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Introduction: Acquired hemophilia A (AHA) is a rare autoimmune hemorrhagic disease occurring in several underlying conditions. Drug‐associated AHA (D‐AHA) is poorly addressed nowadays. Aim: This work aims to identify and characterize which drugs are associated with AHA using the WHO global database of reported potential effects of medicinal products (VigiBase). Methods: First, we realized a disproportionality analysis using the information component (IC) to identify D‐AHA in VigiBase. IC compares observed‐ and expected‐values in order to find associations between drugs and adverse drug reactions (ADRs) using disproportionate Bayesian reporting. IC025 is the lower end of a 95% credibility interval for the IC. Then, we collected cases of drugs significantly associated with AHA from July 2004 to November 2021. Results: 14 drugs with IC025 > 0 were identified representing a total of 185 cases. D‐AHA occurred more frequently in men (59%) than women (41%). The median (min–max) age at onset was 75 years (8–98). The median [Q1–Q3] time to onset of D‐AHA from the start of the suspected drug was 30 days [9.5–73.75] and 10% of cases resulted in a fatality. The drugs associated with the highest IC025 (IC025 > 2) were Clopidogrel, Alemtuzumab, Omalizumab. This study retrieved for the first time three usually used drugs (3/14) that exhibit a significant pharmacovigilance signal for D‐AHA. Conclusion: This worldwide pharmaco‐epidemiologic study updates the list of the drugs associated with AHA. The clinician should be aware of these possible severe ADR, which might require larger epidemiological and pathophysiologic studies. [ABSTRACT FROM AUTHOR]

Introduction: Several bleeding disorders are characterized by haemorrhage into joints and muscles. These conditions are best managed by interdisciplinary teams that include physiotherapists. In 1997, physiotherapists from haemophilia treatment centres in Canada formed the Canadian Physiotherapists in Hemophilia Care (CPHC). The guiding principles of the CPHC reflect a commitment to evidence‐based practice, education and collaboration. Aim: To describe the process used by CPHC to develop evidence‐based clinical practice guidelines to inform best practice, guide decision‐making and help educate physiotherapists, students, and other team members about the physiotherapy management of people with bleeding disorders. Methods: We followed the procedures outlined in the American Physical Therapy Association's Clinical Practice Guideline Process Manual (2018). Namely, we selected a working group, determined the scope of the guidelines, performed a literature search, selected and appraised the evidence, drafted the guidelines as practice statements, assigned a strength of recommendation to each practice statement and disseminated the guidelines. Results: Thirty‐nine practice statements were developed in nine practice areas. Strength of evidence was strong for two statements, moderate for one and weak for three. The remainder were graded as theoretical or best practice. Conclusion: To our knowledge, these are the first evidence‐based clinical practice guidelines that cover all aspects of physiotherapy management of people with bleeding disorders. Some areas, such as exercise and manual therapy, have been well investigated. However, the overall low levels of evidence and low strengths of recommendations highlight the need for more rigorous research with this population. [ABSTRACT FROM AUTHOR]

Introduction: Comprehensive musculoskeletal assessment for monitoring joint health in haemophilia includes both physical assessment with Haemophilia Joint Health Score (HJHS) and assessment of self‐reported function by Haemophilia Activities List (HAL). Methods: Correlation between physical assessment and joint function was undertaken between HJHS and HAL in patients with SHA and SHB who had both assessments at the same visit over a one‐year period. Results: Data from 120 patients (96‐SHA/24 = SHB) with a median age 33 years (range 19‐73) were included. Median total HJHS was 19, increasing with age: 18‐30 years—7, 31‐50 years—25 and 51‐73 years—44. Similarly, median total HAL score was 80 with decreased function associated with increasing age: 18‐30 years—90.4, 31‐59 years—71.7, 51‐73 years—49.5. Median Total HJHS and HAL demonstrated strong correlation (rs = 0.66, P < 0.01). Moderate‐to‐strong correlations were seen across the entire age group between the HJHS LL and UL subtotals and corresponding limb HAL domains. Within age groups, correlations were less significant particularly for the upper UL domains in HAL and the UL HJHS score. The wide range of ROM in joints categorized as markedly affected (ie, ROM loss score = 3) highlights the potential ceiling effect of this domain score and its use in chronically damaged joints. Conclusion: HJHS and HAL showed moderate‐to‐strong correlation with discrepancy in some individual patients. Prospective studies are required to better understand the clinical utility of both especially in severe joint disease where HAL may have a potential advantage. [ABSTRACT FROM AUTHOR]

The article examines a Japanese family with type 2A (IIC) von Willebrand disease (VWD), which is characterized by a recessive mode of inheritance, low von Willebrand factor antigen. Topics discussed include medical history of the family, efforts to explain the genetic basis for the onset of type 2A (IIC) VWD in this family, and seven mutations responsible for type 2A (IIC) VWD.

Background: The thrombin generation (TG) assay can assess individual clotting potential. The thrombin generation potential is correlated with the patient's bleeding phenotype and varies from one patient to the other for the same degree of factor VIII or IX deficiency. Objective: To define in vitro for individual haemophilic patients the target factor VIII or IX level required to normalize their TG. Patients/Methods: Plasmas from 20 haemophilic patients were spiked with increasing levels of the deficient coagulation factor and TG parameters were measured. The relationships between factor levels and TG parameters were determined by linear regression. The normal range of thrombin generation was defined in 39 healthy male volunteers. Results: Despite inter‐individual heterogeneity in basal TG and responses to spiking, a linear relationship was found between factor VIII or IX levels and TG parameters for individual patients. Based on the individual responses of patient plasmas to spiking, it is possible to define in vitro the target factor VIII or IX levels needed to normalize the TG parameters. For both haemophilic A and haemophilic B patients, significant correlations were found between basal peak values and their correction slopes. The correction slope was steeper in haemophilic B patients, so the factor IX level needed to normalize the TG parameters was lower than for haemophilic A patients. Conclusions: The TG assay could be used to determine in vitro the patient‐specific factor VIII or IX level to be reached to effectively normalize their TG. These in vitro results should be confirmed by ex‐vivo studies. [ABSTRACT FROM AUTHOR]

Introduction: The awareness and knowledge on bleeding disorders is generally poor among the rural population. Accredited Social Health Activists (ASHAs) serve as the facilitators between the rural community and the health care system. Training of ASHAs in screening of rural population for early identification of bleeding disorders can enable prompt referral, timely detection and management of bleeding disorders. Aim: The aim of the study was to evaluate the effectiveness of an ASHA training programme for identification of suspected bleeding disorder cases. Methods: A population‐based, cross‐sectional survey was implemented by 586 Accredited Social Health Activists (ASHAs) in rural Udupi district, who underwent a structured training programme on identification of bleeding disorders. A survey record book with a screening tool on assessment of bleeding symptoms was given to each ASHA. The screening tool consisted of symptoms related to bleeding disorders and family history of bleeding disorders. Using the screening tool, ASHAs carried out a door‐to‐door survey. After screening, those who reported with bleeding symptoms were referred by the ASHAs to the investigator, who conducted further assessment. A detailed bleeding history was documented and bleeding symptom assessment was carried out using bleeding assessment tool (BAT) at the haemophilia treatment centre. Further coagulation assessments were carried out as per the treatment centre protocol. This paper highlights the evaluation of an ASHA training programme on identification of individuals with bleeding symptoms in the rural population. Results: A total of 586 trained ASHAs surveyed a population of 318 214 in rural Udupi district. Out of the 124 cases reported by ASHAs, 29 bleeding disorder cases were identified; haemophilia (A and B) was the most commonly found bleeding disorder 22 (75.8%), followed by von Willebrand disease (vWD) 3 (10.3%) and 4 (13.8%) immune‐mediated thrombocytopenic purpura (ITP), with an overall prevalence of 2.2/10 000 population. Conclusion: Training ASHA health care workers, who are the most important link between the community and health services, resulted in increased awareness among the public for the early detection of bleeding disorders. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia is one of the most common inherited bleeding disorders in the Emergency Department (ED). The most dangerous site of bleeding is the central nervous system. Aims: To describe the characteristics of haemophiliacs arrived to our ED following a head trauma and to analyse the incidence of intracranial haemorrhage (ICH). Materials and Methods: Retrospective, analytical, observational study, conducted in a Paediatric ED. We included haemophilic patients aged from birth to 16 years who consulted after a head trauma over a 6‐year period. Data collected included age, type of haemophilia and head trauma, symptoms, prophylaxis status, CT imaging, treatment and number of visits to the ED. Results: About 46 males and 85 episodes were analysed. The median age was 2.38 years. Severe haemophilia A was the most frequent type of disease (50%). All head injuries were mild, and the most frequent mechanism was a collision with an object (38.8%). In 62 episodes (72.9%) the patients were asymptomatic. The rest 23 events had symptomatology, being the most common headache (26%), emesis (21.7%) and drowsiness (17.4%). Head CT was obtained in 31 episodes, founding altered results in 10 (6 of them corresponding to ICH). All the patients with ICH had symptomatology. About 37 episodes required admission. Conclusion: Intracranial haemorrhage is one of the most dangerous events in haemophiliacs and it may occur after a head trauma. Our study suggests that, in case of head trauma, CT must be obtained in symptomatic patients and in those with additional risk factors. Asymptomatic patients must have prolonged observation. [ABSTRACT FROM AUTHOR]

Introduction: Jamaica has an estimated 200 persons with haemophilia (PWH), who face significant constraints in access to specialized haemophilia care, including access to clotting factor concentrates. Aim: The aim of this paper is to establish the current burden of disease in PWH in Jamaica. Methods: PWH were enrolled through the University Hospital of the West Indies, Jamaica. The impact of haemophilia was assessed using a comprehensive battery of heath outcome measures that included the following: laboratory, clinical information and validated outcome measures of joint structure and function, activity, and health‐related quality of life (HRQoL) to provide a health profile of the Jamaican haemophilia population. Results: In all, 45 PWH were registered (mean age: 29, range: 0.17‐69 years), including 13 children (<18 years of age) and 32 adults. In this sample, 41 had haemophilia A (30 severe) and 4 had haemophilia B (3 severe); 10 patients with haemophilia A were inhibitor positive. The results indicate that adults with haemophilia in Jamaica have significant joint damage: mean Haemophilia Joint Health Score (HJHS) = 42.1 (SD = 17.3); moderate activity levels − mean Haemophilia Activities List (HAL) score = 64.8 (SD = 17.8); and low HRQoL scores − mean Haemo‐QoL‐A score = 62.3 (SD = 19.4). Results for children are also reported but should be interpreted with caution due to the small sample size. Conclusions: There is a very high burden of disease in PWH in Jamaica. The health profiles reported in this paper are an essential first step in advocating for a multidisciplinary Comprehensive Care Program for assessment and care of PWH in Jamaica. [ABSTRACT FROM AUTHOR]

The article discusses case study of a 34 years old Chinese male patient diagnosed with haemophilia A at the age of two due to continuous bleeding upon trauma. It is noted that an ultrasound scan performed on the patient revealed mixed echoes extending from posterior axillary line to across the axillary line to the front, and from the sub-hepatic area to the groin.

Introduction Nuwiq® (human-cl rh FVIII) is a 4th generation recombinant human FVIII, without chemical modification or protein fusion, produced in a human cell-line. Aims/Methods This study (NuPreviq) was a prospective, open-label, multicentre, phase IIIb study of the efficacy and safety of personalized prophylaxis with Nuwiq® in 66 previously treated adults with severe haemophilia A. NuPreviq had three phases: (i) a 72-h pharmacokinetic ( PK) phase; (ii) a 1-3 month standard prophylaxis phase; and (iii) a 6-month personalized prophylaxis phase. The personalized prophylaxis regimen was based on individual PK modelling for each patient according to whether their PK profile most closely fitted a two- or one-compartment model (NuPreviq approach). In cases of uncertainty, a noncompartment model was applied. Results The median dosing interval during personalized prophylaxis was 3.5 days, with 57% of patients on ≤2 weekly dosing. Mean annualized bleeding rates during personalized prophylaxis were 1.45 (median [interquartile range, IQR]: 0 [0, 1.9]) for all bleeds, 0.79 (median [ IQR]: 0 [0, 0]) for spontaneous bleeds, and 0.91 (median [ IQR]: 0 [0, 0]) for joint bleeds. During personalized prophylaxis, 83.1% of patients were spontaneous bleed-free. Compared with standard prophylaxis, median weekly prophylaxis dose was reduced by 7.2% from 100.0 to 92.8 IU kg−1 during the last 2 months of personalized prophylaxis. There were no FVIII inhibitors or treatment-related serious or severe adverse events. Conclusion PK-guided personalized prophylaxis with Nuwiq® provided bleeding protection and enabled the dosing interval to be extended to twice weekly or less in many patients and an overall dose reduction. [ABSTRACT FROM AUTHOR]

Background Red blood cells ( RBCs) contribute to hemostasis under blood-flow, and anemia might contribute to a hemorrhagic diathesis. The majority of current laboratory techniques to assess hemostasis do not consider the effects of RBCs. An assay to determine the role of RBCs in hemostasis could be beneficial for clinical management. Objectives To investigate the influence of RBCs in hemostasis. Methods Hemostasis was investigated using a novel microchip flow-chamber system (T- TAS®) in an anemic patient with von Willebrand disease. Subsequently, the effects of RBCs in total thrombus analysis system (T- TAS) were examined using reconstituted whole blood at various hematocrit levels. Results In vivo: When the patient was anemic and demonstrated persisted hemorrhagic symptoms despite the maintained adequate von Willebrand factor ristocetin cofactor activity levels, thrombus formation determined by T- TAS was delayed. However, transfusions of RBCs resolved bleeding symptom and, accordingly, the thrombus formation in T- TAS improved. In vitro: Thrombus formation determined by T- TAS at 1000 s−1 was dose-dependent on hematocrit (the time to reach 10 kPa ( T10): 10.0 ± 0, 9.5 ± 1.4, 6.7 ± 2.4, 2.8 ± 1.6 min at hematocrits of 0%, 12.5%, 25% and 50%, respectively). Markedly defective thrombus formation ( T10 >10 min) was confirmed at a hematocrit <25% at 2000 s−1. Conclusion Red blood cells play an essential role in hemostasis under high shear, and RBC transfusions could be effective for refractory bleeding in patients with anemia. T- TAS measurements appear to reflect the hemostatic consequences of diminished red cell numbers under blood-flow, and could provide a valuable means for monitoring patients. [ABSTRACT FROM AUTHOR]

Background Previously published factor VIII ( FVIII) pharmacokinetic ( PK)-based dosing approaches employ fixed infusion interval with a wide dose range that may lead to increased risk of bleeding, excessive doses or decreased health-related quality of life. Aim The objectives of the study includes (i) personalizing infusion interval in lieu of fixed infusion, (ii) constraining dose within the range of 10-50 IU/kg and (iii) characterizing bleeding risk of PK-based dosing in comparison with empiric standard doses. Methods Patient demographics and PK parameters for conventional FVIII products were obtained from published literatures. Subject-specific PK parameters were derived from FVIII activities vs time data generated through simulation. Results Our data indicated approximately 4%, 38%, 37% and 20% of the subjects can be dosed with infusion interval of every 24, 48, 72 and 96 hours, respectively, for maintaining a target 1 IU/ dL FVIII level within the dose range of 10-50 IU/kg. Maintaining an alternative trough value of 3 or 5 IU/ dL requires more frequent infusion. The predicted median probability of bleeding risk per year was 35.7% (range, 11%-49%) for PK-based dosing maintaining 1 IU/ dL. Predicted median bleeding risk was 37.9% (0%-74%), 32.8% (0%-72%) and 26.7% (0%-70%) for standard dosing of 20, 30 and 50 IU/kg, respectively. PK-based dosing resulted in a dose sparing benefit compared to standard dose of 30 or 50 IU/kg three times per week. Conclusion The results of the study demonstrate the feasibility of individualizing infusion interval, restricting FVIII dose, trough and peak concentration within an acceptable range. [ABSTRACT FROM AUTHOR]

The inherited bleeding disorder von Willebrand disease ( VWD) is challenging to diagnose owing to disease heterogeneity, lack of a definitive laboratory test and variations in diagnostic criteria. We evaluated the impact of diagnosis and diagnostic delay on patient outcomes. The PharMetrics Plus Database was interrogated for medical claims for VWD ( ICD-9 286.4) and bleeding events between 1 January 2006 and 30 June 2015. Longitudinal analysis was performed of patients newly diagnosed with VWD (≥9 months' continuous enrolment before first VWD claim) through 24 months following diagnosis. In total, 32 028 diagnosed, including 18 182 newly diagnosed, patients were identified. Most patients (72%) were female. Prediagnosis, bleeding symptoms were most commonly managed by a hospitalist/emergency room physician. Misrecognition of VWD was common, with 25% of patients visiting the same specialist type at least twice for an episodic bleed before diagnosis. Thirty-seven percentage of patients had no diagnostic laboratory test within 24 months of their initial diagnostic claim. Bleed claims reduced following diagnosis: 41% and 26% of female and male patients, respectively, had claims in the year prediagnosis, falling to 21% and 9% of patients at 1-2 years postdiagnosis. The proportion of patients with multiple bleed claims also decreased, from 17% to 6% (females) and 7% to 3% (males). Serially misrecognized patients continued to have more bleeding episodes than other patients, although bleed frequency was lower than before diagnosis. There is a need for improved patient management from bleeding presentation onward to reduce the time to VWD diagnosis and to enhance patient outcomes. [ABSTRACT FROM AUTHOR]

The authors emphasize the need for a robust implementation strategy of point-of-care ultrasound (POC-US) in haemophilia management. Topics covered include the need to develop guidelines to facilitate appropriate training, use and implementation of POC-US as a diagnostic tool in haemophilia, elements that should be included in the didactic modules and institutional protocols for POC-US use.

Introduction Haemtrack is an electronic home treatment diary for patients with inherited bleeding disorders, introduced in 2008. It aimed to improve the timeliness and completeness of patient-reported treatment records, to facilitate analysis of treatment and outcome trends. The system is easy to use, responsive and accessible. Methods The software uses Microsoft technologies with a SQL Server database and an ASP.net website front-end, running on personal computers, android and I-phones. Haemtrack interfaces with the UK Haemophilia Centre Information System and the National Haemophilia Database ( NHD). Data are validated locally by Haemophilia Centres and centrally by NHD. Data collected include as follows: treatment brand, dose and batch number, time/date of bleed onset and drug administration, reasons for treatment (prophylaxis, bleed, follow-up), bleed site, severity, pain-score and outcome. Results Haemtrack was used by 90% of haemophilia treatment centres ( HTCs) in 2015, registering 2683 patients using home therapy of whom 1923 used Haemtrack, entering >17 000 treatments per month. This included 68% of all UK patients with severe haemophilia A. Reporting compliance varied and 55% of patients reported ≥75% of potential usage. Centres had a median 78% compliance overall. A strategy for progressively improving compliance is in place. Age distribution and treatment intensity were similar in Haemtrack users/non-users with severe haemophilia treated prophylactically. Conclusion The Haemtrack system is a valuable tool that may improve treatment compliance and optimize treatment regimen. Analysis of national treatment trends and large-scale longitudinal, within-patient analysis of changes in regimen and/or product will provide valuable insights that will guide future clinical practice. [ABSTRACT FROM AUTHOR]

The article discusses the results of a survey of the extent and patterns of prophylaxis use in adults with severe haemophilia in countries where long-term prophylaxis in children is routinely used conducted by the International Prophylaxis Study Group (IPSG). Topics covered include distribution of adults with severe haemophilia A (SHA) or severe haemophilia B (SHB) on long -term prophylaxis, and proportion of adults on prophylaxis who were on full dose regimens.

Introduction People with severe haemophilia A have reportedly impaired health related quality of life (utility) mainly due to recurrent bleeding, arthropathy and treatment burden. Aim To estimate utilities and evaluate their potential correlates - most importantly the joint status - among people with severe haemophilia A. Methods In this cross-sectional study, eligible participants had severe haemophilia A, were aged ≥15, negative for factor VIII inhibitor and included in the KAPPA register of Denmark, Norway and Sweden. Data on demographics, treatment history, haemophilia joint health score, and EQ-5D utility were obtained from the register. We used box plots to present utilities and joint status and ordinary least squares regression to evaluate correlates of utilities. Participants were consecutively enrolled in the KAPPA register between April 2013 and June 2016. Results Overall, 173 participants with median age of 34 (interquartile range: 25-45) were included. Twelve (6.9%) participants were on episodic treatment while 161 (93.1%) were treated using prophylaxis. Concomitant diseases and positive inhibitor history were reported for 73 (43.2%) and 21 (12.1%) participants, respectively. The highest median utility (1.0) was observed among those aged <29 on prophylaxis and those aged 30-44 who had started prophylaxis by age 3. In the multi-variable regression, joint scores of 16-25 (Coef. −0.18, 95% CI: −0.30, −0.06), 26-35 (Coef. −0.21, 95% CI: −0.36, −0.06) and >35 (Coef. −0.37, 95% CI: −0.52, −0.23) were associated with lower utilities. Conclusion Moderate to severe joint manifestations are associated with reduced utilities among persons with severe haemophilia A. [ABSTRACT FROM AUTHOR]

Introduction von Willebrand disease ( VWD) is the most common inherited bleeding disorder. In VWD patients, large variations in bleeding tendency are observed, which cannot be completely explained by the variation in von Willebrand factor levels or activities. Thus, there must be additional factors, for instance, changes in fibrinolysis that have an effect on the variation in bleeding tendency in VWD patients. Aim To investigate whether plasminogen activator inhibitor-1 ( PAI-1) level influences the variation in bleeding tendency in VWD patients. Methods PAI-1 antigen levels were measured in the plasma of 633 patients with moderate or severe VWD who participated in the 'Willebrand in the Netherlands' (WiN) study, a nationwide multicentre cross-sectional study. Bleeding severity was assessed using the Tosetto bleeding score. Results PAI-1 levels increased with age (Spearman's rho: 0.225, P < 0.001) and were higher in men (23 [ IQR 12-60] vs. 20 [ IQR 10-44] ng mL−1 in women, P = 0.039), whereas the bleeding score was higher in women (11 [ IQR 7-17] vs. 9 [ IQR 5-14] ng mL−1 in men, P = 0.002). After adjustment for age and sex by stratification, PAI-1 level and bleeding score were negatively correlated (Spearman's rho: −0.170, P = 0.017) in the group of 196 young (age ≤ 45 year) female VWD patients, accounting for 31% of our study population. Conclusion In young female VWD patients, we observed that low PAI-1 levels were associated with a higher bleeding score, which may partly explain the observed variability in bleeding phenotype in VWD patients. [ABSTRACT FROM AUTHOR]

Haemorrhagic disorders like Postpartum haemorrhage and Dengue haemorrhagic fever are life threatening and requires an active and efficient transfusion service that could provide the most appropriate blood product which could be effective in managing them. This would essentially require prompt identification of the coagulopathy so that the best available product can be given to the bleeding patient to correct the identified haemostatic defect which will help control the bleeding. This would only be possible if the transfusion service has a laboratory to correctly detect the haemostatic defect and that too with an accuracy and precision which is ensured by a good laboratory quality assurance practices. These same processes are necessary for the transfusion services to ensure the quality of the blood products manufactured by them and that it contains adequate amounts of haemostasis factors which will be good to be effective in the management of haemorrhagic disorders. These issues are discussed in detail individually in the management of postpartum haemorrhage and Dengue haemorrhagic fever including when these can help in the use of rFVIIa in Dengue haemorrhagic fever. The requirements to ensure good-quality blood products are made available for the management of these disorders and the same have also been described. [ABSTRACT FROM AUTHOR]

The aricle discusses the pharmacokinetic profile of Optivate for the treatment of von Willebrand disease (VWD), the commonest congenital bleeding disorder. It cites the clinical study funded by the biotechnology company Bio Products Laboratory Ltd. which compares the pharmacokinetic (PK) of Optivate and Haemate P in VWD patients. It states that the composition of Optivate has been shown to be comparable to other von Willebrand factor (VWF)/factor III concentrates, and was well tolerated.

Introduction Children at risk for bleeding injuries are restricted from body contact during physical activity but current recommendations are based on expert opinion. Aim Evaluate high-speed digital video recording as an objective measure of body contact risk during physical activity. Methods Observational study of physical activities among healthy children, grouped according to participation in teams (vs. individual) and on their perceived risk of injury (high/low). High speed digital video recordings documented the collision target (floor/ground/ice, people, wall, equipment), estimated speed, and impact rates for team and individual activities, with and without expected body contact. Results Among 348 participating children (3-16 years, 51% female), 32% to 78% experienced at least one contact. Impact type varied significantly (chi-square, p < 0.001) by activity category. Unstructured and Team high risk activity impacts were primarily with the floor/ground, whereas Individual low risk activities were characterized by equipment impacts. Impact speeds were typically 1.0 to 2.1 m s−1. Higher impact speeds occurred during instructional classes (2.1 m s−1), unstructured free swim (1.9 m s−1) and ball hockey (1.7 m s−1). Impact rates were higher during Team high risk and Team low risk sports (3.0 and 1.8 impacts per minute, respectively) compared to Individual (high or low risk) or Unstructured activities (0.2-0.3 impacts per minute). Conclusions High speed video recordings of childhood physical activity are a feasible method for characterizing the frequency, type, direction and speed of impacts. Quantifying the impacts that occur during childhood physical activity could inform the guidelines for physical activity participation among children with identified bleeding risks. [ABSTRACT FROM AUTHOR]

Introduction: Desmopressin is frequently used in patients with bleeding disorders because of its prohaemostatic effects. In recent years desmopressin use increased due to reported high incidence of inhibitors in mild haemophilia after clotting factor infusion and the rising costs of clotting factor concentrates. The safety and frequency of side effects have hardly been assessed in well-designed studies. Aim: We therefore prospectively evaluated side effects of desmopressin in a large unselected cohort of bleeding disorder patients, who received a desmopressin test dose. Methods: Blood was drawn prior to, one, three, six and 24 h after desmopressin. Primary outcome was change in serum sodium, haematocrit, serum- and urine osmolality, body weight and vital signs. Self-reported side effects were evaluated as secondary outcome. Results: In total, 108 patients were included, median age 30 years, the majority of whom had von Willebrand disease type 1 (76%). A significant change in water balance parameters was observed. Four patients (4%) had hyponatraemia (≤135 mmol L−1) after 24 h but no severe hyponatraemia occurred (≤125 mmol L−1). After infusion, 41 (38%) patients were hypotensive (≤90 mmHg SBP and/or ≤60 mmHg DBP) and 10 (9%) presented with tachycardia (>100 min−1). However, none of these effects sustained at 24 h. Infusion was discontinued in one patient because of tachycardia, nausea and malaise. Self-reported side effects included: headache, fatigue, flush and dizziness. Conclusion: Observed side effects correspond with the known antidiuretic and vasomotor effects of desmopressin. Changes in parameters were temporary and not clinically relevant. In conclusion, our study supports desmopressin use as a safe treatment option in patients with various bleeding disorders. [ABSTRACT FROM AUTHOR]

The article presents a case report of the use of two complementary molecular techniques, next-generation sequencing and droplet digital polymerase chain reaction (PCR), for diagnosis of an F8 gene deletion and subsequent carrier analysis in a family with haemophilia. Topics discussed include medical history of the family, and findings of the case study.

Introduction The spectrum of bleeding problems in FVII deficiency is highly variable and FVII levels and causative genetic mutations correlate poorly with the bleeding risk. Long-term prophylaxis is generally initiated in order to prevent subsequent CNS bleeding after a first event or in patients with other major/ life threatening/ frequent bleeding symptoms as gastrointestinal bleeding or hemarthrosis. However few data are available in the literature regarding FVII prophylaxis and clinical decisions cannot be based on evidence. Aims We report the data available in the literature on FVII prophylaxis and our personal experience regarding three patients affected by severe FVII deficiency. Methods Specific papers on long-term prophylaxis in severe FVII deficiency were identified using the database, PUBMED. Results The most frequent indications for long-term prophylaxis were CNS bleeding (58%), hemartrosis (15%) and GI bleeding (9%). Patients were treated with various dosages and frequency. Prophylactic treatment with 10-30U/kg (pd FVII) or 20-30mcg/kg ( rFVIIa) twice or three times/weeks was described to be effective. Conclusions In the literature and in our experience, prophylaxis can be considered in patients with severe FVII deficiency and severe bleeding phenotype. A dose of 10-30U/kg (pd FVII) or 20-30 microg/kg ( rFVIIa) twice or three times/week is usually administrated, but dose and frequency can be tailored based on the clinical follow-up of the patients. Since hemarthrosis is a frequent manifestation, a suggestion to improve the outcomes of patients with severe FVII deficiency is to monitor joint condition in order to identify early arthropathy that could be another indication to start secondary prophylaxis. [ABSTRACT FROM AUTHOR]

Introduction Haemophilia is a rare genetic haemorrhagic disease characterized by partial or complete deficiency of coagulation factor VIII, for haemophilia A, or IX, for haemophilia B. As in any other medical research domain, the field of haemophilia research is increasingly concerned with finding factors associated with binary or continuous outcomes through multivariable models. Traditional models include multiple logistic regressions, for binary outcomes, and multiple linear regressions for continuous outcomes. Yet these regression models are at times difficult to implement, especially for non-statisticians, and can be difficult to interpret. Aims The present paper sought to didactically explain how, why, and when to use classification and regression tree (CART) analysis for haemophilia research. Materials & methods The CART method is non-parametric and non-linear, based on the repeated partitioning of a sample into subgroups based on a certain criterion. Breiman developed this method in 1984. Classification trees (CTs) are used to analyse categorical outcomes and regression trees (RTs) to analyse continuous ones. Results The CART methodology has become increasingly popular in the medical field, yet only a few examples of studies using this methodology specifically in haemophilia have to date been published. Two examples using CART analysis and previously published in this field are didactically explained in details. Conclusion There is increasing interest in using CART analysis in the health domain, primarily due to its ease of implementation, use, and interpretation, thus facilitating medical decision-making. This method should be promoted for analysing continuous or categorical outcomes in haemophilia, when applicable. [ABSTRACT FROM AUTHOR]

Acquired haemophilia A ( AHA) is a rare bleeding disorder caused by autoantibodies against human factor VIII ( hFVIII). OBI-1 is an investigational, B-domain deleted, recombinant FVIII, porcine sequence, with low cross-reactivity to anti- hFVIII antibodies. Efficacy can be monitored with FVIII activity levels in addition to clinical assessments. This prospective, open label, phase 2/3 study was designed to evaluate the efficacy of OBI-1 treatment for bleeding episodes in subjects with AHA. After an initial dose of 200 U kg−1, OBI-1 was titrated to maintain target FVIII activity levels, in correlation with clinical assessments, throughout the treatment phase. All 28 subjects with AHA had a positive response to OBI-1 treatment 24 h after initiation despite inhibition of FVIII activity levels immediately after infusion in 10 subjects with baseline anti-porcine FVIII inhibitors. Control of the qualifying bleed was ultimately achieved in 24 of 28 subjects. No related serious adverse events, thrombotic events, allergic reactions or thrombocytopaenia occurred. The results of this study indicate that OBI-1 is safe and effective in treating bleeding episodes in subjects with AHA. The ability to safely and effectively titrate dosing based on FVIII activity levels in this study demonstrates that OBI-1 fulfils the unmet medical need to monitor the key coagulation parameter in AHA patients. [ABSTRACT FROM AUTHOR]

The discusses a study on high titre inhibitor to factor VII in a haemophilia carrier. The study provides an overview about the haemophilia carriers, which are one of the two X-chromosomes that is inactivated during embryonic life. Also tackled is the case of a 42-year-old woman with a bleeding history of menorrhagia and prolonged bleeding after tooth extractions.

Care for people with haemophilia ( PWH) has improved much over the last two decades leading to near normal lives for those receiving early regular prophylaxis with clotting factor concentrates (CFC). Yet, there are significant limitations of those practices. In the absence of a well-defined optimal prophylaxis protocol, there are wide variations in practices with a two to threefold difference in doses. In those parts of the world where there are constraints on the availability of CFC, episodic replacement remains the norm for most patients even though it is evident that this does not change the natural history of the disease over a wide range of doses. Suitable prophylactic protocols therefore need to be developed wherever possible at these doses. Finally, there are only limited data on long-term outcomes in haemophilia from anywhere in the world. The practice of documenting specific outcomes as part of the regular evaluation of PWH needs to be established and the appropriate instruments used to assess them. Definitions of clinical events and endpoints of interventions in clinical studies are being developed to help such data collection. The correlations between different replacement therapy protocols and specific outcomes will help define what is best at different dose levels. Such data will allow better health planning and treatment choices throughout the world. [ABSTRACT FROM AUTHOR]

Prospective data on the efficacy of secondary prophylaxis in adults with haemophilia A are limited. To analyse bleeding outcomes in the sucrose-formulated recombinant factor VIII [rFVIII-FS (control)] arm of the LIPLONG study, a randomized, double-blind, 52-week trial was conducted in patients with severe haemophilia A receiving prophylaxis with the investigational product BAY 79-4980 or rFVIII-FS. The per-protocol population of previously treated patients with severe haemophilia A without a history of inhibitors ( n = 68 males; mean age, 34.4 years) received 25 IU kg−1 rFVIII-FS three times per week for a median of 50.7 weeks. Annualized bleeding rates were assessed and analysed according to predefined target joint status at study start, prestudy treatment type (prophylaxis vs. on demand), age (<30 or ≥30 years), geographical region, bleeding frequency during the previous 6 months and physical activity status during the study using the Student t-test. The annualized median (range) number of bleeds was 2.2 (0.0-23) bleeds per year. The median (range) number of bleeds per year was significantly lower in patient subgroups without vs. with target joints [0.5 (0.0-17.1) vs. 4.2 (0.0-22.8); P = 0.02] and in those with ≤9 vs. >9 bleeds during the previous 6 months [1.1 (0.0-19.2) vs. 5.3 (0.0-22.8); P = 0.01]. Following randomization to prophylaxis with rFVIII-FS, bleeding frequency was effectively reduced. Absence of target joints and prestudy bleeding frequency were predictors of a low bleeding frequency during prophylaxis treatment. [ABSTRACT FROM AUTHOR]

Many adult patients diagnosed with phenotypically moderate and severe haemophilia living in the Auckland region of New Zealand do not report bleeding episodes within a timeframe that allows for optimal assessment and management. This can result in poor clinical outcomes for patients and poor oversight of the use of expensive clotting factor concentrates. Our goal was to improve both the number and speed at which bleeding episodes were reported to our centre, improving access to care and clinical oversight of the use of expensive factor concentrates and aiding the development of a care partnership with patients. We worked with 70 adult PWH living in the Auckland region of New Zealand with moderate and severe haemophilia A and B. Over a 5-month period between March and July 2013 we used a co-design model to develop and implement a range of strategies to improve the timing and frequency of bleed reporting. Mean bleed reporting time was reduced threefold, with a threefold increase in the number of bleeds reported per month. We reduced the number of bleeding episodes reported outside of a prespecified 48-h time limit by 68%. We significantly improved bleed reporting and time to report, indicating improved access to our services, improved clinical oversight and improved accountability to our national funder. We have achieved a care partnership and a reduction in factor consumption for the study population without compromising the quality of care they receive. [ABSTRACT FROM AUTHOR]

Haemophilia patients with inhibitors require bypassing agents ( BPA) like activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) to control bleeds. Adjunct tranexamic acid ( TXA) may improve haemostasis. The objective of this study was to investigate safety and haemostatic effect of TXA given in combination with BPA. Healthy volunteers ( N = 5) and haemophilia inhibitor patients ( N = 6) were enrolled in a prospective case crossover design. Controls were treated with TXA 20 mg kg−1 orally (O.R.) Patients were treated with aPCC 75 IU kg−1 intravenous (I.V.) on day 1 followed by TXA 20 mg kg−1 O.R. combined with aPCC 75 IU kg−1 I.V. on day 2. A 14-day washout occurred before crossover to rFVIIa 90 μg kg−1 I.V. ± TXA. Safety evaluation and blood sampling processes were performed at baseline, 15, 30, 60, 120, 180 and 240 min post treatment. Primary outcome was maximum clot firmness ( MCF) evaluated by whole blood thromboelastometry using a TF + tissue plasminogen activator-based assay. Healthy controls showed a 20-fold increase in MCF following TXA. Adjunct TXA to aPCC or rFVIIa induced a significant increase in MCF ( P < 0.0001) reaching levels indistinguishable from healthy controls treated with TXA ( P > 0.05). Infusion of aPCC or rFVIIa alone induced only 3-10 fold increase in MCF from baseline, with a decline in MCF starting after 60-120 min. TXA did not increase the endogenous thrombin potential. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed. Combination of aPCC or rFVIIa with TXA normalizes clot stability in haemophilia patients with inhibitor as compared to healthy controls. No clinical or laboratory adverse events were observed. [ABSTRACT FROM AUTHOR]

Management of patients with hereditary bleeding disorders in dentistry causes considerable problems. This study examined different aspects of dental health or disease of Lithuanian children and adults with haemophilia and compared them with the general population. Two study groups of cases and controls were formed. Cases were recruited through census sampling and controls were randomly chosen from the general population matched for gender, age and place of residence. Dental health of permanent and deciduous dentitions was assessed by one examiner employing the WHO Criteria for Oral Health Surveys. The following aspects of dental health/disease were considered: overall caries experience, treatment experience, unmet dental treatment needs and the presence of functional dentition. Data were collected from 76 patients with haemophilia among which 27 were children and 49 were adults and a control group of 76 subjects comprising 30 children and 46 adults. Children with haemophilia had a significantly lower overall caries experience and less unmet dental treatment needs in deciduous teeth as compared to healthy children. In permanent dentitions, overall caries experience, unmet dental treatment needs or treatment experience did not differ between cases and controls either in older children or adult cohorts. There were no differences between the study groups regarding the functional dentition-related indices. Healthier deciduous teeth were observed in children with haemophilia than in children without haemophilia, but other dental health or disease-related outcomes did not differ between cases and controls. [ABSTRACT FROM AUTHOR]

Acquired haemophilia A is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). There is a scarcity of acquired haemophilia A studies from Asian countries. The aim of this study was to evaluate clinical characteristics and outcomes of acquired haemophilia A among Asian populations. Data were collected from a retrospective case series and combined with a systematic review. The case series included all patients with acquired haemophilia A from 1999 to 2012 at Chiang Mai University Hospital. The systematic review searched MEDLINE and EMBASE databases for relevant keywords. A total of 111 patients were reviewed in this study (including 26 patients from the present series). There were 56 male (50.5%) and 55 female (49.5%) patients. We compared the demographic data with ECAH2 and UKHCDO studies. The weighted mean (SD) age at diagnosis was 58.10 (16.96) years compared with 75.70 (14.47) years in the European series (absolute difference 17.6 years, 95% confidence interval [CI] 14.20-20.99, P = 0.025). The mean (SD) FVIII activity was 2.97 (3.81) IU dL−1 and the mean (SD) FVIII inhibitor titre was 26.35 (399.16) BU mL−1. Fifty-six per cent of the patients underwent immunosuppression with steroids alone. The pool complete remission rate was comparable to the European studies, at 67.2% vs. 66.6% respectively (absolute difference 0.7, 95% CI 0.18 to 1.22, P = 0.99). This study reveals a novel finding of younger age at diagnosis of acquired haemophilia A among Asian patients. [ABSTRACT FROM AUTHOR]

Immune tolerance induction (ITI) has been shown to successfully eliminate factor VIII (FVIII) inhibitors in haemophilia patients with inhibitors. We performed a literature search to identify reports from January 1980 to October 2012 on the use of the plasma-derived, von Willebrand factor (VWF)-containing FVIII concentrate Haemate® P/Humate-P® in the setting of ITI. Six reports were identified that specifically evaluated the use of Haemate® P/Humate-P® including 32 children and 9 adults. Dosing regimens ranged from 20 IU kg−1 every 2-3 days in patients with low-responding (LR; n = 5) inhibitors to 300 IU kg−1 day−1 in patients with high-responding (HR; n = 36) inhibitors. Complete success was achieved in all five LR patients, in all three HR patients with good prognostic factors (age ≤7 years, pre-ITI inhibitor titre <10 BU, historical inhibitor titre <200 BU, time between inhibitor detection and ITI start <2 years), and in 24 of 33 (73%) HR patients with poor prognostic factors. The time to complete success was 0.5-4 months in good-prognosis patients and 0.5-42 months in poor-prognosis patients. Few adverse events were observed during ITI, and no cases of inhibitor relapse were reported with follow-up periods of up to 12 years. On the basis of this retrospective review of a diverse range of studies and case reports, we conclude that Haemate® P/Humate-P® for ITI in patients with inhibitors is effective and produces high rates of ITI success. [ABSTRACT FROM AUTHOR]

This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the Kreuth III meeting in April 2013. To optimize the organization of haemophilia care nationally, it is recommended that a formal body be established in each country to include the relevant clinicians, national haemophilia patient organization, health ministry, paying authority and (if appropriate) regulatory authorities. The minimum factor VIII consumption level in a country should be 3 I.U. per capita. Decisions on whether to adopt a new product should not be based solely on cost. Prophylaxis for children with severe haemophilia is already recognized as the optimum therapy. Ongoing prophylaxis for individual adults should also be provided when required based on clinical decision making by the clinician in consultation with the patient. Children with inhibitors who have failed, or who are not suitable for, immune tolerance therapy should be offered prophylaxis with bypassing agents. Single factor concentrates should be used as therapy wherever possible in patients with rare bleeding disorders. Orphan drug designation for a factor concentrate should not be used to hinder the development, licencing and marketing of other products for the same condition which have demonstrably different protein modification or enhancement. [ABSTRACT FROM AUTHOR]

In low-income countries, haemophilia treatment is not supported by national health services. Data on the burden of out-of-pocket (OOP) expenditure on households are unavailable from these countries. This study measured the OOP expenditure on treatment of haemophilia by Indian households. We used 20 weeks of follow-up data of 24 haemophilia A patients to estimate the annual bleeding rate for each patient and the actual OOP expenditure on treatment. We used this observational data to calculate the annual OOP expenditure on treatment if all bleeding episodes were to be treated with clotting factor concentrate. Using previously published methodology, we estimated if the expenditure was catastrophic to households or not. The observed monthly expenditure on treatment ranged from 1.5% to 12% of monthly income as not all bleeding episodes were treated with clotting factor concentrate. The estimated monthly expenditure if all bleeding episodes occurring over 1 year were to be treated would range from 21 to 314 times the monthly income of families. Nearly 68% of households would have experienced catastrophic expenditure. Treatment for haemophilia results in significant OOP expenditure for households, which is avoided by not providing standard treatment to patients. There is a need to mobilize prevention and care services for haemophilia in India and other low-income countries to mitigate the suffering due to lack of affordable treatment. [ABSTRACT FROM AUTHOR]

Spontaneous haemorrhage in patients with haemophilia is generally considered to occur randomly and without a predictable temporal or seasonal pattern; however, there is a lack of evidence in the literature on the effects of weather, temperature and atmosphere on bleeding episodes. This post hoc analysis of a multicentre, open-label crossover study examined the influence of seasonality on bleeding frequency and patient-assessed pain in patients with moderately severe and severe ( FIX C ≤ 2%) haemophilia B. Fifty patients were enrolled and treated on-demand for 16 weeks; 47 were subsequently randomized to one of two prophylactic regimens (nonacog alfa 100 IU kg−1 once weekly or 50 IU kg−1 twice weekly) for 16 weeks. Patients then underwent an 8-week washout period of on-demand therapy before being crossed over to the other prophylactic regimen for 16 weeks. Bleeding episodes during the on-demand treatment periods were analysed. To assess for temporal trends, data were graphed as scatter plots. The primary end point was the annualized bleeding rate ( ABR). Additional measures included raw and median pain scores during every joint bleeding event (spontaneous or traumatic), with pain scored using the Brief Pain Inventory (0 = 'no pain' to 10 = 'pain as bad as you can imagine'). The observed ABRs during the on-demand periods showed no distinguishable trend over time. Analysis of pain associated with joint bleeding episodes also did not demonstrate any discernible temporal trend. No apparent seasonal variation in bleeding pattern or patient-reported pain was observed in this analysis of patients with haemophilia B. [ABSTRACT FROM AUTHOR]

From a young age patients with severe and moderately severe FIX deficiency (haemophilia B) can experience spontaneous or traumatic bleeding and joint destruction may result. The use of coagulation factor IX concentrate to prevent anticipated bleeding, as primary or secondary prophylaxis, has become a common and recommended practice in children. The current practice of using tertiary prophylaxis, in the presence of established joint arthropathy, in adults with haemophilia B is not well characterized. This observational study was conducted to gain a better understanding of the recent Canadian experience with tertiary prophylaxis in adults with severe and moderately severe haemophilia B. Data were collected from all eligible adult (≥ 18 years of age) males with baseline FIX:C ≤ 2% from seven Canadian Hemophilia Treatment centres over a 2-year observation period from 2009 to 2011. Thirty-four per cent of the 67 subjects with moderately severe haemophilia B were exposed to prophylaxis with the majority as continuous prophylaxis (≥45 weeks year-1). The severe subgroup ( FIX:C < 1%) demonstrated a 52% exposure rate. None had primary prophylaxis exposure in childhood. Eighty-one per cent used once or twice weekly infusion regimens and reported a median annual bleeding rate of five bleeds per year versus four bleeds per year for those using on-demand treatment. Annual median factor utilization for all subjects using prophylaxis was 196 283 U year-1 compared to 46 361 U year-1 for on demand. Approximately 50% of adults with severe haemophilia B are using continuous tertiary prophylaxis in Canada, a practice likely to increase which warrants further study. [ABSTRACT FROM AUTHOR]

Numerous case reports have been published on acquired von Willebrand syndrome (a VWS) in patients with hypothyroidism, but no prospective studies have been published. The aim of this study was to investigate laboratory and clinical characteristics of a VWS in patients with newly diagnosed overt hypothyroidism. An observational cohort study was performed between May 2007 and February 2012. Consecutive hypothyroid patients before or within the first 48 h of replacement therapy were enrolled. At inclusion, blood was sampled for coagulation tests and bleeding history was documented by means of a standardized bleeding questionnaire. Repeat samples were obtained after restoration of euthyroidism. The prevalence of a VWS, defined as von Willebrand factor antigen (VWF:Ag) ≤50% and/or VWF ristocetin activity (VWF:RCo) ≤50%, was calculated. Patients with a VWS were subsequently divided into severe (VWF:Ag and/or VWF:RCo ≤10%), moderate (VWF:Ag and/or VWF:RCo between 10 and 30%) or mild (VWF:Ag and/or VWF:RCo between 30 and 50%). A total of 90 patients were included among whom a prevalence of a VWS of 33% was found. There were no patients with severe a VWS. Eight patients (9%) had moderate a VWS and 21 (23%) had mild a VWS. Bleeding score was negatively correlated with both VWF:Ag (β −0.32, P = 0.03) and VWF:RCo (β −0.32, P = 0.02). After restoration of euthyroidism, VWF:Ag had significantly increased by 44%, VWF:RCo by 36%, factor VIII by 39%, and endogenous thrombin potential by 10%. a VWS has a high prevalence in hypothyroid patients. Highest bleeding scores in patients with lower VWF levels suggest clinical relevance. [ABSTRACT FROM AUTHOR]

Recombinant activated factor VII ( rFVIIa) has been available for the treatment of acute bleeding and for prevention of bleeding during surgery and invasive procedures in patients with congenital haemophilia with inhibitors ( CHwI) and acquired haemophilia since 1996. The study objective was to assess the efficacy and safety of rFVIIa in patients with CHwI, acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia, in a real-life clinical setting. There were no specific inclusion or exclusion criteria; participation was offered to all German haemophilia centres known to use rFVIIa to treat patients with the above indications. Data on rFVIIa use and efficacy for the treatment of acute bleeding episodes and invasive procedures were recorded. Adverse drug reactions and recurrent bleeding episodes were also monitored. In total, 64 patients (50.0% women) received rFVIIa treatment. Patients experienced 281 evaluable bleeding episodes and underwent 44 invasive procedures. In 252 of 281 (89.7%) bleeding episodes, a stop (66.5%) or a significant reduction (23.1%) in bleeding was observed. No bleeding complications were reported for 42 of 44 (95.5%) invasive procedures covered with rFVIIa. A clear positive association was observed between early initiation of rFVIIa treatment for acute bleeding and efficacy. The total cumulative dose and number of injections were 468.3 ± 545.8 μg kg−1 and 3.6 ± 4.6 respectively. No drug-related adverse events were reported. rFVIIa use in Germany provided effective haemostatic cover without associated adverse events in the management of acute bleeds and invasive procedures across a range of bleeding disorders. [ABSTRACT FROM AUTHOR]

Haemophilia carriers and women with inherited bleeding disorders ( IBD) experience menorrhagia, bleed following dentistry, surgery, injury or childbirth. Symptoms are easily treated leading to full and active lives. Nevertheless, some girls and women suffer with abnormal bleeding for many years before diagnosis. We explored the experiences of girls and young women (aged 9-34 years) with IBD by means of focus groups which consisted of moderated discussion addressing specific aspects of bleeding, management and coping strategies. Subsequently, these issues were explored further though a paper-based questionnaire distributed via five specialist haemophilia centres in the UK. The study suggested that young women with IBD who are managed at haemophilia centres receive appropriate care and feel well supported. Although the clinic-based literature available to these women is 'fit for purpose', it does not fully address the perceived needs specifically regarding sex, menorrhagia, conception and childbirth, the Pill, tattoos/piercings and so on, leading many to turn to other information sources. Most of those who responded to our survey are confident in their lives, able to manage their IBD and take pragmatic views towards the inherited nature of their condition. But there is a substantial subgroup of women who experience stigmatization, isolation and bullying and express concerns relating to fertility and conception. Overall, this cohort would benefit from opportunities for mutual support. This could be via Internet-based social networking and may be of particular value to those who are unable to seek help from traditional medical services due to religious or other cultural barriers. [ABSTRACT FROM AUTHOR]

Although many people with haemophilia discontinue prophylaxis in their late teens or early adulthood, the consequences of this decision are largely not known. This 18-month, observational, case-controlled, multicentre study evaluated long-term prophylaxis and the consequences of switching from prophylaxis to on-demand treatment in late teens and young adults with severe haemophilia A. Participants with haemophilia (aged 14-29 years) on prophylaxis ≥60% of the time for the 5 years before study entry were enrolled into 1 of 2 prospective or 1 retrospective group. Group 1 was prophylaxis, group 2 had voluntarily discontinued prophylaxis ≤12 months before study entry and group 3 had voluntarily discontinued prophylaxis ≥13 months before study entry. Assessments included bleeding frequency (primary endpoint), Haemo-QoL-A health-related quality of life (HRQoL) scores, Gilbert score, development of target joints, Haemophilia Activities List, Godin Leisure-Time, treatment satisfaction and State-Trait Anxiety Inventory (secondary and exploratory endpoints). Descriptive statistics were provided for all variables. Thirty-eight participants (group 1, n = 22; group 2, n = 5; group 3, n = 11; median age, 19.5 years) were enrolled. The median annualized number of bleeding events was 0, 4.8 and 24 in groups 1, 2 and 3 respectively. HRQoL was lower in participants who discontinued prophylaxis vs. those who remained on prophylaxis. Changes in the remaining secondary and exploratory variables were small, but were generally worse in participants who discontinued prophylaxis. Following a switch from prophylaxis to on-demand therapy, the number of bleeding events increased and HRQoL worsened in late teens and young adults with severe haemophilia A. [ABSTRACT FROM AUTHOR]

Recombinant factor VIII ( rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety and efficacy of turoctocog alfa, a new rFVIII product. The primary objective was to evaluate safety. A total of 150 patients (24 adolescents and 126 adults) with severe haemophilia A ( FVIII activity ≤1%), with at least 150 exposure days ( EDs) to any FVIII product and no history of inhibitors were enrolled, and 146 patients (97%) completed the trial. All patients received prophylaxis with turoctocog alfa for approximately 6 months and had a mean of 85 EDs during the trial. None of the patients developed FVIII inhibitors, there were no indications of early FVIII inhibitor development and no safety concerns were identified. A total of 225 adverse events were reported in 100 (67%) patients, with the most common being events associated with dosing procedures, headaches, and nasopharyngitis. A total of 499 bleeding episodes were reported during the trial, the majority (89%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 81%. The overall median annualized bleeding rate was 3.7 (interquartile range: 8.7) bleeds/patient/year. In conclusion, turoctocog alfa provides a new, safe and effective alternative for prophylaxis and treatment of bleeding episodes in patients with haemophilia A. [ABSTRACT FROM AUTHOR]

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety, efficacy and pharmacokinetics ( PK) of turoctocog alfa, a new rFVIII product, in a paediatric population. The primary objective was to evaluate safety. A total of 31 younger children (0-5 years) and 32 older children (6-11 years), with ≥50 exposure days to any factor VIII (FVIII) product and no history of inhibitors, received prophylaxis with turoctocog alfa (25-50 IU kg−1 every second day or 25-60 IU kg−1 three times weekly). PK assessments of turoctocog alfa and the patients' previous FVIII product were performed in 28 patients. Mean exposure to turoctocog alfa was 60 exposure days per patient. This corresponds to approximately 4.5 months in the trial. None of the patients developed inhibitors (≥0.6 BU) and no safety concerns were raised. A total of 120 bleeding episodes (95%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 92%. Overall, the median annualized bleeding rate was 3.0 (interquartile range: 8.5) bleeds patient−1 year−1. PK parameters were comparable between the two age groups. In conclusion, the present large global clinical trial showed that turoctocog alfa was safe, effective in treatment of bleeding episodes and had a prophylactic effect in paediatric patients. [ABSTRACT FROM AUTHOR]

Joint damage from bleeding episodes leads to physical or functional limitations in people with haemophilia. Various factors may influence the frequency and severity of joint damage. This study examined whether age, prophylaxis, history of high-titre inhibitors ( HTI) and bleeding events influenced the Haemophilia Joint Health Score ( HJHS) in children. Medical and physiotherapy notes of boys with severe haemophilia, aged 4-18 years, were reviewed to identify factors associated with increased HJHS. The HJHS of 83 boys (median age: 11) ranged from 0 to 25, with 44/83 (53%) having a score of zero. The median HJHS was 0 (mean 2.6). In the non- HTI group, the HJHS for boys on late prophylaxis was 2.68 times higher than those who started early and the HJHS was on average 10% higher for every additional recent bleed. In this group the odds of having a zero score fell by 30% for every year increase in age. Boys with a history of HTI had higher HJHS scores than the non- HTI group, and age, number of recent bleeds and tolerized status were positively associated with HJHS. The score rose on average by 28% for every year of age and by 76% for non-tolerized boys. This study provides further evidence supporting early prophylaxis use and the importance of immune tolerance therapy. The HJHS is a useful tool for identifying and tracking changes in joint health with respect to therapy or disease progression. With improvements in haemophilia treatment, the disproportionate number of zero scores will continue to make interpretation of the HJHS challenging. [ABSTRACT FROM AUTHOR]

Type 3 von Willebrand's disease ( VWD) is a rare bleeding diathesis with complete or near complete deficiency of von Willebrand factor ( VWF) and low factor VIII ( FVIII) levels. In contrast, only FVIII is decreased in haemophilia A ( HA). Both disorders are complicated by arthropathy. The purpose of this study was to further clarify the roles of FVIII and VWF: Antigen ( VWF:Ag) in joint range of motion ( ROM) loss over time. We compared joint ROM loss and other bleeding manifestations in 100 Type 3 VWD subjects ( FVIII <5%) and 1814 moderate HA subjects ( FVIII 1-5%) within the U.S. Universal Data Collection ( UDC) database. High rates of bleeding were reported at baseline. During follow-up, moderate HA patients reported a joint (46% vs. 34%, P < 0.0001) or muscle bleed (27% vs. 16%, P < 0.0001) in a higher proportion of visits than VWD patients. Other bleeds, including mucosal, were reported in a greater proportion of visits among patients with Type 3 VWD than among those with HA (49% vs. 32%, P < 0.0001). Multivariate analysis revealed no difference in joint ROM loss over time in the Type 3 VWD vs. moderate HA populations. A higher FVIII level was protective in both VWD and HA ( P < 0.001). Our findings support the hypothesis of primacy of the FVIII level in determining risk of joint haemorrhage, and may help target therapy in Type 3 VWD and moderate HA to prevent joint disability. [ABSTRACT FROM AUTHOR]

Type 2M von Willebrand disease ( VWD) includes qualitative defects in von Willebrand factor ( VWF) function, with normal multimer distribution but a defect in VWF activity with respect to platelet or collagen binding. We characterized novel VWF gene mutations found in type 2M VWD subjects enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD. Subjects were enrolled based on a pre-existing diagnosis of type 2M VWD. Testing included full-length gene sequencing, VWF antigen ( VWF:Ag), VWF ristocetin cofactor activity ( VWF: RCo), VWF collagen binding and multimer distribution. Recombinant VWF variants were synthesized using site-directed mutagenesis and expressed in HEK293T cells. Platelet binding was measured by flow cytometry with fixed platelets and ELISA with recombinant glycoprotein Ibα ( GPIbα). Four novel VWF A1 domain mutations were found in individuals with type 2M VWD: S1358N, S1387I, S1394F and Q1402P. All subjects had a history of bleeding, VWF: RCo < 40 IU dL−1, VWF: RCo/ VWF: Ag ratios <0.6 and normal multimer distribution. No defect in expression, secretion, or multimerization was found for any of the mutations. All showed decreased binding to intact platelets, and decreased or absent binding to a mutant GPIbα construct with spontaneous VWF binding. 1387I had decreased binding to all collagen types tested. 1402P had reduced binding exclusively to type VI collagen. Type 2M VWD is a heterogeneous category comprised of both collagen- and platelet-binding defects. Understanding the precise defect for each mutation may ultimately lead to better diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Clotting factor replacement therapy has a major impact on the quality of life in patients with haemophilia. To analyse and compare the outcomes of on-demand and prophylactic treatment regimens in child- and adulthood, a self-evaluation questionnaire was sent to 182 patients over 30 years of age with severe haemophilia A or B. Analysis of the questionnaire results revealed that most study participants had been treated on-demand in childhood, but that the majority of these patients subsequently switched to prophylaxis. However, of those patients who began with prophylaxis as children, the vast majority maintained prophylactic treatment as adults. Inhibitor development was reported significantly more frequently by patients who started with on-demand treatment than by those who started with prophylaxis. In the year prior to completing the questionnaire, adults with severe haemophilia who received prophylactic treatment reported a significantly lower incidence of bleeding as a result of more frequent factor consumption. These results are in close accordance with published prospective data. Although nearly all patients with severe haemophilia had joint pain due to bleeding, those who had always had prophylactic treatment reported superior outcomes in terms of the need for joint replacement, walking speed and distance, participation in school sports and further education. These data clearly underline the superiority of prophylactic treatment for the majority of individuals with severe haemophilia. The worst outcomes were found in those treated on-demand in childhood who later switched to prophylaxis. In contrast to most studies which have compared treatment regimens on the basis of data from healthcare professionals, this study reflects treatment outcomes from the patient's perspective. [ABSTRACT FROM AUTHOR]

Most health care professionals involved in the management of people with haemophilia ( PWH) believe that exercise is beneficial and its practice is widely encouraged. This article aims to demonstrate that appropriate exercise (adapted to the special needs of the individual PWH) may be beneficial for all PWH through improved physical, psychosocial and medical status. Based on evidence gathered from the literature, many PWH, particularly those using long-term prophylaxis or exhibiting a mild/moderate bleeding phenotype, are as active as their healthy peers. PWH experience the same benefits of exercise as the general population, being physically healthier than if sedentary and enjoying a higher quality of life (QoL) through social inclusion and higher self-esteem. PWH can also gain physically from increased muscle strength, joint health, balance and flexibility achieved through physiotherapy, physical activity, exercise and sport. Conversely, very little data exist on activity levels of PWH in countries with limited resources. However, regarding specific exercise recommendations in PWH, there is a lack of randomized clinical trials, and consequently formal, evidence-based guidelines have not been produced. Based on published evidence from this review of the literature, together with the clinical experience of the authors, a series of recommendations for the safe participation of PWH in regular physical activities, exercises and sport are now proposed. In summary, we believe that appropriately modified programmes can potentially allow all PWH to experience the physical and psychosocial benefits of being physically active which may ultimately lead to an improved QoL. [ABSTRACT FROM AUTHOR]

Recent data from the Dosing Observational Study in Hemophilia diary study has described home treatment with recombinant activated factor VII ( rFVIIa) in congenital haemophilia with inhibitors (CHwI). The current analysis compares prescribed and patient/caregiver-reported rFVIIa administration in paediatric and adult CHwI patients in this study. Patients with ≥4 bleeding episodes within a 3-month period prescribed rFVIIa as first-line therapy for bleeding episodes were eligible. Patients/caregivers completed a diary for ≥90 days or until the patient experienced four bleeds. Initial, total and mean rFVIIa doses reported for each bleeding episode were calculated and compared with the physician-prescribed doses. Of 52 enrolled patients (25 children; 27 adults), 39 (75%) completed the study. Children and adults had similar mean durations of bleeding episodes. Both patient groups were administered higher initial rFVIIa doses for joint bleeds than prescribed: median (range) 215.2 (74.1-400.0) mcg kg−1 vs. 200.0 (61.0-270.0) mcg kg−1 for children, and 231.3 (59.3-379.7) mcg kg−1 vs. 123.0 (81.0-289.0) mcg kg−1 for adults. The median infused dose for joint bleeds was higher in adults than children (175.2 vs. 148.0 mcg kg−1), but children received significantly more doses per joint bleed than adults (median 6.5 vs. 3.0). The median total dose per joint bleed was higher in children than adults (1248.7 vs. 441.6). For children and adults, both initial and additional doses administered for bleeds were higher than prescribed. Children received higher total doses per bleed due to an increased number of infusions per bleed. [ABSTRACT FROM AUTHOR]