rates from 3.1 ± 0.7 to1.2 ± 0.3 (p < 0.028). 5 out of 8 target joint resolved. Sixteen doses were escalated. At study exit, the heterogeneous treatment outcomes of the SHA boys were 5 at step 4 (20-25 lU/kg, every other day), 10 at step 3 (15-20 IU/kg, 3×/week), 2 at step 2 (10-15 lU/kg, 3×/week) and 1 at step 1 (10-15 lU/kg, 2×/week). The mean FVIII consumption was 2964 IU/kg/year, with savings. The quality of life improved, with Canadian Haemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT, Chinese Version 2.0) scores ranging from 68.8 to 78.8. There was no change in the ultrasound score. CONCLUSION: Our follow-up data on the 18 SHA boys after completing one year on the CHIPS verify the long-term efficacy of the CHIPS for haemarthrosis reduction, joint health preservation, improvement in the quality of life of the boys and cost savings.

Peripheral Blood Lymphocyte Subsets in Factor VIII Inhibitor-Positive Patients with Severe Hemophilia A: A Case-Control Study.

INTRODUCTION AND OBJECTIVES: The present study aimed to investigate different peripheral lymphocyte subsets in patients with severe hemophilia A (HA) and factor VIII (FVIII) inhibitor production. For this, age-matched cases of 19 FVIII inhibitor-positive (IP), 21 FVIII inhibitor-negative (IN) and 45 healthy controls were selected for study. METHODS: Flow cytometry was used to analyze the peripheral lymphocyte subsets, including T, B, natural killer (NK) and NKT cells. The T cell subsets included CD3 + CD4-CD8- [double negative T (DNT)], CD3 + CD4 + CD8+ [double-positive T (DPT)], CD3 + CD4 + CD8- and CD3 + CD4-CD8+ T cells. Pairwise comparisons of absolute lymphocyte subset values were conducted among the three groups. The cut-off value for absolute lymphocyte counts was determined using receiver operating characteristic curve analysis. RESULTS: The results demonstrated that the absolute values of DPT cells in the IN and IP groups were significantly lower than those in the healthy control group (P = 0.007). The DNT values were also lower in severe HA patients with or without inhibitor than those in healthy subjects, but these differences were not statistically significant (P = 0.053). In addition, the absolute value of CD4+ Th cells in the IP group was lower than that in the healthy controls (P = 0.013). Although not statistically significant (P = 0.064), the absolute values of NKT cells were higher in the IN group compared with the IP group, and higher in the IP group compared with the healthy control group. There were no statistically significant differences in total T, B, CD8 + and NK cells among the IN, IP and healthy control groups. The cut-off value for absolute CD4+ Th cells in the IN group was < 598/µl. CONCLUSION: The decrease in absolute values of CD4+ Th cells in severe HA patients may contribute to the establishment of infused FVIII immune tolerance. If the CD4+ Th value remains > 598/µl, clinicians should be vigilant for possible FVIII inhibitor production, especially on days prior to FVIII exposure.

Severe acquired hemophilia A associated with COVID-19 vaccination: A case report and literature review.

RATIONALE: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by an antibody that inhibits coagulation factor VIII activity. More than half of patients with AHA cannot identify underlying disorders. The remaining patients are associated with malignancies, autoimmune diseases, skin diseases, infections, and medications. Here, we present a case of 56-year-old Korean man with underlying hypertension, dyslipidemia, and diabetes mellitus who developed AHA following the second dose of BNT162b2 COVID-19 vaccination. PATIENT CONCERNS: He presented with a large 20 × 30 cm-sized hematoma along the psoas muscle and intracranial hemorrhage, necessitating intensive care with mechanical ventilation and continuous renal replacement therapy. Laboratory testing demonstrated that activated partial thromboplastin time and prothrombin times were 74.7 seconds (normal range 29-43 seconds) and 17.2 seconds (normal range 12.5-14.7 seconds), respectively. DIAGNOSES: Laboratory tests confirmed AHA with undetectable factor VIII activity (<1.5%) and a positive factor VIII antibody with a titer of 8.49 Bethesda units/mL. INTERVENTIONS: Recombinant factor VIIa (NovoSeven®) was administered every 2 hours to control the bleeding, alongside immunosuppression with methylprednisolone 1 mg/kg daily and cyclophosphamide 2 mg/kg daily to eliminate the autoantibody. OUTCOMES: Despite the treatments, the patient developed sepsis and succumbed 14 weeks after admission. LESSONS: This rare case underscores the importance of monitoring for AHA following COVID-19 vaccination. Although the benefits outweigh the risks of vaccination, AHA should be considered in the differential diagnosis of unusual bleeding following the vaccinations. Early diagnosis and management before severe bleeding are critical for successfully controlling life-threatening bleeding.

Mutational Profile in Romanian Patients with Hemophilia A.

Hemophilia A (HA) is an X-linked recessive bleeding disorder caused by mutations in the F8 gene, resulting in deficient or dysfunctional factor VIII (FVIII). This study aimed to characterize the mutational profile of HA in Romanian patients using next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA). A total of 107 patients were analyzed, revealing pathogenic or likely pathogenic variants in 96.3% of cases. The identified mutations included missense (30.5%), nonsense (9.1%), small deletions (6.4%), small insertions (2.1%), splice-site variants (4.3%), large deletions (1.6%), and large duplications (1.1%). Large intron inversion was previously found in 37.5% of the patients. Novel variants accounted for 21.5% of identified mutations, expanding the spectrum of F8 variants in this population. This study underscores the genetic heterogeneity of HA and provides insights into genotype-phenotype correlations, aiding in clinical management and prenatal diagnosis.

Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.