Joint Bleeding Research Articles

How to assess, detect, and manage joint involvement in the era of transformational therapies: Role of point-of-care ultrasound.

Patients with haemophilia experience recurring hemarthroses, mainly involving knees, elbows and ankles, which lead to haemophilic arthropathy, the major chronic complication of haemophilia. With new approaches to haemophilia treatment leading to fewer joint bleeds and, in some cases, no bleeding events, assessing whether current outcome assessment tools provide adequate sensitivity and specificity for management and care of patients with haemophilia is needed. An overview of current imaging tools for monitoring joint health, novel osteochondral damage and synovial proliferation biomarkers, and the relationship between assessments for functionality and imaging modalities is provided. Usefulness and sensitivity of point-of-care ultrasound (POCUS) to complement other assessments and use of ultrasound to monitor haemophilic arthropathy are also examined. This review provides rationale for haemophilia teams to move beyond traditional outcomes in joint imaging, as well as guidance and evidence on assessment of joint health for potential new treatment modalities, such as gene therapy. The role of POCUS in the existing paradigm for haemophilia care and management along with the use of ultrasound as a complement to other outcome assessment tools are also discussed. Finally, the clinical effects of subclinical bleeding on joint function are described, to motivate screening for synovial proliferation. POCUS can facilitate the early detection of joint damage and can monitor disease progression while providing insights into the efficacy of treatment regimens, and should be considered as an essential assessment tool for managing the care of patients with haemophilia.

Pharmacokinetic parameter driven outcomes model predicts a reduction in bleeding events associated with BAY 81–8973 versus antihemophilic factor (recombinant) plasma/albumin-free method in a Chinese healthcare setting

BackgroundLong-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population.MethodsHead-to-head PK profile data of BAY 81–8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year.ResultsCumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3% for BAY 81–8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81–8973 compared to rAHF-PFM. BAY 81–8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM.ConclusionBased on modeled head-to-head comparisons, differences in PK-properties between BAY 81–8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81–8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.

Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1–3

BackgroundBleeding in people with hemophilia A can be life threatening, and intra‐articular bleeds can result in joint damage. Most clinical studies focus on treated bleeds, while bleeds not treated with coagulation factor(s) (untreated bleeds) are underreported. ObjectivesWe assessed the incidence of untreated bleeds during a noninterventional study (NIS) wherein people with hemophilia A, with or without factor VIII (FVIII) inhibitors, were managed according to standard practice. Patients/MethodsUsing the Bleed and Medication Questionnaire, we prospectively collected data from three cohorts: Cohort A, adults/adolescents (age ≥12 years) with FVIII inhibitors; Cohort B, children (aged <12 years) with FVIII inhibitors; Cohort C, adults/adolescents without FVIII inhibitors. Untreated bleeds were analyzed for site, frequency, and etiology of bleeding and compared with those during emicizumab prophylaxis in the same individuals after transferring to a Phase III HAVEN trial. ResultsIn the 221 participants enrolled in the NIS (Cohort A, n = 103; Cohort B, n = 24; Cohort C, n = 94), the incidence of untreated bleeds was approximately 40% of all bleeds in people with FVIII inhibitors and 26.2% in adolescents/adults without inhibitors. Approximately 70% of treated bleeds and approximately 54% of untreated bleeds in adults/adolescents were in joints. Untreated joint bleeds were less common (7.1%) in children. Overall, intra‐individual comparisons showed reduced treated/untreated bleeds following transition from standard to emicizumab prophylaxis. ConclusionA significant proportion of bleeding events are untreated in people with hemophilia A. There is a need to further understand why bleeds remain untreated and to capture such events in clinical studies.

Comprehensive approach to hemophilia

Hemophilia A, B are X-linked recessive bleeding disorder that typically results from a deficiency of clotting factor VIII (FVIII) and factor IX (FIX). The severity of the disease is determined according to the FVIII and FIX levels. Hemophilia A and B have similar symptoms and are both characterized by bleeding, particularly in large joints such as ankles, knees, elbows. Recurrent bleeding in joints eventually causes progressive hemophilic arthropathy. Life-threatening hemorrhages may occur rarely. Treatment of hemophilia has improved significantly in recent years with clotting factor concentrates. The average life expectancy was

Individualised prophylaxis based on personalised target trough FVIII level optimised clinical outcomes in paediatric patients with severe haemophilia A.

As standard care of severe haemophilia A (SHA), prophylaxis should be individualised. This study aimed to investigate the effectiveness of this new-proposed individualised prophylaxis protocol. Boys with SHA were enrolled and followed a PK-guided, trough-level escalating protocol of prophylaxis after a six-month observational period. In the next 2 years, clinical assessments including joint bleeds, ultrasound (US) scores and Haemophilia Joint Health Score (HJHS) in both sides of ankles, knees and elbows were conducted every 6 months as a scoring system, which determined whether the trough level's escalation. Adjustment of dosing regimen was based on WAPPS-Hemo. Fifty-eight SHA boys were finally analysed. Their age and bodyweight were 5.3(2.8,6.9) years and 21.5(16,25) kg. During the study, 47 escalations were conducted. At study exit, the patient number and proportion of different trough level groups were:<1IU/dl, 17.2% (10/58); 1-3IU/dl, 53.5% (31/58); 3-5IU/dl, 15.5% (9/58);>5IU/dl, 13.8% (8/58). Significantly reduced annualised bleeding rate [4(0,8) to 0(0,2), p<.0001] and annualised joint bleeding rate [2(0,4) to 0(0,.25), p<.0001] was observed at study exit as well as the continuous trend of increased zero bleeding proportion (ZBP) (27.6%-69.0%) and zero joint bleeding proportion (46.5%-81.3%). Besides, 85% (6/7) of the target joints vanished. Statistical improvements of US scores (p=.04) and HJHS (p=.02) were also reported at study exit. Our results showed the effectiveness of our protocol based on individualised target trough level and emphasise the importance of personalised prophylaxis.

Total knee arthroplasty in patients with haemophilic arthropathy is effective and safe according to the outcomes at a mid-term follow-up

BackgroundHaemophilic arthropathy (HA), a common complication of haemophilia, is secondary to recurrent joint bleeding and increases the prevalence of end-stage osteoarthritis (OA). Total knee arthroplasty (TKA) is a reliable treatment for haemophilia patients. This study was performed to evaluate the mid-term outcomes of TKA for end-stage HA. We hypothesized that the rate of complications of TKA is higher for patients with haemophilia than for patients without haemophilia.MethodsPatients with HA undergoing TKA from January 2015 to December 2016 in our centre were retrospectively reviewed. All patients were managed by a multidisciplinary team. The improvements in flexion contracture, range of motion (ROM), Knee Society Score (KSS; clinical and functional), Visual Analogue Scale (VAS) score, and satisfaction at final follow-up were analysed to evaluate the effectiveness of TKA in HA. The complications were analysed to evaluate the safety of TKA in HA.ResultsTwenty-eight patients (32 knees) were included in the study. The follow-up was 69.1 ± 5.1 months. Significant differences between the preoperative and final follow-up values of flexion contracture (which changed from 21.1 ± 6.5° to 14.3 ± 4.1°, P < 0.001), ROM (from 53.9 ± 15.0° to 70.3 ± 16.3°, P < 0.001), clinical KSS (from 33.5 ± 14.4° to 62.7 ± 9.5°, P < 0.001), functional KSS (from 46.1 ± 15.5° to 62.9 ± 9.7°, P < 0.001), and VAS score (from 6.8 ± 1.4 to 4.9 ± 1.3, P < 0.01) were observed. Importantly, the incidence of complications was 15.6% and the satisfaction was 100% in our mid-term study.ConclusionUnder elaborative and comprehensive management, TKA is effective and safe in patients with advanced HA on the basis of mid-term follow-up outcomes.

RFVIII-Fc in severe haemophilia A: The incentive switch in case of high risk of joint bleedings.

Efmoroctocog alfa, the first recombinant factor VIII fusion protein with extended half-life (rFVIII-Fc), has been hypothesized to lower FVIII consumption in patients with severe Haemophilia A (pwSHA), without reducing clinical efficacy. What about real life? MOTHIF-II was a noninterventional, multicentre, before/after study, via the collection of retrospective data from July 2015 to June 2016 (called T1), and from July 2017 to June 2018 (called T2), in 7 French haemophilia treatment centres. We examined the prescriptions and dispensations of factor VIII and the Annual Bleeding Rate (ABR), in pwSHA without current inhibitors on prophylaxis, before and after the introduction of rFVIII-Fc. The data gathered from the BERHLINGO research database and from the French Healthcare claims database with a determinist pairing process based on the national unique identification number. A total of 156 pwSHA were included in the prescription cohort and 83 in the ABR cohort. For switched patients, the mean amounts of prescribed FVIII were significantly higher during T1 compared to T2 (4333 (2052) vs. 3921 (2029) IU/kg/year/patient, p: 0.028); a significant decrease in their ABR was also observed between T1 and T2 (6.3 (6.0) vs. 4.4 (5.4), p: 0.047). These patients had a more severe bleeding profile centred on haemarthrosis. The results are related to those of the pivotal clinical trials for the reduction in FVIII consumption following the switch to rFVIII-Fc, with a significant improvement in the haemorrhagic phenotype for pwSHA.

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

: Coagulation factor VII (FVII) is a vitamin K-dependent serine protease that plays a pivotal role in normal hemostasis. Mature FVII is a glycoprotein comprised γ-carboxyglutamic acid-rich (Gla) domain, two epidermal growth factor (EGF)-like domains, an activation domain, and a serine protease domain. FVII requires proteolytic activation followed by tissue factor (TF) binding for maximal activity. The F7 gene (14.8 kb) is located on 13q34, composed of nine exons and eight introns. The congenital FVII deficiency is a rare coagulopathy with an autosomal recessive pattern of inheritance that occurs due to mutation in the F7 gene. A considerable number of mutations of different types have been identified throughout this gene affecting the expression, structure, and post-translational alterations of the protein. FVII deficiency is the most frequently recessively inherited bleeding disorder. Subjects with FVII deficiency show a wide range of symptoms, including cutaneous hemorrhage, mucosal hemorrhage, gastrointestinal bleeding, joint bleeding, and central nervous system (CNS) hemorrhage. Unlike other coagulation factor deficiencies, serum levels of FVII do not demonstrate the severity of the disease, and there is no direct correlation between serum levels and clinical complications. Replacement therapy is the treatment of choice for FVII deficiency. Various therapeutic products such as prothrombin complex concentrate, plasma-derived FVII concentrate, fresh frozen plasma, and activated recombinant FVII are available to treat FVII deficient individuals. This review aims to provide information on molecular, biochemical, and clinical aspects of coagulation FVII, its role in hemostasis, and the consequences of its deficiency.

Clinical Audit of Low Dose Prophylaxis Programme for Nigerian Children with Haemophilia

Introduction: The evidence of benefits for prophylaxis especially low dose prophylaxis is incontestable yet most children in developing countries as Nigeria do not have access to this treatment protocol.&#x0D; Aim: The aim was to audit the low dose prophylaxis treatment in Nigerian children with haemophilia.&#x0D; Methodology: A multicentre clinical audit of five haemophilia treatment centres; University of Nigeria Teaching Hospital Enugu, Lagos University Teaching Hospital, National Hospital Abuja, University of Port Harcourt Teaching Hospital Port Harcourt, and Federal Teaching Hospital Gombe. Eighteen children with mild-severe haemophilia were enrolled into low-dose prophylaxis treatment programme. The reduction of joint bleeding, improvement of joint function and Quality of Life (QoL) during prophylaxis were analysed.&#x0D; Results: In total 18 children - 17males and 1 female (median age 8 years) were enrolled. The median duration of observation was 7 months (range 3-15months). Seven of the children were on primary prophylaxis (41%) while 10 of the children (59%) were on secondary prophylaxis. The number of joint bleeds decreased from a total of 162 (individual range 5-20, mean 10.3) to 42 (range 0-7, mean 3.0) during the observation period with an overall reduction of 74%. Joint function improved in 94.1% of disease joints, while only 5.6% reported no improvement (due to poor compliance). School attendance improved in all subjects, sports participation and daily activity improved moderately.&#x0D; Conclusion: Low dose prophylaxis was beneficial in reduction of joint bleeds, improvement of joint function and improvement of QoL of Children with haemophilia in Nigeria.&#x0D; &#x0D; Authors&#x0D; T U Nwagha 1, H C Okoye 1, C E Udo 2, S Yuguda 3, K I Korubo 4, T A Adeyemo 5&#x0D; &#x0D;

The long-term clinical benefits and economic costs associated with increased use of prophylaxis among patients with haemophilia A in China: Population-based predictions from 2018 to 2033.

To predict the long-term benefits and economic costs of the improvements in haemophilia care in China demonstrated by increasing use of prophylaxis, compared with the current status. City-level predictions from 2018 to 2033 were conducted for five representative cities in China. The long-term clinical and economic outcomes in the scenario where haemophilia care has significantly improved and the existing scenario of haemophilia care were calculated and compared. The model input data were obtained from local records, expert interviews, published literature, and other sources. Outcome measures including number of bleeds and joint bleeds, number of target joints, disability rate, direct and indirect costs were calculated at the patient and population levels. The long-term predictions for 2033 demonstrated significantly improved bleed control and joint outcomes due to increased use of prophylaxis. The total number of averted bleed events per patient ranged from 3.9 in Shenyang to 16.1 in Zhengzhou in 2033, and the population-level averted bleed events ranged from 1963 in Xiamen to 14,868 in Zhengzhou. The treatment improvement also leads to significant economic costs driven by increase in clotting factor costs (more than 90%). At the population level, the additional total costs were highest in Zhengzhou (CNY 177.4 million) and lowest in Shenyang (CNY 45.4 million), due to their different population sizes and various existing treatment regimens. The outpatient and hospitalization costs decreased, while the factor costs increased. The long-term prophylaxis is associated with avoided bleed events and disabilities. The improved treatment regimens are also associated with a significant economic burden, driven by factor costs.

Pharmacokinetic and clinical improvements after PK-guided switch from standard half-life to extended half-life factor VIII products

IntroductionExtended half-life (EHL) factor VIII (FVIII) products have been designed to allow less frequent infusions and higher bleeding protection than standard half-life (SHL) products. Only few reports analyzed this switch in clinical practice.AimTo analyze the differences observed in pharmacokinetics (PK) and clinical outcomes after the switch from SHL to EHL products in severe/moderate haemophilia A (HA) prophylaxis. Materials and methodsObservational, cross-sectional, multicenter, prospective study comparing PK parameters and clinical variables between SHL FVIII replacement therapy followed by EHL along two consecutive one-year periods. PK estimations were performed through WAPPS-Hemo. FVIII consumption, annual bleeding rate (ABR) and annual joint bleeding rate (AJBR) of each period were compared between both periods. ResultsSeventy-five patients were included (median age 26.0 years). After the switch median reductions of 33.3 % in weekly infusion frequency and 20.4 % in dose/kg/week were observed, avoiding 39.1 infusions/patient/year. Significant improvements were achieved in all PK parameters with EHL, showing mean ratios in half-life and area under the curve (AUC) of 1.5 and 1.9. Significant decreases in median ABR (2.0 vs. 0.0), AJBR (1.0 vs. 0.0) and target joints, and zero total bleeds (27.4 % vs. 54.8 %) and zero joint bleeds (42.5 % vs. 72.6 %) were increased after the switch to EHL. Similar improvements were reported in patients <12 and ≥12 years. No differences were observed in PK parameters between EHL products, but lower AJBR were associated to PEGylated products. ConclusionsPK-guided switch to EHL FVIII provided significant improvements in PK and lower bleeding rates, treatment burden and consumption compared to SHL products.

Clinical outcome and incidence of inhibitor development in severe hemophilia patients receiving low-dose prophylaxis: a 3-year follow-up study in Senegal, West Africa

IntroductionIn Africa, where access to diagnosis and treatment of hemophilia is the lowest in the world, prophylaxis is rarely used in preference to on-demand treatment. There are limited data of prophylaxis treatment from sub-Saharan Africa. The aim of this study was to evaluate clinical outcomes and inhibitor development in people with hemophilia receiving low-dose prophylaxis (LDP) in a sub-Saharan African setting. MethodsWe conducted a three-year prospective study. A once or twice weekly prophylaxis regimen of 25 IU/kg of rFVIIIFc or 30 IU/kg of rFIXFc was given to Hemophilia A and B, respectively. We evaluated clinical outcomes and inhibitors occurrence, determined by screening and titration using the Nijmegen technique. ResultsA total of 15 patients were included in the LDP regimen. The mean age was 6.3 years (1.5 - 10). A significant reduction was noted in the annualized bleeding rate, from 7.53 to 1.33 (p = 0.0001); the annualized joint bleeding rate passed from 3.6 to 1.4 (p = 0.001) and the proportion of severe bleeding, from 86.1% to 16.7% (p = 0.0001). The Hemophilia Joint Health Score (HJHS) moved from 9.6 to 3.4 (p = 0.0001) and the Functional Independence Score in Hemophilia (FISH) improved from 25.8 to 30.9 (p = 0.0001). School absenteeism decreased from 7.33% to 2.59%. Adherence to prophylaxis was 89.5% versus 60%. Consumption was 580 IU/kg/year versus 1254.6 IU/kg/year before and after prophylaxis, respectively. Incidence of inhibitors was 23% (3 /13 HA). ConclusionThe LDP in Hemophilia improves the clinical outcome without a surplus risk of inhibitor development. Using extended half-life clotting factor concentrates (CFCs) is better for prophylaxis in resource-limited countries, as they allow better compliance in treatment.

The bleeding phenotype in people with nonsevere hemophilia

AbstractDetailed information on the onset, frequency, and severity of bleeding in nonsevere hemophilia is limited. We aimed to assess the bleeding phenotype of persons with nonsevere hemophilia and to analyze the association between baseline factor VIII/IX (FVIII/IX) levels and the joint bleeding rate. In the DYNAMO (Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B) study, an international multicenter cohort, we included males with nonsevere hemophilia (FVIII/IX, 0.02-0.35 IU/mL) aged 12 to 55 years. Information on age at first treated (joint) bleed, annual bleeding rates (ABRs), and annual joint bleeding rates (AJBRs) was collected from the medical files. The association between baseline FVIII/IX levels and the joint bleeding rate was assessed by using a frailty model for recurrent events. In total, 304 persons (70 with moderate hemophilia and 234 with mild hemophilia) were included. The median age was 38 years (interquartile range [IQR], 25-49 years), and the median baseline FVIII/IX level was 0.12 IU/mL (IQR, 0.05-0.21 IU/mL). In total, 245 (81%) persons had experienced at least 1 bleed, and 156 (51%) had experienced at least 1 joint bleed. The median age at first bleed and first joint bleed was 8 and 10 years, respectively. The median ABR and AJBR was 0.2 (IQR, 0.1-0.5) and 0.0 (IQR, 0.0-0.2). From baseline FVIII/IX levels 0.02 to 0.05 IU/mL to >0.25 IU/mL, the median ABR decreased from 0.6 (IQR, 0.2-1.4) to 0.1 (IQR, 0.0-0.2) and the AJBR from 0.2 (IQR, 0.0-0.4) to 0.0 (IQR, 0.0-0.0). Baseline FVIII/IX was inversely associated with the joint bleeding rate (P < .001). Low bleeding rates were observed in persons with nonsevere hemophilia. However, one-half of all adolescents and adults had experienced a joint bleed.

Clinical application of extended half-life factor VIII in children with severe haemophilia A.

Only few studies have presented results from real-world clinical use of Extended Half-Life (EHL) products in children with haemophilia (CWH). To retrospectively examine real-life experience with EHL factor VIII products use in CWH A, comparing with clinical experience from standard half-life products (SHL). A retrospective review of medical records of CWH A who have been prescribed EHL factor concentrates was conducted. All before/after comparisons were performed with the Wilcoxon matched-pairs signed-ranks test. Twenty-three children with severe haemophilia A were enrolled in the study (3-6 years old: n=4, 7-12 years old: n=7 and 13-18 years old: n=12). Median length of time that patients were treated with EHL products was 78weeks. Median dosing interval was significantly lengthened from 2.3 to 3.5days after switching from SHL to EHL concentrates. Mean trough FVIII levels were significantly increased from 2.3% to 4.1% after treatment with EHL products. Also, CWH A had a reduction of mean annual bleeding rate (ABR) and mean annual joint bleeding rate (AJBR) from 1 and .8 to .3 and .2, respectively, following treatment with EHL concentrates (ABR: p=.02, AJBR: p=.05). However, after switching to factor EHL, actual FVIII consumption, including bleeds, was significantly increased from 94IU/kg/week to 118IU/kg/week in CWH A. There was no inhibitor development. This study demonstrates the successful transition of 23 CWH A from SHL to EHL factor concentrates.

Joint status of patients with nonsevere hemophilia A

BackgroundJoint bleeding in hemophilia may eventually lead to joint damage. In nonsevere hemophilia, joint bleeds occur infrequently. Currently, knowledge on the joint status of patients with nonsevere hemophilia using objective imaging is limited. ObjectiveTo investigate the joint status in patients with nonsevere hemophilia A. MethodsThis cross‐sectional study included patients with nonsevere hemophilia A aged 24–55 years. Joint status was assessed by magnetic resonance imaging (MRI) of the elbows, knees, and ankles and International Prophylaxis Study Group (IPSG) scores were calculated. Lifetime joint bleeding history was collected from medical files. The contribution of factors to joint outcome was explored using multivariable linear regression analysis. ResultsIn total, 51 patients were included, of whom 19 (37%) had moderate and 32 (63%) had mild hemophilia. Patients had a median age of 43 years (interquartile range [IQR] 32–50), a median factor VIII activity of 10 IU/dl (IQR 4–16) and a median annual joint bleeding rate (AJBR) of 0.0 (IQR 0.0–0.2). Soft‐tissue changes (IPSG subscore > 0) in the elbows, knees, and ankles were present in 19%, 71%, and 71% of patients, respectively. Osteochondral changes (IPSG subscore > 0) in the elbows, knees, and ankles were present in 0%, 20%, and 35% of patients, respectively. In 14% of bleed‐free joints, hemosiderin depositions were observed. Age and AJBRs were most strongly associated with the IPSG score. ConclusionThis study demonstrates that a substantial proportion of adults with nonsevere hemophilia has joint changes on MRI despite low joint bleeding rates.

Low dose prophylaxis and antifibrinolytics: Options to consider with proven benefits for persons with haemophilia.

Prophylaxis has become standard of care for persons with severe phenotype haemophilia (PWsH). However, 'standard prophylaxis' with either factor or non-factor therapies (emicizumab) is prohibitively expensive for much of the world. We sought to evaluate whether haemophilia care can be provided at a lower cost yet achieve good results using Lower dose/Lower frequency prophylaxis (LDP) and with increasing use of antifibrinolytics (Tranexamic acid and Epsilon amino caproic acid). We identified 12 studies that collectively included 335 PWsH using LDP. Additionally, we undertook a literature search regarding the benefits of antifibrinolytics in haemophilia care. Identified studies show that LDP is far superior to no prophylaxis (On demand [OD] therapy) resulting in significant patient benefits. Patients on LDP showed (in comparison to patients OD) on average: 72% less total bleeds; 75% less joint bleeds; 91% less days lost from school; 77% less hospital admission days; and improved quality of life measures. These benefits come at similar or only slightly higher (<2-fold greater) costs than OD therapy. Antifibrinolytics are effective adjunctive agents in managing bleeds (oral, nasal, intracranial, possibly other) and providing haemostasis for surgeries (particularly oral surgeries). Antifibrinolytics can substitute for more expensive factor concentrates or can reduce the use of such concentrates. There is evidence to show that antifibrinolytics may be used in conjunction with factor concentrates/emicizumab for more effective/less costly prophylaxis. The use of LDP along with appropriate and increased use of antifibrinolytics offers less resourced countries good options for managing patients with haemophilia.

Effectiveness of long-term prophylaxis using pdFVIII/VWF concentrate in patients with inherited von Willebrand disease.

BackgroundPatients with symptomatic von Willebrand disease (VWD) should be offered long‐term prophylaxis (LTP) to prevent recurrent bleedings. Our objective was to evaluate the effectiveness and safety of Voncento®, a plasma‐derived FVIII/VWF concentrate (ratio 1:2.4), administrated in LTP.MethodsWe included patients from the OPALE study (May 2016 to April 2021), a French multicenter observational study following patients with inherited VWD, who received a Voncento® LTP during the study period.ResultsAmong the 130 OPALE‐study patients, 23 patients (12 women) received a LTP and were therefore included. The median (range) age was 16 (1–85) years; 16 patients were type 3, 1 was type 2A, 6 were type 2B. Before inclusion, 19 (83%) were under LTP and 4 (17%) received on‐demand (OD) treatment. The indications for initiating prophylaxis in the overall population were joint bleeding (43%), ear, nose, and throat (ENT) bleeding including epistaxis or oral bleeding (39%), and recurrent muscle hematoma (22%). The medians (ranges) dose of Voncento® per infusion, frequency, and weekly dose were 45 (33–109) IU/kg, 2 infusions per week, and 96 (44–222) IU/kg/week, respectively. The median (range) annualized bleeding rate (ABR) was 0.8, 0.7 (0–3.5), and 0 (0–2.3) for type 2A, 2B, 3 patients, respectively. There was no difference regarding to the dose, frequency of infusion, or in terms of ABR in 9/19 patients who replaced previous concentrates with Voncento®. During the study period, no adverse event was reported.ConclusionThese results suggest that Voncento® is effective to prevent recurrent bleedings in patients symptomatic VWD.

Clinical Evaluation of Balance in Children With Hemophilic Arthropathy.

Hemophilia is a hereditary coagulation disorder characterized by acute hemorrhages into the musculoskeletal system, leading eventually to arthropathy and disability. Chronic inflammation of the synovial membrane arises as a result of frequent joint hemorrhage. Proteolytic enzymes in the blood and cartilage cause deterioration after that, and joint space narrows. Chronic hemophilic arthropathy develops as a result of these unfavorable developments, which occur more quickly, especially in the target joints. Balance is a process that allows us to maintain our orientation in three-dimensional space while also regulating our body posture to avoid falling. After the central nervous system evaluates deep stimuli from sensory, visual, and auditory receptors, movement of the corresponding muscle groups is delivered. The goal of this study was to investigate how impairment to deep sensory receptors (proprioception) in the arthropathic joint structure affected hemophiliacs' balance. The study comprised 34 patients with hemophilic arthropathy, and 34 age and weight matched healthy volunteers. When balance tests of patients with hemophilic arthropathy were compared to healthy controls, hemophiliacs had a greater risk of falling. As the degree of arthropathy increased, so did the risk of falling and balance test values in individuals with hemophilic arthropathy. Treatment and coagulation factor prophylaxis to prevent the onset of arthropathy will improve patients' quality of life and reduce morbidity associated with frequent falls and bleeding. The online version contains supplementary material available at 10.1007/s12288-022-01526-0.

Evaluation of bone mineral density (BMD) and the effect of type of factor replacement therapy on BMD in children with hemophilia: A single-center observational study

BackgroundThe higher life expectancy in patients with hemophilia (PWH) due to better care has increased the incidence of age-related complications such as osteoporosis. This study was conducted to assess the bone mineral density (BMD) and its correlation with determinants of hemophilic arthropathy and to evaluate the effect of type of factor replacement therapy on BMD in Indian hemophilic children. MethodsThis study was conducted on 39 hemophilic children and 40 healthy controls. Total range-of-motion (ROM) score was calculated for major affected joints and BMD was measured by dual-energy x-ray absorptiometry at baseline and repeated at follow-up after 6 months period during which all patients received either prophylaxis or on-demand therapy. ResultsBMD and BMD Z-scores were significantly reduced in hemophiliacs as compared to controls (p < 0.05). The prevalence of low BMD in hemophiliacs ranged from 30.8 to 41% at various sites. A significant correlation was found between BMD Z-score and episodes of joint bleed, number of target joints, and total joint ROM score (p < 0.05). BMD Z-score showed a significant difference between the prophylaxis group and on-demand therapy group at baseline, and a significant increase in BMD Z-score was observed among patients in prophylaxis group at follow-up after 6 months compared to baseline (p < 0.05) but not among patients in on-demand therapy group. ConclusionsHemophilic children showed reduced BMD that correlated with hemophilic arthropathy. Prophylaxis, as compared to on-demand therapy, markedly decreased hemarthrosis and consequent immobilization, and thereby retarded the progression of bone mineral loss and improved BMD in these patients.

An observational study of haemophilia patients attending a tertiary care centre in West Bengal

Background: Haemophilia is the most common inherited coagulation disorders transmitted by X-linked recessive fashion affecting the males and females are the carriers of the disease. Haemophilia is distributed worldwide and has heterogeneous presentation depending on its severity starting from neonatal period. Knowledge of spectrum of the presentation of haemophilia helps in early diagnosis and planning of management. Aims and Objectives: This study aims to evaluate the socio-demographic profile of the patients, clinical presentations, epidemiological profiles, and the outcomes of the hemophilic patients in a tertiary care teaching hospital in West Bengal. Materials and Methods: This study was a prospective, observational, single center study conducted in the Pediatrics haemophilia treatment center at Midnapore Medical College, Paschim Medinipore from May 2020 to April 2021. Detailed history was taken and recorded in a predesigned pro forma Case Record Form. Analyses were done only after completion of CRF of the last patient. Statistical analyses were performed using SPSS version 20.0 software. Continuous variables were compared by Paired t-test. Dichotomous events were analyzed using the Fisher’s exact test and Chi-squared Test. Statistical significance was defined as P&lt;0.05. Results: Mean age of children was 93.64 months (SD 6.38). All children of haemophilia were male. This study noted that majority of patients of haemophilia were staying at rural area (67.19%) and rest at urban area (32.81%). BMI of majority children was within normal limit (51.56%), followed by underweight children (32.81%), overweight children (12.50%), and obese child (3.13%). Factor assay showed that 51 children (79.69%) had severe factor deficiency and 13 children (20.31%) had moderate factor deficiency. Positive family history was seen in 41 children (64.06%), and rest 23 children (35.94%) had no family history of haemophilia or any other bleeding disorder. Majority of patients (26 patients) came with their first bleed during infancy (40.63%), 21 children presented between the age of &gt;12 months to ≤24 months (32.81%). Bruises were the most common presentation (37.50%), followed by joint bleeding (31.25%), muscle bleed (10.94%), and gum bleeding (7.81%). Conclusion: Facility of counseling for children of hemophilia is required at regular interval (trimester wise/semester wise) with the aim to enhance the knowledge of personal care, treatment, and to boost up themselves for their academics, activities, etc.