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Introduction: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level. Aim: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency. Methods: Data on bleeding episodes retrospectively recorded during follow‐up visits over 5–10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet‐poor plasma (PPP) and platelet‐rich plasma (PRP) using calibrated automated tomography (CAT). Results: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two‐fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤4.9$ \le 4.9$, AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR. Conclusion: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia A (HA) is a rare bleeding disorder. Patients with severe HA have a factor VIII activity of < 1%. The clinical picture of severe HA consists of a propensity for spontaneous haemorrhages to the skin, muscles, joints, and internal organs. To prevent severe complications of bleeds, patients with severe HA receive prophylaxis with deficient clotting factor. Obese people have larger absolute fat free mass (FFM) as well as fat mass than non-obese individuals of the same age, gender and height. Factor VIII (FVIII) concentrates are typically confined to the vascular space. Although the pharmacokinetics (PK) based FVIII dosing is becoming a standard in tailoring the prophylaxis for HA patients, the majority of them are still dosed according to total body weight and this may result in an overdose of FVIII. This study aimed to evaluate the PK of FVIII considering patients' body weight and body composition using electrical bioimpedance. Material and methods: Twenty-one boys with severe HA undergoing plasma-derived factor VIII prophylaxis were enrolled in the study. Patients underwent physical examination, body weight and height measurements, had body composition assessed using electrical bioimpedance, FVIII concentration was measured before and 30 min after FVIII administration, and FVIII recovery was evaluated. Patients completed a questionnaire regarding treatment, physical activity, and bleeding. Results: Of the patients who underwent the study, 47.6% had a normal body mass index (BMI), 42.8% were overweight, and 9.5% of patients were underweight. There was a correlation between patients' BMI and FVIII recovery, FFM and FVIII recovery, and fat mass and FVIII recovery. No relationship was found between FVIII recovery and bleeding rate. Conclusions: Determining factor VIII dosage according to FFM requires further study. [ABSTRACT FROM AUTHOR]

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Introduction: Microstructural alterations of brain structure in haemophilic boys were found in our previous study. Aim: We investigated alterations of brain function in school‐age boys with severe haemophilia A (HA) with resting‐state functional magnetic resonance imaging (rs‐fMRI). Methods: We obtained rs‐fMRI scans from 24 boys with HA and 25 demographically matched healthy children. Spontaneous brain activity parameters were calculated. Graph theoretical analyses on rs‐fMRI data at the global and regional levels were performed. Two‐sample t tests were used to analyze differences, and correlation analyses identified relationships between altered neural properties and psychological characteristics. Results: Children with severe HA showed small‐worldness organization but with an increased efficiency and compactness in functional segregation. The whole brain showed an overtight connection pattern. At the regional level, significantly increased nodal efficiency in the salience network (SN), default mode network (DMN) and executive control network was found. Social Anxiety Scale for Children (SASC) scores were positively correlated with these alterations. Spontaneous brain activity alterations in regions including the cerebellum, frontal gyrus (orbital part), temporal gyrus and thalamus were observed; some of these regions have been closely related to social anxiety and family or social support. Conclusion: Our study is the first to evaluate the neurological functional changes in school‐age boys with severe HA. Disruptions in topographic characteristics and abnormal activity were closely related to social conditions. These data could help us to understand early neurological alterations in haemophilic children, improve the traditional view of family support and strengthen normal school life at an early stage. [ABSTRACT FROM AUTHOR]

Introduction: In good risk patients (historic inhibitor peak < 200BU), the International Immune Tolerance Study demonstrated equal efficacy to induce tolerance between high (200iu/kg/day) and low dose (50iu/kg ×3 times/week) immune tolerance induction (ITI) regimens. However, the trial stopped early on account of the excessive bleed rate in the low dose ITI arm. Methods: United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) Paediatric and Inhibitor working parties considered available ITI data alongside the bi‐phenotypic antibody emicizumab (Hemlibra®) efficacy and safety data to develop a consensus guideline for the future UK ITI guideline. Results: This revision of UKHCDO ITI guidance incorporates the recommendation to use emicizumab as a prophylaxis haemostatic agent to reduce bleeding rates and to facilitate low dose and reduced frequency of FVIII CFC for ITI in the majority of children. Conclusion: This consensus protocol will facilitate future evaluation of ITI outcomes in the evolving landscape of haemophilia therapeutics and ITI strategies. [ABSTRACT FROM AUTHOR]

Objectives: To explore the long‐term joint outcomes of low‐dose prophylaxis in Chinese children with severe haemophilia A and to analyse their related factors. Methods: We retrospectively analysed follow‐up data from 21 severe haemophilia A children on regular low‐dose prophylaxis for 6–10 years. We used International Prophylaxis Study Group magnetic resonance imaging score (IPSG MRI score), Hemophilia Joint Health Score (HJHS), number of target joints, and Hemophilia‐Specific Quality of Life Index (Haemo‐QoL) to evaluate joint outcomes. Factors associated with these outcomes were evaluated by statistical analysis. Results: (1) The children were 1.75 to 17 years age at prophylaxis initiation. Median prophylactic factor VIII dose was 22.9 IU/kg per week. (2) At the end of follow‐up: (a) The total IPSG MRI scores were 2–24 with 90.5% children exhibiting moderate to severe joint involvement (score 7–24); (b) The HJHS ranged 2–27, with 0–10 for 46.7% children and >10 for 53.3% children. There was a positive correlation between the MRI score and HJHS (p <.05); (c) Compared to their on‐demand treatment period before prophylaxis, target joints numbers decreased, and no child needed auxiliary devices to walk; (d) Joint outcomes were positively correlated with the age at initiation of low‐dose prophylaxis (p <.05) and negatively correlated with the treatment dose. Conclusion: Long‐term low‐dose prophylaxis had positive effect on joint outcomes compared with on‐demand treatment. However, a certain degree of joint damage remained in all children indicating the need for improving the current strategy of low‐dose prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Subclinical synovitis occur long before clinical haemophilic arthropathy (HA). New biomarkers are needed for early detection of HA. Aim: To compare the levels of tissue inhibitors of metalloproteinase‐1 (TIMP‐1) and vascular endothelial growth factor (VEGF)in severe haemophilia A boys on prophylaxis and on‐demand therapy to healthy boys and correlate them with the haemophilia joint health score (HJHS) & the Denver magnetic resonance imaging (MRI) scale; hence, determine their values in early detection of HA. Methods: Haemophilia joint health score, serum TIMP‐1, VEGF and Denver MRI score were assessed in 50 boys with severe haemophilia A (31 on prophylactic factor VIII therapy (62%) with a dose of 15 IU/kg/twice weekly) and 50 age‐matched healthy boys. Results: Boys with severe haemophilia A had significantly higher TIMP‐1 240 ng/mL, SD200‐350 (P <.001) and VEGF 600 pg/mL, SD400‐1100 (P <.001). Their mean HJHS was 4.5 ± 3.0 (0‐11) and their mean Denver MRI score was 5.55 ± 1.6 (2.00‐8.00). A significant positive correlation was found between TIMP‐1 and VEGF (P <.001), BMI Z‐score (P =.029), HJHS (P =.041)and total MRI score (<.001). Significant correlations were found between VEGF and age (P <.001), HJHS (P =.003) and total MRI score (P <.001). Boys with severe haemophilia A on prophylaxis therapy had significantly lower HJHS (P =.021), VEGF (P <.001), TIMP‐1 (P =.002) and total MRI score (P =.021) than those on on‐demand therapy. Receiver operating characteristic curve, defined a cut‐off value of 160 ng/mL for TIMP‐1 with a sensitivity of 90% and specificity of 60% and that of 350 pg/mL for VEGF with a sensitivity of 78% and specificity of 88% for discrimination between severe haemophilia A and healthy boys. Conclusion: Vascular endothelial growth factor and TIMP‐1 can be used for early detection of HA. Further prospective studies should include larger study populations. In addition, studies should address the role of various anti‐VEGFs as potential therapy for HA and their impact on prevention and treatment of HA. [ABSTRACT FROM AUTHOR]

Background: Decreased bone mineral density (BMD) is a significant morbidity in haemophilia. Vitamin D is important for the bone health of people with haemophilia. Regular factor VIII prophylaxis can prevent bleeding and arthropathy. Aim: To determine the 25(OH) vitamin D level in severe haemophilia A patients and correlate it to their Hemophilia Joint Health Score (HJHS) and dual‐energy X‐ray absorptiometry (DEXA). We also compared the 25(OH) vitamin D and DEXA in haemophilia A and healthy children and in haemophilia A children on prophylaxis versus on‐demand therapy. Methods: Fifty severe haemophilia A patients were compared to 50 age‐matched healthy boys. Patients were recruited from the Pediatric Hematology Clinic, Ain Shams University from May 2017 to April 2018. Full medical history was taken with emphasis on frequency of bleeding episodes, duration and amplitude of pain assessed by the pain score. Weight, height, body mass index and HJHS were assessed. 25(OH) vit‐D3, calcium, phosphorus and alkaline phosphatase were measured. BMD was assessed using Lunar DEXA, paediatric software. Results: People with haemophilia had significantly lower 25(OH) vit‐D3 (P <.001) and DEXA z‐score (P <.001) than controls. Seventy per cent of patients were on factor VIII prophylaxis twice weekly (15U/kg/dose). Significant difference was found regarding DEXA z‐score (P =.012), 25(OH) vit‐D3 (P =.033) and HJHS (P =.022) among patients on prophylaxis and on‐demand therapy. Conclusion: Severe haemophilia A patients showed significantly lower 25(OH) vit‐D3 and DEXA than controls. Hence, vitamin D deficiency should be tested in all people with haemophilia for early diagnosis and treatment. Low‐dose prophylaxis in severe haemophilia preserves BMD and increases vitamin D. Further studies are required to evaluate the effect of different prophylaxis protocols on BMD and haemophilic arthropathy. [ABSTRACT FROM AUTHOR]

Introduction: In many countries, there is a shift from standard half‐life (SHL) to extended half‐life (EHL) clotting factor concentrates (CFCs). Aim: To describe the experience of switching from SHL to an EHL FVIII CFC and the impact of this on frequency of infusions, factor consumption, bleeding rates and HRQoL using the Canadian Hemophilia Kids' Life Assessment Tool (CHO‐KLAT). Methods: A retrospective chart review was conducted at a single haemophilia treatment centre in 2018 that included boys (ages: 4‐18 years) with moderate/severe haemophilia A, without inhibitors, who switched from a SHL to an EHL FVIII CFC in the previous 2 years and for whom HRQoL data were available. Results: The study cohort comprised 38 boys [mean (SD) age: 11.0 (3.4) years] with moderate (n = 5)/severe (n = 33) haemophilia A. The switch was associated with a 33% reduction in the number of weekly infusions from a median of 3.5 to 2.3 (P <.0001) and a 17% reduction in median FVIII consumption from 103 IU/kg/wk to 85.5 IU/kg/wk (P =.004). There was no significant change in annualized joint bleed rates or in CHO‐KLAT scores. Conclusions: Despite documenting several benefits of switching to EHL FVIII (less infusions, lower factor consumption with no increase in bleeding), our study did not demonstrate any improvement in HRQoL. We conclude that either the current CHO‐KLAT tool is not optimized to measure burden of treatment administration in boys with low bleed rates switching from SHL to EHL FVIII CFCs or that a reduction of 1.2 infusions/week does not result in a meaningful change in HRQoL. [ABSTRACT FROM AUTHOR]

Aim: To determine the impact of 10‐year intermediate‐dose prophylaxis on haemarthropathy progression in patients with severe haemophilia A (SHA). Methods: Prophylactic treatment with intermediate dose was given maximally for 10 years to 42 patients with SHA in a haemophilia treatment centre in Korea. Patients were divided into three groups based on prophylactic treatment started age: 1‐10 (group A'), 11‐20 (group B'), and ≥21 (group C'). Average annual increase of Pettersson score (P‐score) was compared between the treatment groups. Results: Average ages and P‐scores at initiation of prophylaxis were 4.65±3.43 years and 2.09±3.25, 16.13±1.73 years and 7.37±4.38, and 28.33±7.25 years and 12.33±6.50 for groups A', B', and C'. Average annual increase of P‐score in groups A', B', and C' was 0.039±0.11, 0.063±0.123, and 0.078±0.124. Assuming that intermediate‐dose prophylaxis started at the average age, P‐score and annual increase of P‐score would be the average values of each group; it would thus take 210 and 46.5 years to reach –2SD of the average critical level of haemarthropathy (The level of haemarthropathy (P‐score 13.0 ± 2.7) above which there is a significant impact on quality of life in Korean) in groups A' and B'. However, it would take 55 and 15.75 years if the annual P‐score increase were +2SD of the average value in groups A' and B'. Conclusion: Intermediate‐dose prophylaxis for patients with SHA in Korea would maintain arthropathy below the critical level for most of the patients' lifetime when started before adolescence. However, this would not be achieved in some adolescent patients with rapid progression of arthropathy and in most adult patients. [ABSTRACT FROM AUTHOR]

Background: Inhibitor development in previously untreated patients (PUPs) with severe haemophilia A is a multifactorial event. It is unknown whether paediatric vaccinations given in close proximity to factor VIII (FVIII) are associated with inhibitor development. Objective: To assess whether paediatric vaccinations in close proximity to FVIII within the first 75 exposure days (EDs) are associated with inhibitor development in PUPs with severe haemophilia A. Methods: We included 375 PUPs with severe haemophilia A (<0.01 IU/mL) from the PedNet Registry who had received vaccinations between the first and 75th ED or inhibitor development. Inhibitor risk was compared between patients who did and who did not receive vaccinations within 24, 72 or 120 hours of FVIII infusion. Unadjusted and adjusted hazard ratios were calculated for any or repeated vaccinations in close proximity to FVIII, using Cox regression. Results: Inhibitor development occurred in 77 of 375 patients (20.5%). Overall inhibitor development appeared similar or lower in patients receiving vaccinations in close proximity to FVIII as compared to patients receiving vaccinations without FVIII: for 24 hours, this was 19.2% and 21.4% (P = .186), for 72 hours, 16.4% and 27.3% (P = .023) and for 120 hours, 18.3% and 25.0% (P = .085), respectively. Conclusion: We found no association between vaccinations given in close proximity to FVIII exposure within the first 75 EDs and inhibitor development. Our data do not support avoiding administration of FVIII at time of routine vaccinations. [ABSTRACT FROM AUTHOR]

Introduction Patients with haemophilia A (HA) have impaired thrombin generation (TG) capacity and TG assay (TGA) values are linearly related to plasma factor VIII (FVIII) levels. Aim This study carried out in patients with unmeasurable FVIII (<1 IU dL−1) was aimed at unravelling any difference in TG capacity in patients with or without inhibitors. Methods Blood samples were collected from patients in a non-bleeding state, after a 5-day wash-out period from last treatment. Results TGA was performed in 102 patients with severe HA (15% with high-responding inhibitors; 51% with null F8 mutations, that as expected were more prevalent in inhibitor than in non-inhibitor patients). TG capacity was significantly lower in inhibitor than non-inhibitor patients and in those with null mutations than in those with non-null mutations. When the TG capacity was evaluated only in patients with null mutations with and without inhibitors it was lower in the presence of inhibitors. Conclusions This study shows a greater TG impairment in inhibitor patients irrespective of FVIII levels, inhibitor titre and F8 mutation type, suggesting a role for the TGA in unravelling functional interferences of anti-FVIII inhibitors on coagulation system activation. [ABSTRACT FROM AUTHOR]

Introduction In persons with severe haemophilia A (pwshA), infused factor VIII ( FVIII) half-life can vary according to such determinants as blood group, von Willebrand factor ( VWF) level or age; however, FVIII pharmacokinetics ( PK) has not been well studied in pwshA during exercise. Aim To investigate FVIII PK in pwshA performing moderate-intensity aerobic exercise. Methods Twelve young-adult pwshA with the intron-22 inversion mutation, on relatively low-dose FVIII prophylaxis regimens, and relatively good musculoskeletal status were recruited. Abbreviated PK of FVIII activity and von Willebrand factor antigen ( VWF:Ag) level were compared - during rest, and with 60-min exercise (2 × 15 min each of moderate-intensity stationary cycling and treadmill walking). During rest and exercise visits, a baseline blood specimen was drawn, routine prophylaxis FVIII infused; then six blood specimens were taken over the following 24 h. Results For all subjects, mean half-life of infused FVIII did not change significantly with exercise vs. at rest (577 ± 190 vs. 614 ± 163 min; P = 0.4131). VWF:Ag rose transiently by 40-50% for 6-8 h with exercise ( P < 0.01), particularly in non-O blood group subjects. No musculoskeletal bleeds occurred during the study. Conclusion Four × 15 min of moderate-intensity aerobic exercise increased VWF:Ag levels for 6-8 h, and showed no evidence of accelerated FVIII clearance or of musculoskeletal bleeding in these young-adult pwshA with relatively good musculoskeletal status, on relatively low-dose FVIII prophylaxis regimens. However, O blood group impact would merit larger studies, with longer durations of similar or more vigorous exercise intensities. [ABSTRACT FROM AUTHOR]

Aim This observational study was undertaken with the aim to describe the characteristics and evaluate the outcomes of prophylactic treatment in children with severe haemophilia A ( HA) treated at our centre. Methods Twenty-five patients aged 4-19 years with severe HA, no history of inhibitors and treated with at least two infusions of factor VIII (FVIII) per week were studied. Prophylactic doses and annual joint bleeding rate ( AJBR) were retrospectively evaluated over the last 5 years. Current joint status was assessed using the Haemophilia Joint Health Score ( HJHS) (136 joints of 23 patients) and the Haemophilia Early Arthropathy Detection with Ultrasound ( HEAD- US) procedure (124 joints of 21 patients). Results Median AJBR was 0.2 and median prophylaxis dose 65.4 IU−1 kg−1 week−1. Median total HJHS was 0 (range 0-13) and total HEAD- US 1 (0-8). At the joint level, 85.3% of joints were normal on HJHS and 79.0% on US. The ankle was the joint most commonly affected, considering bleeding and ultrasound results. Correlation was found between HEAD- US scores and bleeding scores but not between HEAD- US and HJHS scores. HJHS and HEAD- US scores were concordant in 91/124 (73.4%) joints (86 joints normal and five abnormal). Ultrasound detected minimal changes in 19.6% of joints with normal physical function, whereas 12.2% of joints considered normal on ultrasound showed changes at HJHS. Conclusion A well-preserved joint status was found in our cohort. High-resolution US detected a higher percentage of abnormalities than the physical evaluation, but the clinical implications of these findings still need to be ascertained. [ABSTRACT FROM AUTHOR]

In Mexico, 15% of haemophilia A ( HA) patients develop inhibitory alloantibodies in response to replacement therapy with factor VIII ( FVIII), requiring bypass therapy such as activated prothrombin complex concentrate ( APCC). Because bypass therapy has not been broadly available in Mexico even in recent years, this study aimed to evaluate the thrombin generation assay ( TGA) in assessing the response to FVIII or APCC treatment in patients with severe HA positive to inhibitors. We studied 189 patients with severe HA. Clinical severity was verified by one-stage APTT-based clotting assay. Inhibitors to FVIII were investigated by the Nijmegen-Bethesda (N-B) method, and type of inhibition was assessed through serial plasma dilutions. Thrombin generation was measured with the calibrated automated thrombogram in inhibitor-positive plasmas previously spiked and incubated with FVIII or APCC. Data were analysed using anova, Student or Fisher's exact tests. We detected 47 (24.9%) subjects with high-titre (5-1700 N-B U mL−1) and 25 (13.2%) subjects with low-titre inhibitor antibodies (0.6-4.7 N-B U mL−1). We found an association between kinetic behaviour and clinical response to FVIII ( P = 0.0049) or vs. FVIII response evaluated with TGA ( P = 0.0007). Global concordance between clinical and in vitro response was 70%. By evaluating the capacity of thrombin formation in a plasma sample, TGA predicts the response to FVIII or APCC therapy and allows individual optimization of resources in patients with severe HA and high-titre inhibitors. The inhibition pattern of the antibodies to FVIII:C correlated with the TGA parameters and showed an association with the clinical response to FVIII. [ABSTRACT FROM AUTHOR]

Human Leucocyte Antigen ( HLA) alleles, cytokine polymorphisms and the type of factor VIII ( FVIII) gene mutation are among predisposing factors for inhibitors (inh) development in children with severe haemophilia A ( HA). The aim was to investigate the correlations among (i) FVIII gene intron-22 inversion, (ii) HLA alleles and haplotypes and (iii) certain cytokine polymorphisms, with the risk for FVIII inhibitors development in 52 Greek severe HA children, exclusively treated with recombinant concentrates. We performed Long-Range PCR for detection of intron-22 inversion and PCR- SSP, PCR- SSO for genotyping of HLA-A, B, C, DRB1, DQB1 alleles and also for cytokine polymorphisms of TNF-α, TGF-β1, IL-10, IL-6 and IFN-γ. Chi-squared test and Fischer's exact test were used for statistical analysis. A total of 28 children had developed inhibitors (Group I), 71.4% high responding, while 24 had not (Group II). No statistically increased intron-22 inversion prevalence was found in Group I compared with Group II ( P = 0.5). Comparison of HLA allele frequencies between the two groups showed statistically significant differences in the following genotypes (i) promoting inhibitors development: DRB1*01( P = 0.014), DRB1*01:01( P = 0.011) and DQB1*05:01 ( P = 0.005) and (ii) possibly protecting from inhibitors development: DRB1*11 ( P = 0.011), DRB1*11:01 ( P = 0.031), DQB1*03 ( P = 0.004) and DQB1*03:01 ( P = 0.014). Analysis of cytokines revealed a higher incidence of inhibitor detection only in homozygotes of the haplotypes ACC and ATA for IL-10 polymorphisms ( P = 0.05). There is evidence that HLA alleles and cytokine polymorphisms play an important role in FVIII inh development. On the contrary, no statistically significant results were obtained for intron-22 inversion and its impact on FVIII inhibitors formation. [ABSTRACT FROM AUTHOR]

von Willebrand disease (VWD) type 3 is a rare disorder characterized by absent or <0.1 UmL−1 of ristocetin cofactor (VWF:RCo), and a very low level of factor VIII (FVIII:C). A total absence of FVIII:C has never been reported in type 3 VWD. This case illustrates the effect of severe von Willebrand factor (VWF) deficiency on the factor VIII level. [ABSTRACT FROM AUTHOR]

Management of patients with severe haemophilia A who develop inhibitors is difficult and expensive. Standard treatment of this complication is immune tolerance induction (ITI) therapy, but is successful in only 60–80% of the patients. Failure of ITI results in a higher risk of morbidity and mortality. We used rituximab, an anti-CD20 antibody, in three patients with severe haemophilia A and inhibitors. Two patients with high-titre inhibitors had marked reduction in the inhibitor level; the third patient with low-titre inhibitor had a disappearance of the inhibitor. All patients improved clinically, with fewer bleeding episodes and a better quality of life. Inhibitor level increased with time in these patients, but the clinical benefit continued in two patients with high-titre inhibitors initially, after a follow-up of 48 and 22 months. One of the patients with concomitant human immunodeficiency virus (HIV) infection and a very low CD4 lymphocyte count developed severe truncal herpes zoster after the third weekly dose of rituximab. Caution is required in such patients, and we recommend avoiding rituximab use in HIV-infected patients with very low CD4 lymphocyte count. In conclusion, rituximab is useful in reducing the inhibitor level with clinical benefit in patients with severe haemophilia A and inhibitors, but it cannot eradicate the inhibitors for long periods with the currently used protocol of up to five doses. [ABSTRACT FROM AUTHOR]

A total of 107 unrelated severe haemophilia A patients living in the southern Brazilian state of Rio Grande do Sul were studied in relation to the prevalence of inversions present in introns 22 and 1 and a subsample of them (95) tested for the presence of Factor VIII inhibitors. These data were then incorporated with those from 15 other countries and 3871 patients. The frequencies of these two inversions show a remarkable homogeneity in series collected in different continents, from people with diverse ethnic extraction. The prevalence of inhibitors among patients with inversion 22, on the other hand, varies widely (5–51%; seven countries, 1482 patients), the value observed by us being the highest. The importance of obtaining data from patients throughout the world to clarify the aetiology of this important complicating factor in the therapeutics of the disease is emphasized. [ABSTRACT FROM AUTHOR]

Individuals with severe haemophilia A may be at risk for reduced bone mineral density because of reduced weight-bearing exercise and hepatitis C infection. For confirming the reduced bone density, in the current cross-sectional study, we tried to address bone mineral density in individuals with severe haemophilia A and surveyed the relation of reduced bone density with hepatitis C viruses. To fulfil these aims, bone density and biochemical indexes in 18 individuals with severe haemophilia A and also in 18 individuals matched for age, sex, weight and height, as the control group, were examined. The obtained results showed that individuals with severe haemophilia A had reduced bone density (1.136 ± 0.118, 0.801 ± 0.238) in lumbar and femur regions, respectively, in comparison with the age- and sex-matched group (1.299 ± 0.237, 1.458 ± 0.505). The major complications of coagulation disorders are various types of excessive bleeding. The current study describes an association between severe haemophilia A and osteopenia, specifically at both the femur and the lumbar spine. [ABSTRACT FROM AUTHOR]

The long-term prophylactic administration of clotting factor concentrate in patients with haemophilia reduces bleeding events, slows joint deterioration, and improves quality of life. Prophylaxis can also be effective when used short-term to prevent or reduce bleeding associated with trauma, surgery, and athletic activities. While clinical trials are needed to establish the optimal length of prophylaxis following injury, several weeks and possibly months of treatment may be needed. Discontinuing therapy prematurely can result in rebleeding in the injured area. [ABSTRACT FROM AUTHOR]

We report a haemophilia A boy with high inhibitor titre (170 BU) who experienced five life-threatening bleeding episodes during a one-year period from 9 to 21 months. At the age of 22 months, he received rituximab (375 mg m−2 per dose) at one- and three-week intervals, three courses each and alternative daily treatment with factor VIII concentrate at doses of 100 units kg−1 for 24 weeks and 50 units kg−1 for the following 28 weeks. Although the pretreatment inhibitor level of 4.5 BU showed an anamnestic response reaching the maximum level of 200 BU at the 9th week of treatment, it gradually declined to 30 BU at the 22nd week and was constantly maintained at 25–30 BU for the following 30 weeks. Only three bleeding episodes of two haematomas and one haemarthrosis were found during the one-year treatment period. No opportunistic infection occured during this period. [ABSTRACT FROM AUTHOR]

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto. [ABSTRACT FROM AUTHOR]