Search Results (27)

This perspective discusses the critical role of laboratory assessments in assessing factor VIII (FVIII) inhibitors. These are auto- and alloantibodies that can develop against both endogenous and exogenous FVIII, respectively. Assessment for inhibitors represents a key part of the management of both congenital hemophilia A (CHA), an inherited deficiency, and acquired hemophilia A (AHA), an autoimmune condition. Both conditions pose significant bleeding risks, necessitating careful monitoring of FVIII levels and inhibitor presence and level. Laboratory assays, particularly the Bethesda assay, are essential for detecting these inhibitors and assessing their levels. The complexities of FVIII inhibitor kinetics may pose challenges to interpretation of assay results, such that even normal FVIII levels do not always exclude inhibitor presence. Clinical practice guidelines recommend ongoing monitoring of AHA/CHA patients until inhibitors are no longer detectable. Overall, timely laboratory evaluations are essential to optimizing treatment strategies for patients with hemophilia, aiming to improve patient outcomes and quality of life. We summarize our approach to the laboratory assessment of FVIII inhibitors, as reflecting our perspective and as informed by local practice. Full article

Hemophilia, which is a rare disease, results from congenital deficiencies of coagulation factors VIII and IX, respectively, leading to spontaneous bleeding into joints, resulting in hemophilic arthropathy (HA). HA involves complex processes, including synovial proliferation, angiogenesis, and tissue remodeling. Despite ongoing research, factors contributing to HA progression, especially in adults with severe HA experiencing joint pain, remain unclear. Blood markers, particularly collagen-related ones, have been explored to assess joint health in hemophilia. For example, markers like CTX-I and CTX-II reflect bone and cartilage turnover, respectively. Studies indicate elevated levels of certain markers post-bleeding episodes, suggesting joint health changes. However, longitudinal studies on collagen turnover and basement membrane or endothelial cell markers in relation to joint outcomes, particularly during painful episodes, are scarce. Given the role of the CX3CL1/CX3XR1 axis in arthritis, other studies investigate its involvement in HA. The importance of different inflammatory and bone damage biomarkers should be assessed, alongside articular cartilage and synovial membrane morphology, aiming to enhance understanding of hemophilic arthropathy progression. Full article

Acquired hemophilia A (AHA) is a bleeding disorder characterized by the immunological inhibition of factor VIII (FVIII) of the hemostatic pathway leading to hemorrhagic events. Different domains of FVIII are the target of autoantibodies (mainly immunoglobulin (Ig) G) leading to the deficiency of FVIII. Several factors have been associated with the activation of the auto-immunity towards FVIII. Emerging evidence implicates CD4+ T cell activation in mediating this autoimmune response, with their involvement like that observed in congenital hemophilia A. Several genes such as HLA II DRB*16, DQB1*0502, and CTLA-4 + 49 are responsible for the pathogenesis of AHA. Epigenetic modifications and mainly long-coding RNAS (lncRNAs) are potentially contributing to the pathogenesis of AHA. The treatment approach of AHA includes the management of acute bleeding events and the administration of immunosuppressive medications. This review aimed to summarize the published data on the genetics and epigenetics of AHA. The severity and the mortality of this disease are creating an emerging need for further research in the field of the genetics and epigenetics of acquired hemorrhagic disorder. Full article

Background: This study aimed to gather data on physical activity (PA), bleeding, health-related quality of life, and health status, using a wearable device and an electronic patient-reported outcome (ePRO) app, in individuals with moderate or severe hemophilia A (HA) without inhibitors receiving treatment according to the clinical practice. Methods: This is a 12-month multicenter cohort study conducted in Italy. The primary outcomes included the description of PA by type and intensity, adherence to World Health Organization guidelines, bleeding, and health-related quality of life by EQ-5D questionnaire. PA data were collected continuously through a fitness tracker worn by the patient; all the other variables were collected through ePRO questionnaires. Results: Only 54 of the 103 enrolled subjects (52.4%) used their fitness tracker for the defined valid period; adolescents were the least compliant age group. PA was performed at low rates and intensity. Approximately 52% of the subjects had sedentary behavior. The mean EQ-5D values did not change over time. At least one bleeding was reported in 43.7% of the subjects, mostly with sedentary behavior. The PA in the 2 days preceding the bleeding was comparable to the one observed in the overall observational period. Conclusions: The systematic recording of data through a fitness tracker and ePRO app shows that subjects with HA without inhibitors have lower-than-expected PA and that they still experience issues related to bleeding. Full article

Hemophiliacs can develop cardiovascular diseases, including valvulopathies of various etiologies and severities. Some require surgical treatment. Performing cardiac surgery in hemophiliacs is a challenge because they maintain an increased risk of bleeding throughout their lives. Our review shows that with a multidisciplinary team and careful planning, cardiac surgery can be safely performed in these patients. Valve repair and bioprosthetic valves should be preferred over mechanical valves to avoid life-long anticoagulation. In patients who cannot receive a bioprosthetic valve, the use of the On-X mechanical valve might be considered because it requires less intensive anticoagulation after 3 months of treatment. Antithrombotic treatment is feasible in hemophiliacs only if the coagulation factor level is kept constantly above a specific trough limit. Our review is valuable because, for the first time, the available data on the modern surgical treatment of valvular disease in hemophiliacs have been synthesized and systematized. Full article

Hemophilia is a congenital disorder associated with impaired blood clotting. Routine dental intervention to prevent oral bleeding in patients with hemophilia is considered important, but its effectiveness remains unknown. In the present study, we evaluated the effect of continual dental support on periodontal status and oral health habits in young patients with hemophilia. Of the 168 young patients with hemophilia who visited our clinic for 5 years, we selected subjects who had visited annually since 2015 and were in the mixed and permanent dentitions. To evaluate the periodontal status of these subjects, Community Periodontal Index (CPI) values in the molars and anterior teeth were measured. In addition, a questionnaire regarding oral health habits, including floss use, frequency of brushing by parents, and attending a family dentist, was administered to the subjects and their parents. In the patients with mixed dentition, the CPI values for the upper right molars and lower left central incisor decreased significantly in later years compared with the first year (p < 0.05). In the patients with permanent dentition, only one year recorded a significant decrease in CPI values compared with the first year (p < 0.05), localized in the upper right molars. The results of the questionnaire revealed that continual dental support improved dental floss use and the frequency of brushing by parents only in the mixed dentition group. Furthermore, these oral health habits significantly affected CPI values only in the mixed dentition group (p < 0.01). These results suggest that continual dental support improves the periodontal condition and oral health habits of hemophilic patients, especially those with mixed dentition. Full article

Hemophilia A is a hemorrhagic disorder caused by insufficient or inadequate coagulation factor VIII activity. Two different forms are described: congenital, hereditary X-linked, and acquired. Acquired hemophilia A (AHA) is a rare condition and it is defined by the production of autoantibodies neutralizing factor VIII, known as inhibitors. We report the case of a 72-year-old man with a clinical diagnosis of AHA after SARS-CoV-2 infection, which has been described in association with several hematological complications. SARS-CoV-2 infection could represent the immunological trigger for the development of autoantibodies. In our patient, SARS-CoV-2 infection preceded the hemorrhagic complications by 15 days. This lag time is in line with the other cases reported and compatible with the development of an intense immune response with autoantibody production. It is possible that since our patient was affected by type 1 diabetes mellitus, he was more prone to an immune system pathological response against self-antigens. A prompt, appropriate therapeutic intervention with activated recombinant factor VII administration and cyclophosphamide has led to rapid remission of clinical and laboratory findings. Full article

Advances in the treatment of hemophilia have increased the life expectancy of this population and we are currently facing diseases associated with aging, including cardiovascular ones. Coronary atherosclerosis, with acute myocardial infarction as the most severe form of manifestation, has been recognized as part of the comorbidities of hemophiliacs. However, little is known about peripheral artery disease. Available data show that hemophiliacs have cardiovascular risk factors and atherosclerosis similar to the general population. Impaired thrombus formation and phenotype of atheroma plaque rather than the burden of atherosclerosis explains their lower cardiovascular mortality. Since the effect of traditional cardiovascular risk factors overpowers that of decreased coagulability and promotes the onset and progression of atherosclerotic lesions, screening for traditional cardiovascular risk factors and peripheral artery disease should be integrated into standard hemophilia care. There is evidence that invasive treatments and long-term antithrombotic therapy are generally safe, provided that coagulation factor levels are taken into account and replacement therapy is given when necessary. Full article

Background: Hemophilia is associated with an increased risk of developing osteoporosis and osteopenia. The aim of the study was to interpret the usefulness of fractal analysis of the trabecular bone of the mandible (FD) and selected radiomorphic indices (the antegonial index (AI) and Klemetti index (KI)) to assess the risk of reduced bone mineral density (BMD) in patients with hemophilia A/B. Methods: The study group consisted of 50 patients with type A/B hemophilia. The control group consisted of 25 males without congenital bleeding disorders. The patients had a panoramic radiograph taken with the same X-ray machine (Vistapano S, Durr Dental, Bietigheim-Bissingen, Germany). The AudaXCeph software (Audax d.o.o., Ljubljana, Slovenia) was used to evaluate the AI index, and the ImageJ, software with a specially prepared script, was used to evaluate the FD. The mandibular cortex was assessed distal to the mental foramen using the Klemetti index. Results: There were no statistically significant differences between the AI, KI and FD values between the study group and the control group. Conclusions: This study indicated the lack of usefulness of AI, KI and fractal analysis in identifying patients with hemophilia at risk of reduced bone mass. Full article

Hemophilia is a chronic, congenital/hereditary and X-linked disease, characterized by an insufficiency of factors VIII or IX, which are necessary for blood clotting. Those affected by hemophilia often suffer from particular psychosocial problems, both in the acceptance, coping, treatment and self-management of their disease and in their family and social relationships, which are often mediated by these circumstances. The aim of this study was to explore the experiences of people with hemophilia or their family members, of in a specific region of Spain, regarding the impact of having hemophilia. Structured interviews were conducted and developed, using the studies of the World Federation of Hemophilia and Osorio-Guzmán et al. as a guide, as well as a literature review of qualitative work on hemophilia. Data were analyzed using a six-step thematic analysis. A total of 34 interviews were thematically analyzed. The results showed that three key themes emerged from the data: (1) the daily impact of having hemophilia, (2) uncertainty about the disease, (3) the role of associations and (4) support from institutions. The results make it clear that the disease has a major impact on their lives (work, family, leisure and personal environment). The main conclusion is that hemophilia has a negative impact on the daily lives of patients, families and caregivers. Full article

Congenital Hemophilia is an X-linked bleeding disorder caused by a deficiency of coagulation factor VII (in hemophilia A) or factor IX (in hemophilia B). The deficiency is the result of mutations of respective clotting factor genes. In the Gaza strip, 124 cases of hemophilia were observed. The main treatment for those patients is replacement of the missing factors along with supportive measures. To our knowledge, no studies were conducted in the Gaza Strip concerning nutritional status in hemophilic patients. A descriptive study that utilized a questionnaire to assess nutritional status among 27 adult male hemophilic patients managed at the Hemophilia and Thalassemia Clinic in the European Gaza Hospital from March to April 2019 was conducted. All the patients fully answered the questionnaires that included sociodemographic, socioeconomic, medical, nutritional and anthropometric characteristics. The diet diversity score for all the participants patients using mean (SD) was the following: Starches, 9.8 (0.769); Beverages, 9.6 (1.000); Vegetables, 7.8 (1.545); Fruits, 6.7 (2.215); Snacks, 6.3 (3.667); Legumes, 6.8 (1.459); Poultry, 5.0 (0.337); Meat, 4.9 (1.154); Eggs, 4.7 (1.846); Grains, 4.5 (2.375); Dairy Products, 4.2 (2.991); Soups, 4.1 (2.100); Fish, 3.8 (2.088); Nuts, 3.7 (2.270); and Sweeteners, 3.4 (2.857). Notably, only 17 patients (63.0%) were aware of the current dietary reference intakes. Moreover, most participants acknowledged the importance of providing nutritional patient education. In addition to medical treatment, hemophilic patients need to improve their nutritional status. This can be achieved through education and increase in patient awareness. Full article

Factor VIII (FVIII) is an important component of blood coagulation as its congenital deficiency results in life-threatening bleeding. Current prophylactic therapy of the disease (hemophilia A) is based on 3–4 intravenous infusions of therapeutic FVIII per week. This poses a burden on patients, demanding reduction of infusion frequency by using FVIII with extended plasma half-life (EHL). Development of these products requires understanding FVIII plasma clearance mechanisms. This paper overviews (i) an up-to-date state of the research in this field and (ii) current EHL FVIII products, including recently approved efanesoctocog alfa, for which the plasma half-life exceeds a biochemical barrier posed by von Willebrand factor, complexed with FVIII in plasma, which results in ~1 per week infusion frequency. We focus on the EHL FVIII products’ structure and function, in particular related to the known discrepancy in results of one-stage clotting (OC) and chromogenic substrate (CS) assays used to assign the products’ potency, dosing, and for clinical monitoring in plasma. We suggest a possible root cause of these assays’ discrepancy that is also pertinent to EHL factor IX variants used to treat hemophilia B. Finally, we discuss approaches in designing future EHL FVIII variants, including those to be used for hemophilia A gene therapy. Full article

Hemophilia A is a rare congenital bleeding disorder caused by a deficiency of functionally active coagulation factor VIII (FVIII). Most patients with the severe form of the disease require FVIII replacement therapies, which are often associated with the development of neutralizing antibodies against FVIII. Why some patients develop neutralizing antibodies while others do not is not fully understood. Previously, we could demonstrate that the analysis of FVIII-induced gene expression signatures in peripheral blood mononuclear cells (PBMC) obtained from patients exposed to FVIII replacement therapies provides novel insights into underlying immune mechanisms regulating the development of different populations of FVIII-specific antibodies. The aim of the study described in this manuscript was the development of training and qualification test procedures to enable local operators in different European and US clinical Hemophilia Treatment Centers (HTC) to produce reliable and valid data for antigen-induced gene expression signatures in PBMC obtained from small blood volumes. For this purpose, we used the model antigen Cytomegalovirus (CMV) phosphoprotein (pp) 65. We trained and qualified 39 local HTC operators from 15 clinical sites in Europe and the US, of whom 31 operators passed the qualification at first attempt, and eight operators passed at the second attempt.  Full article

Hemostasis reflects a homeostatic mechanism that aims to balance out pro-coagulant and anti-coagulant forces to maintain blood flow within the circulation. Simplistically, a relative excess of procoagulant forces can lead to thrombosis, and a relative excess of anticoagulant forces can lead to bleeding. There are a wide variety of congenital disorders associated with bleeding or thrombosis. In addition, there exist a vast array of autoimmune diseases that can also lead to either bleeding or thrombosis. For example, autoantibodies generated against clotting factors can lead to bleeding, of which acquired hemophilia A is the most common. As another example, autoimmune-mediated antibodies against phospholipids can generate a prothrombotic milieu in a condition known as antiphospholipid (antibody) syndrome (APS). Moreover, there exist various autoimmunity promoting environments that can lead to a variety of antibodies that affect hemostasis. Coronavirus disease 2019 (COVID-19) represents perhaps the contemporary example of such a state, with potential development of a kaleidoscope of such antibodies that primarily drive thrombosis, but may also lead to bleeding on rarer occasions. We provide here a narrative review to discuss the interaction between various autoimmune diseases and hemostasis. Full article

Aging hemophiliacs face cardiovascular disease. Lots of evidence has been gathered that hemophiliacs have a more unfavorable cardiovascular profile than the general population does, especially due to the increased prevalence of hypertension (HTN). Among the existing scattered evidence, our study provides the most comprehensive and systematized analysis of the determinants of HTN in hemophiliacs. We discussed the contribution to the HTN substrate of hemophilia-specific factors, such as type, severity and the presence of inhibitors. The complex mechanism of kidney dysfunction in relation to hematuria and viral infections was meticulously addressed. Furthermore, we highlighted the new pathogenic concepts of endothelial dysfunction and the association between HTN and hemophilic arthropathy. The clustering of cardiovascular risk factors is common in hemophiliacs, and it enhances the negative vascular effect of HTN and aggravates HTN. It usually leads to an increased risk for coronary and cerebrovascular events. Our work provides reliable evidence to guide and improve the management of HTN in hemophiliacs. Full article