Treatment Of Hemophilia Research Articles

Complement protein C3a enhances adaptive immune responses towards FVIII products.

The most serious complication in the treatment of hemophilia A (HA) is the development of factor (F)VIII inhibitors or antidrug antibodies (ADA) occurring in 25-35% of patients with severe HA. The immunological mechanisms underlying the development of ADA against FVIII products have not been completely understood yet. Immunological danger signals associated with events such as infection or surgery have been suggested to play a critical role. In previous studies, we demonstrated that plasma-derived (pd)FVIII but not recombinant (r)FVIII can activate human monocyte-derived dendritic cells (DC) in a danger signal-dependent manner, which subsequently mediate the proliferation of autologous CD4+ T cells. In this study, we investigated the ability of plasma components, naturally present in pdFVIII products, to mediate T-cell responses. In fact, we show that addition of plasma to rFVIII plus lipopolysaccharide (LPS)-stimulated DC induces proliferation of autologous CD4+ T cells. Interestingly, although DC pulsed with LPS plus plasma induce T-cell proliferation upon co-culture, the addition of FVIII significantly increases the number of proliferating as well as FVIII-specific CD4+ T cells. Total proliferating CD4+ T cells and FVIII-specific subsets were identified mainly as central memory T cells. Experiments using blocking antibodies and receptor antagonists revealed that the complement proteins C3a and, to a lesser extent, C5a are critically involved in these LPS-mediated T-cell responses. Collectively, our results indicate that complement proteins are potent drivers of T-cell responses to FVIII. Data presented provide a model how event-related substitution of FVIII in HA patients might contribute to inhibitor development.

Health and quality of life of patients with haemophilia: A national study of 124 Danish men.

In the past decades, haemophilia treatment has greatly improved the health of persons with haemophilia (PWH). This study compares PWH to the general population on social conditions and health. In December 2021, all Danes with moderate or severe haemophilia A or B, or von Willebrands disease type 3 were invited to participate in an online self-report survey concerning sociodemographic factors, self-rated health, teeth status, chronic health conditions, symptoms and loneliness. This study compares responses from the 124 adult male PWH with responses from a male general population sample (N=4849). Analyses used logistic regression, controlling for age and highest completed education. Fewer PWH were in the oldest age group (65-84 years). Controlling for age, no significant differences were found regarding cohabitation status or education. Fewer PWH were employed (OR=.48, [.33-.71])-particularly in the 45-64 age group. PWH were less likely to report good health (OR=.49, [.31-.77]). The odds of joint disease was much higher (OR=13.00, [8.37-20.28]). Also, hypertension (OR=2.25, [1.13-5.65]) and previous stroke (OR=2.51, [1.44-3.50]) were more frequent. PWH were more likely to report pain in the arms/hands/legs/hips (OR=2.94, [1.92-4.52]), but less likely to report pain in the head/neck/shoulder (OR=.66, [.45-.96]). The disease burden of haemophilia has improved so PWH resembles the general population in areas such as marriage and education. However, even for young PWH, the disease still imposes a significant burden from hemophilia arthropathy and pain in extremities and joints. Middle-aged PWH also have poorer levels of employment than same-aged peers.

POSTER ABSTRACTS

POSTER ABSTRACTS

Impact of Emicizumab on Hemophilia Management

Hemophilia A is an X-linked inherited bleeding disorder caused by a deficiency of coagulation factor VIII(FVIII) that occurs in approximately 1 in 5,000 male births. Patients with plasma factor activity levels < 1% areclassified as having severe hemophilia. To prevent recurrent joint bleeding, which leads to QOL loss due to severearthropathy, patients need to receive regular intravenous infusions (prophylaxis) of FVIII products. However,there are many concerns regarding 1) the requirement of 2–3 times/week venipuncture for intravenous infusion, 2)frequent visits to the hospital (2–3 times/week in childhood), and 3) one-third of patients with severe hemophiliaA developing anti-FVIII neutralizing alloantibodies (inhibitors) toward the infused factor. Given this, patients andtheir caregivers encounter not only physical stress but also mental and social stress. To resolve these problems,prophylaxis with subcutaneous long-acting nonfactor products that improve in vivo thrombin generation is nowsuccessfully employed in hemophilia patients. These nonfactor products caused a paradigm shift in the treatmentand management of hemophilia. The novel agent emicizumab (Hemlibra®) is a recombinant humanized, bispecificmonoclonal antibody that simultaneously binds to activated factor IX and factor X, thereby mimicking the cofactor function of activated FVIII. Emicizumab has been shown to be safe and effective for the prevention of bleedsin patients with severe hemophilia A, both with and without inhibitors, but it has no indication in hemophilia B.One time/2 or 4 weeks administration was required for maintenance therapy. These benefits contributed by thelong half-life and subcutaneous administration make emicizumab an attractive therapeutic option for prophylaxisin infants with severe hemophilia; however, clinical data to inform treatment decisions in infants are almost absent. As the QOL of hemophilia patients and their caregivers is improved by emicizumab administration, emicizumab might be changed as a mainstream treatment for severe hemophilia in all patients, including infants.

The combination of emicizumab and recombinant factor VIII in plasma: Which assays can we use for accurate measurement?

The bispecific antibody, emicizumab, is a prophylactic therapy used for the treatment of haemophilia A (HA). Patients may require additional replacement factor VIII (FVIII) to ensure adequate haemostasis. This study investigated the laboratory measurement of severe HA (SHA) plasma spiked with 36 combinations of emicizumab plus recombinant (r) FVIII concentrates. FVIII assays were performed by one stage assay (OSA) using eight APTT reagents from three manufacturers and chromogenic assays (CSA) using seven kits. CSA kits comprised a range of bovine FX/FIXa, bovine FX/human FIXa or human FX/FIXa. Thrombin generation (TG) was assessed by CAT and ST-Genesia. Emicizumab-calibrated modified OSA and human FX CSA both overestimated rFVIII in the presence of emicizumab; median FVIII:C of up to 89% higher was observed in plasma spiked with both drugs compared to just rFVIII. In bovine FX CSA assays, there was a FVIII:C increase of up to 11% in plasmas spiked with both drugs compared to rFVIII alone. TG parameters were not all normalized by the presence of emicizumab however addition of rFVIII increased TG. ETP and peak thrombin were normalized at 50 μg/ml emicizumab using ST-Genesia but were still reduced at 75 μg/ml with CAT. Addition of rFVIII further normalized results. Modified OSA and human FX CSA could not distinguish between rFVIII or emicizumab. The presence of both emicizumab and rFVIII increased thrombin generation to normal levels compared to each drug alone. Bovine FX CSA can be used to accurately determine FVIII activity of rFVIII in plasma which also contains emicizumab.

How we manage cardiovascular disease in patients with hemophilia.

With the striking advances in hemophilia care that have materialized particularly in the last two decades, an increasing number of persons with hemophilia (PWH) have achieved a quality of life and life expectancy very close to that of unaffected individuals. With aging, a growing number of PWH develop age-related co-morbidities, including cancer and cardiovascular disease. The latter (particularly coronary artery disease and atrial fibrillation) represent a new challenge for the hemophilia treatment centers because their management implies a delicate balance between the thrombotic risk and bleeding tendency, that is further enhanced by the concomitant use of antithrombotic agents. Because evidence from clinical trials is lacking, the management of PWH with cardiovascular diseases is mostly based on expert opinions, personal experiences, and the adaptation of the evidence stemming from studies on people without hemophilia. In this article, we focus on how to manage coronary artery disease and atrial fibrillation in patients with hemophilia.

Diagnostic and treatment methods of skeletal symptoms of haemophilia and education of patients regarding the disease – review study

Introduction. Haemophilia is a genetic haemorrhagic disorder that characterises with extensive and prolonged bleeding. In severe stages of the disease, joint haemorrhages may occur and eventually result in joint degeneration and haemophilic arthropathy. Aim of the study. Summary and evaluation of diagnostic and treatment methods of skeletal problems in patients with haemophilia. Review of patients’ knowledge about the disease. Material and methods. Review of the newest medical journal literature published on PubMed database. Results. Ultrasonography is a non-invasive imaging method used to diagnose acute hemarthrosis and early stages of joint damage. Magnetic resonance is a standard tool in evaluation and scoring of haemophilic arthropathy. X-rays and computed tomography can also be additionally used, but are ineffective in imaging soft tissue and cartilage. Substitution of clotting factors is a standard treatment in haemophilia which reduces the frequency of bleeding. Arthrocentesis, synovectomy for example radiosynovectomy are effective in case of joint disorders. Intra-joint injections of hyaluronic acid are also effective. In advanced stages of haemophilic arthropathy joint replacement is recommended. Majority of patients with haemophilia claim that they are sufficiently educated about their disease. Conclusion. Haemophilic arthropathy is a severe joint destructing condition that causes limited mobility, chronic pain and a reduced quality of life. Its early diagnosis and proper treatment is necessary to avoid total destruction of the affected joint. Multidisciplinary care of the patient is an approach of great importance. Education of patients about their disease and up-to-date treatment methods is necessary.

Hemgenix - A Gene Therapy for Hemophilia B

Etranacogene dezaparvovec-drlb (Hemgenix – CSL Behring), an adeno-associated virus vector-based gene therapy, has been approved by the FDA for treatment of hemophilia B in adults who currently receive factor IX prophylaxis therapy or have had life-threatening or repeated, serious, spontaneous bleeding episodes.

Review of Potential Barriers to Effective Hemostatic Management of Acquired Hemophilia A by Non-Hemophilia Experts in the United States.

Acquired hemophilia A (AHA) is an ultra-rare autoimmune disorder caused by autoantibodies against factor VIII. It often presents with life-threatening bleeding to non-hemophilia experts, who have limited awareness of this condition. This review evaluated hemostatic management and identified barriers to optimal management of AHA by non-hemophilia experts in the United States through a literature review. AHA case reports published by non-hemophilia experts from January 2016 through November 2021 in non-hematology journals were critically reviewed for a chronology of clinical course and management, consultation with a hemophilia expert, referencing of available AHA recommendations, discussion of all hemostatic options, and bleed control outcomes; 24 case reports representing 24 patients were identified. Twelve patients had an apparent delay in diagnosis, 17 cases did not seek expert consultation, and 15 did not reference the 2009 International AHA Recommendations, including six in whom hemostatic treatment was not consistent with the recommendations. Of the 17 articles published after the 2017 AHA Guidance, eight did not reference them. Of the five articles published after the 2020 International Recommendations for AHA, three did not reference them. Overall, 14 articles did not discuss all available hemostatic treatment options. Four patients died. Our findings reveal variability in hemostatic management of AHA by non-hemophilia experts in the United States. Lack of AHA awareness remains a primary barrier for optimal management of AHA among non-hemophilia experts. Increasing education about existing AHA guidelines, including available therapies and access to expert care at hemophilia treatment centers, may help improve the outcomes of patients with AHA.

Expert opinion paper on the treatment of hemophilia A with emicizumab

ABSTRACTIntroductionProphylaxis with emicizumab, a bispecific monoclonal antibody that mimics FVIII function, has shown encouraging results in clinical trials in terms of efficacy and safety. However, current experience is limited, and many areas of concern to clinicians have yet to be reviewed.Areas coveredThis paper reviews the experience of hemophilia A patients treated with emicizumab based on the results of clinical trials and real-life studies. The authors place special emphasis on issues such as the management of these patients in situations of hemorrhage and/or surgical interventions, joint health or laboratory monitoring.Expert opinionTreatment with emicizumab has been shown to improve joint health and reduce bleeding, of particular interest to patients with inhibitors and high bleeding rates. However, there are still concerns about its administration in neonates and previously untreated patients due to limited reported experience. Laboratory monitoring is not strictly necessary due to the stable pharmacokinetics emicizumab has been shown to exhibit, however, tests that globally assess hemostasis may be useful especially in cases of bleeding or surgery. The authors are also of the opinion that prophylaxis before minor surgery is not necessary and that major surgeries can be safely performed with additional prophylactic coagulation factor.

Big stride in gene therapy for hemophilia B in China.

Big stride in gene therapy for hemophilia B in China.

The state of oral health in patients with haemophilia in the Netherlands.

Previous studies show contradictory outcomes regarding dental, gingival and periodontal status in persons with haemophilia (PWH) compared to healthy controls. PWH may experience disease-specific barriers to access dental care due to their bleeding tendency, which may lead to delays in oral care and severe dental problems. To determine the current subjective and objective oral health status in adult PWH. Randomly selected PWH of the Erasmus MC Haemophilia Treatment Center (HTC), Rotterdam, the Netherlands, were invited to participate. Data was collected using the Oral Health Impact Profile (OHIP-14NL) and personal interviews. A dentist used the DMFT index, the Dutch Periodontal Screening index (DPSI), plaque and bleeding index to score the dental status. Forty-eight adult PWH were included in this study, 20 mild, 15 moderate-severe and 13 severe haemophilia with a mean age of 44.7. PWH scored low on the OHIP-14 questionnaire (median total score 1.0; IQR .0-3.0), indicating a high self-rating oral health status. The number of bleeding events, bleeding- and plaque index score was not statistically significant between patients with mild, moderate or severe haemophilia. The mean number of decayed, missing, and filled teeth (DMFT-score) was significantly lower in the group of patients with severe haemophilia (median 2.0) compared to mild haemophilia (median 16.0) (p=.04). Twenty-five patients (52.1%) reported to have encountered bleeding problems during or after dental interventions during their lifetime. Dutch adult PWH A/B have good dental status and oral health status.

Women and girls with haemophilia: A retrospective cohort study in China.

Women and girls with haemophilia (WGH) may have spontaneous/traumatic bleeding similar to that in males with haemophilia, and in addition excessive bleeding during menstruation and delivery. To characterize WGH in China and provide guidance for better management. We retrospectively analysed the characteristics of WGH registered in the Haemophilia Treatment Center Collaborative Network of China(HTCCNC) Registry, including demographics, diagnosis and treatment, bleeding characteristics, obstetrical and gynaecological experiences, and surgical history. A total of 61 females had confirmed haemophilia. Diagnosis and treatment were typically delayed, longer in mild haemophilia than in severe and moderate. The most frequently reported bleeding manifestations were haemarthrosis in severe and moderate patients, and cutaneous bleeding in mild patients. Among 45 postmenarcheal WGH, 21 (46.7%) had history of heavy menstrual bleeding, but only three received treatments. Prenatal diagnosis and management of perinatal haemorrhage were inadequate. Of 34 deliveries in 30 women, nine deliveries were complicated by postpartum haemorrhage, and 22 offspring carried mutations causing haemophilia. Forty-four surgical procedures were performed in 29 patients. Those procedures receiving preoperative coagulation factors coverage were significantly less likely to have excessive bleeding than those who did not (P=.003). This is the first and largest study describing WGH in China. There are currently deficiencies in the identification, diagnosis, and management of these patients. Improving health insurance policies, establishing haemophilia centres, and multidisciplinary teams for bleeding and perinatal or perioperative management will help reduce morbidity and mortality.

The effect of a next generation factor VIII mimetic bispecific antibody (Mim8) on assays of factor VIII activity and thrombin generation

BackgroundMim8 is a next generation bispecific antibody developed for the prophylactic treatment of hemophilia A. The sensitivity of activated plasma thromboplastin time (APTT), assays measuring factor VIII activity (FVIII:C) and thrombin generation to plasma containing Mim8 was assessed. MethodsCongenital severe hemophilia A plasma was spiked with Mim8 at 0 μg/mL to 20 μg/mL. APTT was measured with 4 reagents, one-stage FVIII with 9 reagents, and chromogenic FVIII with 6 assays. Thrombin generation was assessed in a low tissue factor system. ResultsAt 1-μg/mL Mim8, the APTT was shortened to within normal limits and one-stage FVIII:C was >1.00 IU/mL with all APTT reagents. Modified one-stage assays calibrated with Mim8 reference material calibrated recovered within 20% of the target Mim8 concentration with most APTT reagents. Factor VIII:C of bovine only chromogenic assays was <0.04 IU/mL at all Mim8 concentrations. Factor VIII:C of human only chromogenic assay was >4.00 IU/mL at 20-μg/mL Mim8. Factor VIII:C of hybrid bovine FX, human FIXa chromogenic assays ranged from 0.076 to >3.00 IU/mL at 20-μg/mL Mim8. Normal thrombin generation was restored at 5-μg/mL Mim8. ConclusionsAPTT-based assays are sensitive to Mim8 and should not be performed in the presence of the drug. Chromogenic assays containing human proteins or hybrid human/bovine proteins demonstrated variable sensitivity to Mim8. Bovine only chromogenic assays were largely insensitive to the presence of Mim8. Thrombin generation normalized at increased Mim8 concentrations. Modified one-stage and chromogenic assays could be used to quantify the Mim8 concentration in plasma.

Out-of-pocket expenditure incurred during treatment of hemophilia at a government facility in North India

Out-of-pocket expenditure incurred during treatment of hemophilia at a government facility in North India

Current status and future perspective of treatment for hemophilia

Hemophiliacs are X-linked inherited bleeding disorders. The treatment of hemophilia is based on periodic replacement treatment with coagulation factor products to avoid the development of hemophilic arthropathy, as well as to control fatal bleeding. However, because of the coagulation factor's incredibly short half-life, the medication must be often given intravenously throughout one's life. Extended half-life coagulation factor preparations have lowered the burden of treatment by enhancing pharmacokinetics. However, the patients remain at risk of developing inhibitors to significantly interfere with the therapeutic effectiveness of coagulation factor concentrates. Recently, nonfactor replacement therapies have gained a lot of interest as a new class of therapeutic drugs preventing bleeding in patients with or without inhibitors. Moreover, gene therapy drugs for hemophilia have recently been approved in Europe and the United States. Because gene therapy can preserve coagulation factor levels in the blood for at least several years with a single treatment, it may become a curative treatment that removes the need for the therapy for a long time.

Mutation Analysis of F8 Gene and Phenotypic Characterization of Hemophilia A

Background Hemophilia A HA is a congenital bleeding disorder caused due to deficiency of Factor VIII clotting protein in the blood. It follows an X-linked recessive mode of inheritance.Aim In the present study clinical and haematological manifestations have been analysed and their correlation with molecular mutations in patients with haemophilia A has been tested.Methods A total of 90 HA patients were included in the study. Plasma coagulation test PT APTT and correction study factor VIII assay inhibitors screening test and quantification tests were done for all the patients. Mutation analysis was carried out to evaluate the molecular alteration in F8 gene only on exon.Results Among the 90 Hemophilia A patients included 3 3.3 were diagnosed as mild 15 16.6 as moderate and 72 80 were diagnosed as severe hemophilic patients. Positive family history was observed in 62 68.8 patients while 35 38.8 were born to consanguineous couples. Joint bleeding 88.8 was most commonly observed followed by mucocutaneous bleeding 66.6 dental bleeding 48.8 genitourinary bleeding 16.6 gastrointestinal bleeding 15.5 muscle bleeding 14.4 and intracranial bleeding 10. Around 13 14.4 HA patients developed inhibitors among which five were of low titer and eight were of high titer. Mutation analysis of 90 HA patients recorded a total of 21 mutations including 52.4 missense mutations 23.8 nonsense mutations 23.8 frameshift mutations. No novel mutation was noted.Conclusion The present study showed several missense mutations in severe HA patients. This result is a slight deviation from the reports of earlier Indian studies which could be due to difference in geographic population ethnicity and other factors. Hence a detailed genotype and phenotype screening in relation to severity and development of inhibitors is much essential for timely monitoring and appropriate treatment of Hemophilia A.

Seroprevalence of hepatitis B, hepatitis C, and human immunodeficiency virus in hemophilia A patients: A descriptive study

Background: Hemophilia A (Factor VIII deficiency) is a X-linked coagulopathy that affects approximately 1/10,000 male live births. In the past, the treatment of hemophilia A consisted of cryoprecipitated plasma and purified factor preparations. As a result, they experienced unusually high incidence of hepatitis and human immunodeficiency virus (HIV) seroconversion. Aims and Objectives: The aims of this study were to find out the seroprevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV infection, among hemophiliacs attending a tertiary care center in Kerala, southern India. Materials and Methods: A cross-sectional study was conducted on hemophilia A patients who attended the departments of medicine and pediatrics. Demographic details and treatment history were obtained by questionnaire. Enzyme-linked immunosorbent assay was used to detect HBV surface antigen, HCV antibodies, and HIV. The statistical data analysis was performed using SPSS software version. Results: Out of 90 hemophilia A patients who underwent testing for the seroprevalence of transfusion-transmitted viral infections, one (1.1%) patient tested positive for HIV, two (2.2%) for HCV, and one (1.1%) for HBV. Among patients with hemophilia A, the prevalence of transfusion-transmitted infection was 4.4%. Patients with HIV- and HCV-positive tests belonged to the severe hemophilia A group. Moreover, the HBV-positive patient belonged to moderate hemophilia A. Conclusion: The present paradigm of management of hemophilia A patients is with plasma-derived or recombinant Factor VIII concentrates, cryoprecipitates, and fresh frozen plasma. Due to the risk, however remote, of transfusion-transmitted viral infections, all hemophiliacs should receive the hepatitis B vaccine and undergo routine testing for HIV, HCV, and HBV viruses.

Shared decision-making for gene therapy in haemophilia care

Abstract Shared decision-making (SDM) is an important part of patient-centred care in which healthcare professionals (HCPs) and patients/caregivers jointly reach care decisions through a two-way exchange and synthesis of information based on clinical evidence and patient preference. SDM was described in haemophilia care in 2014 as two-sided intervention to aid patient decision-making. However, as the range of haemophilia treatments has expanded, identifying the optimal haemophilia treatment for an individual has become more complex. This is particularly so in the case of gene therapy, a onetime-only, irreversible treatment. In this context, it is vital that people with haemophilia (PwH) and their families continue to be involved in care decisions in an informed and interactive way. For gene therapy, this must include being well informed about the gene therapy process, enabling the patient to engage in fully informed SDM and consent, and ensuring that issues around long-term durability, potential side effects, the need for long-term follow-up are understood with a recognition that the ‘unknown unknowns’ are also unknown to HCPs. Both HCPs and patient organisations have a key role to play in providing PwH with access to relevant information and education, tailored to individual needs and free of jargon. Considerable education and support are required before PwH can make a truly informed decision about having gene therapy. Use of structured SDM tools such as the SHARE approach can help to support this. There is a need for SDM educational tools that include written/visual information and the use of standardised checklists may be helpful for both PwH and HCPs. The most important part of this process is that PwH want to undergo gene therapy – and this is only an option if they are fully educated and informed by fully educated and informed healthcare teams.

Clinical internship at UC San Diego Hemophilia and Thrombosis Treatment Center

Clinical internship at UC San Diego Hemophilia and Thrombosis Treatment Center