Mild Hemophilia Research Articles

Mortality caused by intracranial bleeding in non‐severe hemophilia A patients

Background Non-severe hemophilia (factor VIII concentration [FVIII:C] of 2-40 IU dL-1 ) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on bleeding-related causes of death, such as fatal intracranial bleeding, in non-severe patients are scarce. Such data may provide new insights into areas of care that can be improved. Aims To describe mortality rates, risk factors and comorbidities associated with fatal intracranial bleeding in non-severe hemophilia A patients. Methods We analyzed data from the INSIGHT study, an international cohort study of all non-severe hemophilia A patients treated with FVIII concentrates during the observation period between 1980 and 2010 in 34 participating centers across Europe and Australia. Clinical data and vital status were collected from 2709 patients. We report the standardized mortality rate for patients who suffered from fatal intracranial bleeding, using a general European male population as a control population. Results Twelve per cent of the 148 deceased patients in our cohort of 2709 patients died from intracranial bleeding. The mortality rate between 1996 and 2010 for all ages was 3.5-fold higher than that in the general population (95% confidence interval [CI] 2.0-5.8). Patients who died from intracranial bleeding mostly presented with mild hemophilia without clear comorbidities. Conclusion Non-severe hemophilia A patients have an increased risk of dying from intracranial bleeding in comparison with the general population. This demonstrates the need for specialized care for non-severe hemophilia A patients.

New Surgical Technologies Could Facilitate Surgical Hemostasis in Hemophilic Patients.

BACKGROUND:It’s assumed that surgery in haemophilia can be accomplished these days safely.AIM:The aim of this study was to investigate the influence of new surgical technologies in the perioperative management and outcome of surgical procedures in haemophiliacs.METHODS:Two patients with mild haemophilia A underwent surgery (laparoscopic appendectomy and inguinal hernia repair). In both patients, the replacement therapy, with factor VIII, started 30 min before surgery. We used the available surgical technologies and techniques with a proven value in the best clinical practice, to achieve proper and permanent hemostasis. Postoperatively, the replacement therapy and thromboembolic prophylaxis was continued according to the international guidelines for the management of haemophilia.RESULTS:The operative and post-operative periods were uneventful. No significant differences were found in the operation time in our hemophilic patients versus non-hemophilic patients. Significant differences related to the hospital stay duration were found in both patients compared with controls, due to the necessary replacement therapy.CONCLUSION:With new surgical technologies, proper and permanent hemostasis can be achieved, without prolonging the operation time.

Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders

Dental extractions challenge the body’s haemostatic mechanism. Postoperative bleeding from dental extraction can be prolonged, or even life threatening in patients with inherited bleeding disorders. Pre- and postoperative clotting factor replacements or systemic desmopressin (ddAVP) have been advocated at our institution to prevent bleeding complications in these patients. This study aimed to assess the postoperative bleeding rate in patients with inherited bleeding disorders that underwent dental extractions at our institution between 2003 and 2012. Patients with inherited bleeding disorders such as haemophilia A, haemophilia B, and von Willebrand’s disease were included. Retrospective chart review was conducted. The result showed 53 extraction events occurred in 45 patients over the 10-year period. Ten out of 53 extraction events (18.9%) had postoperative bleeding requiring further factor replacement or ddAVP. Postoperative bleeding in one patient with mild haemophilia A was complicated by the development of inhibitors. Type and severity of bleeding disorder, bone removal, and use of a local haemostatic agent did not have any significant effect on postoperative bleeding. Despite the use of perioperative factors and desmopressin, the postoperative bleeding rates remain high for patients with inherited bleeding disorders. More studies are required to assess the safety and effectiveness of using local haemostatic control to achieve haemostasis following extractions.

軽症先天性血友病Aに合併した誘因のない腹腔内自然出血の1例(A case report of spontaneous intraperitoneal hemorrhage complicated with mild congenital hemophilia A)

要旨患者は38歳の男性。27歳で軽症の先天性血友病Aと診断され，歯科治療時に1度だけ血液凝固第VIII因子が投与されたが，以後は無治療で出血することなく経過していた。発症までに軽微なものを含めて明らかな腹部外傷歴はなかった。前日からの左上腹部痛を主訴に近医を受診した。腹部単純CTで腹腔内出血を疑われて同日当院へ紹介搬送となった。腹部造影CTで造影剤の血管外漏出像と腹腔内液貯留の増加がみられた。血液検査では，活性化部分トロンボプラスチン時間（activated partial thromboplastin time: APTT）が47.3秒と延長していた。後日判明した血液凝固第VIII因子活性値は21.9%であった。軽症血友病Aに合併した外傷などの明らかな誘因のない腹腔内自然出血と診断し，血液凝固第VIII因子製剤を4,000単位投与した後に血管造影検査を行った。しかし，明らかな血管外漏出像はなく，動脈塞栓術は行わなかった。その後再出血はなく，第11病日まで補充療法を継続した後，第14病日に軽快退院した。軽症血友病A患者に外傷などの誘因の明らかでない腹腔内自然出血が起こることは非常に稀である。このような腹腔内出血で止血を得るためには，APTTを指標とした早期の血液凝固因子製剤の投与が重要と考えられる。

Evaluating the psychosocial impact of hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

The needs of individuals living with hemophilia B, especially those with mild or moderate hemophilia and affected females, are not well understood. The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) initiative was developed in an effort to obtain greater insights into the unique issues and challenges faced by those with hemophilia B. This study explored the impact of hemophilia B on education, employment, engagement in physical activities and other psychosocial aspects of the lives of affected individuals and their families. The B-HERO-S findings reveal a number of unmet needs in the hemophilia B population, and these results may be leveraged to inform patient outreach and education initiatives.

Incidence of low-titre factor VIII inhibitors in patients with haemophilia A: meta-analysis of observational studies.

A few studies have been focused on low-titre inhibitors in patients with haemophilia A. Although several putative factors have been implicated in the development of these inhibitors, solid data are still lacking. The aim of this study was to perform a proportion meta-analysis on the incidence of low-titre inhibitors in haemophilia A. We surveyed the PubMed database to identify studies on de novo development of low-titre inhibitors in haemophilia A patients. On the basis of these data, we carried out a proportion meta-analysis to summarize information on incidence and between-study variability. Furthermore, the following three covariates were assessed by meta-regression: (i) mild disease vs. severe haemophilia; (ii) status of previously untreated patient (PUP) as opposed to multi-transfused and (iii) type of factor VIII. Our literature search on PubMed extracted 340 eligible articles. From these, we selected 33 patient cohorts that were included in our meta-analysis (19 cohorts for PUPs and 14 cohorts for multi-transfused or unselected patients). The pooled incidence of low-titre inhibitors was 10.3% (95%CI: 8.3-12.5%) for studies including PUPs and 5.8% (95%CI: 2.5-10.4%) for the other studies; the difference was statistically significant (P = 0.003). Meta-regression of 31 patient cohorts found that mild disease and type of factor VIII were not associated with an increased incidence of low-titre inhibitors. Our results confirmed that PUPs show a higher incidence of low-titre inhibitors than the other patients. Furthermore, our data showed that mild haemophilia was not associated with an increased incidence of low-titre inhibitors.

Comparative burden of arthropathy in mild haemophilia: a register-based study in Sweden.

Mild haemophilia is a congenital bleeding disorder affecting males. The burden of arthropathy in mild haemophilia has not been comprehensively described. The aim of this study was to compare the incidence, age at diagnosis and surgery for arthropathy and related hospitalizations between people with mild haemophilia and the general population in Sweden. This was a register-based cohort study. Eligible participants were those with mild haemophilia born between 1941 and 2008 and a randomly selected, birthdate and sex-matched comparison group from the general population. Follow-up was from birth (or earliest 1984) until death, emigration or end of the study in 2008. Data on arthropathy were obtained from a national patient register. Negative binomial and competing risk regression and Kaplan-Meier estimate curves were used in the analysis. Overall, 315 people with haemophilia and 1529 people in the comparison group were included. Participants with haemophilia born between 1984 and 2008 had a ninefold (95% CI: 3.3-27.2) and 16-fold (95% CI: 6.7-36.5) increased incidence of arthropathy-related hospital admission and arthropathy diagnosis respectively. None in this cohort underwent surgery. Among participants with haemophilia born prior to 1984, the rates of arthropathy diagnosis and surgery of the index joints (knee, elbow, ankle) were increased twofold (95% CI: 1.0-3.2) and fivefold (95% CI: 1.7-17.8) respectively. Our data suggested a higher burden of arthropathy among individuals with mild haemophilia compared to the general population. Further research should investigate the need for targeted joint screening programmes among individuals with mild haemophilia.

Perceived confidence for injury self‑management increases for young men with mild haemophilia with the use of the mobile app HIRT?

Abstract Background: Young men with mild haemophilia have unique challenges pertaining to bleed management. They may not always identify musculoskeletal injury requiring medical attention as they do not bleed frequently, potentially resulting in significant health consequences. In response to these challenges, a team of clinicians, researchers and young men with mild haemophilia developed a self-assessment pathway which was converted into a mobile app. Aim: This study examined the influence of the mobile app, HIRT? (Hemophilia Injury Recognition Tool) on perceived injury self-management in young men with mild haemophilia in Canada. Methods: We used a mixed methods design. The quantitative data, through a self-report questionnaire, evaluated perceived injury self-management strategies and participant confidence levels. Non-parametric Wilcoxon signed-rank test and McNemar chi-square test were used to determine association between perceived self-management strategies when using and not using the app, with significant levels set at p<0.05. Qualitative data was created using interpretive description and inductive content analysis of recorded and transcribed interviews. Results: 12 young men, aged 18-35 years, participated. Perceived confidence levels significantly increased (p=0.004) with the use of the app. Five qualitative themes were identified: accessibility, credibility, the benefit of alarms, confidence and usefulness. Conclusion: This study provides promising evidence to support the feasibility and use of HIRT? as an injury self-management tool for young men with mild haemophilia. Future research should prospectively investigate the effect of the app on injury selfmanagement confidence.

Cross-reacting Material-positive Hemophilia A Diagnosed in a Patient with a Spontaneous Thigh Hemorrhage

A 53-year-old man, who had been diagnosed with mild hemophilia A (HA) at 35 years of age, was hospitalized with a thigh hematoma. His bleeding continued despite the administration of recombinant factor VIII (FVIII). The results of an FVIII/von Willebrand factor binding assay were normal. The patient's FVIII coagulant activity (FVIII:C) was low, but his FVIII antigen levels were within the normal limits, suggesting FVIII protein dysfunction. The FVIII:C measurements obtained by one-stage clotting and chromogenic assays were different. An FVIII gene analysis revealed a missense mutation p.Ser308Leu, which is rare in Japan. This case highlights that gene analyses and chromogenic assays are necessary to interpret the discrepancies between FVIII:C and the bleeding phenotype of patients with mild HA.

Calidad de vida en una población con hemofilia: estudio de corte transversal en un centro de tratamiento de hemofilia

IntroductionIn patients with haemophilia, quality of life can be affected by factors like arthropathy, age, and pain intensity. ObjectiveTo evaluate the health-related quality of life in patients with haemophilia in Medellin during 2014. Patients and methodsAn observational, descriptive, cross-sectional study was conducted on 60 patients with confirmed diagnosis of haemophilia. Demographic, clinical and lifestyle characteristics are described. Functional test were performed including measuring ranges of mobility and the six-minute walk test. The health-related quality of life (SF-36 and KIDSCREEN-27), disability (WHODAS II), pain (VAS), and depressive symptoms (PHQ-9) were also evaluated. ResultsA total of 59 patients agreed to participate in the study. The mean age was 28 years (SD±14.8), with mild haemophilia in 5%, moderate haemophilia in 20.3%, and severe haemophilia in 74.5%. Almost all (96.6%) of the patients were under treatment with prophylaxis, and 84% of the patients were having physiotherapy. The main comorbidity was haemophilic arthropathy in 71% of cases, followed by dyslipidaemia (27%), overweight (20%), and smoking (11.8%). The six-minute walk test reported mean distance of 584.2 metres, and the SF-36 scores were similar to the general population. ConclusionThis group of patients with haemophilia reported a quality of life as high as the general population in Colombia without haemophilia. This finding reiterated the importance of the treatment with prophylaxis and the active participation of patients in a rehabilitation program, which promotes functional independence and a healthy lifestyle.

Factors Associated with Toothache in Patients Affected by Hereditary Coagulopathies

Objective: To determine a probabilistic model that represents the likelihood of the event Dental Pain to occur in Brazilians patients affected by hereditary coagulopathies. Material and Methods: In this cross-sectional study, information on use and access to dental services, oral morbidity, self-perceived oral health and behavioral health habits were obtained through semi-structured questionnaire and analyzed by means of logistic regression. Results: High prevalence of dental caries was observed for children aged 1-5 years (50%) and for adolescents aged 13-19 years (66%). Cumulative pattern of dental caries in the age groups of 20-35 years and 36-59 years was observed. Most patients did not report pain in the last six months prior to the survey (24.5%). It was observed that searching for dental care for the last time in case of localized pain (OR=26.7), for feeling uncomfortable when brushing teeth (OR=7.3) and difficulty searching for health professionals, not only the dentist (OR 3.7) was considered risk factors for the determination of Dental Pain diagnosis. However, if the patient has mild hemophilia A (OR=0.21), this likelihood decreases, being thus a protective factor. Conclusion: Patients affected by hereditary coagulopathies have high prevalence of caries, indicating the cumulative nature of this disease, which suggests the symptomatic effect of Dental Pain.

Chromogenic Factor VIII Assays for Improved Diagnosis of Hemophilia A.

Hemophilia A is an inherited bleeding disorder caused by a reduced level of factor VIII coagulant activity (FVIII:C) in blood. Bleeding episodes may occur spontaneously in the severe form of hemophilia or after trauma in the milder forms. It is important that patients are diagnosed correctly, which includes placing them into the correct severity category of the disorder so that appropriate treatment can be given. Diagnosis is made by determination of the amount of FVIII:C in the blood, usually using a one-stage factor VIII:C assay. However, approximately one third of patients with mild or moderate hemophilia will have much lower results by the chromogenic assay, with some of them having normal results by the one-stage assay. The chromogenic factor VIII assay is used in some specialized hemophilia reference centers and is recommended for the diagnosis of mild hemophilia A, as this assay is considered to better reflect the severity status of hemophilia patients than the one-stage assay.

Quality of life in a population with haemophilia: A cross-sectional study from a single haemophilia treatment center

Abstract Introduction In patients with haemophilia, quality of life can be affected by factors like arthropathy, age, and pain intensity. Objective To evaluate the health-related quality of life in patients with haemophilia in Medellin during 2014. Patients and methods An observational, descriptive, cross-sectional study was conducted on 60 patients with confirmed diagnosis of haemophilia. Demographic, clinical and lifestyle characteristics are described. Functional test were performed including measuring ranges of mobility and the six-minute walk test. The health-related quality of life (SF-36 and KIDSCREEN-27), disability (WHODAS II), pain (VAS), and depressive symptoms (PHQ-9) were also evaluated. Results A total of 59 patients agreed to participate in the study. The mean age was 28 years (SD ±14.8), with mild haemophilia in 5%, moderate haemophilia in 20.3%, and severe haemophilia in 74.5%. Almost all (96.6%) of the patients were under treatment with prophylaxis, and 84% of the patients were having physiotherapy. The main comorbidity was haemophilic arthropathy in 71% of cases, followed by dyslipidaemia (27%), overweight (20%), and smoking (11.8%). The six-minute walk test reported mean distance of 584.2 m, and the SF-36 scores were similar to the general population. Conclusion This group of patients with haemophilia reported a quality of life as high as the general population in Colombia without haemophilia. This finding reiterated the importance of the treatment with prophylaxis and the active participation of patients in a rehabilitation program, which promotes functional independence and a healthy lifestyle.

Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B

BackgroundHaemophilia B is caused by genetic aberrations in the F9 gene. The majority of these are non-synonymous mutations that alter the primary structure of blood coagulation factor IX (FIX). However,...

Diagnosing von Willebrand disease: genetic analysis.

Investigation of a patient with possible von Willebrand disease (VWD) includes a range of phenotypic analyses. Often, this is sufficient to discern disease type, and this will suggest relevant treatment. However, for some patients, phenotypic analysis does not sufficiently explain the patient's disorder, and for this group, genetic analysis can aid diagnosis of disease type. Polymerase chain reaction and Sanger sequencing have been mainstays of genetic analysis for several years. More recently, next-generation sequencing has become available, with the advantage that several genes can be simultaneously analyzed where necessary, eg, for discrimination of possible type 2N VWD or mild hemophilia A. Additionally, several techniques can now identify deletions/duplications of an exon or more that result in VWD including multiplex ligation-dependent probe amplification and microarray analysis. Algorithms based on next-generation sequencing data can also identify missing or duplicated regions. These newer techniques enable causative von Willebrand factor defects to be identified in more patients than previously, aiding in a specific VWD diagnosis. Genetic analysis can also be helpful in the discrimination between type 2B and platelet-type VWD and in prenatal diagnosis for families with type 3.

Patient Reported Outcomes to Assess Quality of Hemophilia Care in North India - Results of a Global Partnership

Deficiency of clotting factors VIII (Hemophilia A) and IX (Hemophilia B) represent one of the most debilitating inherited groups of bleeding disorders. According to the most recent survey report from the World Hemophilia Federation, an estimated 178,500 patients suffer from hemophilia globally (143,000 Hemophilia A, 28,000 with Hemophilia B approximately). By most recent estimates from 2014 India has surpassed every country in the global database with a total of 17,470 patients with hemophilia ahead of USA with its 17,131 reported cases. Infectious disease and perinatal mortality take precedence for resource allocation in evolving economies like India, presenting an ongoing challenge for "rare" diseases like hemophilia.This study assesses the quality of hemophilia care at the SMS Medical School which is the flagship medical care center in the northwestern Indian city of Jaipur, the capital of the largest Indian state with an area of 0.34 million square kilometers and population of 68.55 million. Since the introduction of the free factor distribution in the fall of 2012, the program grew from a modest patient population size of 60 patients to a robust 700 plus patients within 4 years aided by the World Hemophilia Twinning program grant. A standardized self-administered questionnaire was administered to all the hemophilia patients seen at the outpatient comprehensive hemophilia program (CHP) at the SMS Medical College between February 1, 2016 and May 5, 2016.Two hundred patients met the inclusion criteria and participated in the study. One hundred eighty-seven (94%) and 13 (6) patients were diagnosed with hemophilia A and B respectively; 126 (63) had severe disease while 65 (33) had moderate and 9 (5) had mild hemophilia. In an expected male predominant sample (n=198 males [99.5]), the median age at the time of study was 12 years (range=1-53 years), and 144 (72) patients were from rural outskirts of the resource poor state visiting the tertiary care center for hemophilia care. Contrary to popular belief, only a minority 11% and 1% of patients identified themselves of the Muslim and Sindhi faith respectively, versus a majority 87% who followed Hinduism. Tenets of consanguinity and family size have often led to misunderstanding and stigmatization of the disease in the Asian subcontinent prior to this study thus far. Despite a majority 63% patients suffering from severe hemophilia, nearly half (44%) reported a delay of more than 6 months in diagnosis time from the first bleed. Remarkably, 96 % reported to know their diagnosis fully and 93% reported understanding that hemophilia is a genetically transmitted disorder but approximately 82.5 % did not know if they ever underwent testing for viral infections (H.I.V, Hepatitis B, C ) since their diagnosis . Nearly 45 % were offered genetic counseling services at some point during their care, a remarkable feat for a hemophilia program in a resource strapped environment. Inpatient stay for bleeds and complications in this predominantly severe mix of patients was encouragingly less than 1-5 days in 93% of the patients but despite free drug delivery program 79% families reported an out of pocket expense of more than 10,000 Indian rupees (INR; approximately 147 USD) during the hospital stay. This in a state where 65% of patients reported per capital household income less than 100,000 INR (1,485 USD) was particularly concerning. Nearly 18 % of the respondents identified themselves as below poverty (BPL) and enjoyed the benefits of free transportation under the governmental subsidies through a BPL card. Household income and below poverty status were not associated with hemophilia care outcomes (p-values <0.1).Reported favorable patient satisfaction (86%) and continued access to free factor infusion services irrespective of socio economic status as demonstrated by this study, for a resource limited setting caring for over 600 hemophilia patients should be considered a success. New epidemiologic insights from this study will help researchers and clinicians alike to design care delivery models for hemophilia. Not only does this study reflect the power of international collaborations in remarkably improving services for such ignored debilitating diseases in the resource limited nations but also presents as a unique first quality assessment tool for the nation with the largest number of identified hemophilia patients in the world. DisclosuresParnes:Pfizer: Consultancy; Baxalta: Research Funding. Neufeld:Pfizer: Consultancy; baxalta: Consultancy, Research Funding.

Hemophilia Joint Health Score Poorly Predicts the Need for Musculoskeletal Referrals in Routine Clinical Practice

IntroductionEarly detection of joint problems and musculoskeletal (MSK) abnormities is a priority in hemophilia care worldwide; however, there is no standard approach to screening. The World Haemophilia Federation Hemophilia Joint Health Score (HJHS) is well validated but requires time-intensive evaluation by a MSK expert (e.g. physical therapist, PT). Joint screening popularized for the US Center for Disease Control Universal Data Collection (UDC) focuses on range of motion (ROM) assessment only but is quick and easy to implement with modest staff training of non-experts. The approach used at our center, here dubbed UDC-plus, combines ROM measurements with pain and functional evaluation. In 2012 our center found that HJHS was sensitive but non-specific (high false positive rate) and correlated poorly with need for MSK referral or imaging [Morrison et al, Haemophilia, 18 suppl. 3 p.120]. The aim of this study was to evaluate the utility of using HJHS in clinical practice to predict need for MSK referral within 5 years of initial assessment. We also evaluated the ability of UDC-plus to predict actionable MSK findings at 5 years.MethodsThis is a single center, retrospective, observational study. Patients diagnosed with hemophilia A or B of any severity, a HJHS assessment between 2009 and 2011 and a PT evaluation 5 years later (between 2014-2016) during annual comprehensive visits at Boston Children's Hospital were eligible for the study. HJHS includes evaluation of 6 joints (elbows, knees, ankles) with score range from 0 to 124 points, considered positive if greater than 0. UDC-plus score includes the same joints with score range from 0 to 3, considered positive when 2 or greater. Outcomes included need for MSK-related referral during the 5-year observation period. Clinical and demographic characteristics were summarized using descriptive statistics; logistic regression was used to determine whether baseline joint scores were prognostic of referral. Sensitivity and specificity of joint scores were calculated.ResultsSeventy-one male patients met inclusion. Median observation time was 5.7 years (range: 3.2-6.8); median baseline age was 10.3y (3-21). Thirty-six (51%) had severe, 8 (11%) moderate and 27 (38%) mild hemophilia; 92% of severe and 25% of moderate patients were on regular prophylaxis. Nine (13%) patients had at least one TJ, reflecting that even for young patients in the prophylaxis era (after 1996 at our center), TJs are not eliminated. An abnormal score was found in 47 (66%) patients; only 6 (13%) of them required referral for PT, orthopedic or radiologic assessments. Of patients with abnormal baseline HJHS without initial MSK referral, 17/41 (42%) required at least one referral by 5 years while only 4/41 (10%) had an MSK concern at the 5-year comprehensive visit (other concerns were transient). Of patients with a normal baseline HJHS, 11/24 (46%) required at least one referral by 5 years and 3/24 (12.5%) required a referral at 5 years. Baseline HJHS was not prognostic of need for referral at 5 years, Table 1. An abnormal UDC-plus score occurred at baseline in 38 (54%) patients, 6 of whom (16%) received a referral. The sensitivity and specificity for the UDC-plus score were slightly less sensitive but more specific than HJHS.ConclusionWhile high sensitivity of HJHS makes it useful in a research setting, the time requirement by an expert PT and its poor correlation with need for either acute or long-term clinical intervention (low specificity) render it less desirable for screening in routine hemophilia care. UDC-plus, has modest sensitivity for acute and 5-year referral prediction, but is correspondingly more specific. Hemophilia comprehensive clinics require a basic joint assessment, which is neither time- nor resource-intensive. These data suggest HJHS does not meet this need; however, a more concise examination focusing on ROM of key joints, pain and functional status may be an important foundation. The UDC-plus with revised scoring criteria may support routine integration into hemophilia care without compromising clinic flow or costs. [Display omitted] DisclosuresNeufeld:Novartis: Consultancy.

Impact of Mild to Severe Hemophilia B on Quality of Life Including Pain and Functional Abilities in Affected Men/Women and Caregivers of Affected Boys/Girls: Analysis of Patient Reported Outcomes in the Bridging Hemophilia B Experiences Results and Opportunities into Solutions (B-HERO-S) Study

Introduction: Health-related quality-of-life (HRQoL) is impaired in patients with severe congenital hemophilia due to pain and functional impairment associated with hemophilic arthropathy. The impact of mild or moderate hemophilia on HRQoL and on women with hemophilia in particular is less well characterized. Use of standardized instruments for assessment of pain/depression/anxiety also remains uncommon in patients with hemophilia.Objective: B-HERO-S was designed to characterize factors that affect HRQoL in adult patients with hemophilia B (PWH) and caregivers (CG) of affected children (CWH).Methods:US PWH (either gender, age ≥18 years) and CG (age >18 years) of CWH (either gender, age <18 years) were recruited through 3 patient organizations to complete distinct (PWH/CG) ~1 hour internet-based, IRB-approved surveys. In addition to descriptive surveys, adults completed 4 standardized patient reported outcome (PRO) instruments (EQ5D-5L with VAS [0–100 scale] and calculated index [-0.11–1.00], brief pain inventory [BPI SFv2, 0–10 scale], PHQ9 [0–27 score], and international physical activity questionnaire [IPAQ, low/moderate/high category]); and one disease-specific PRO (hemophilia activities list [HAL, 0–100 score for domains]). Caregivers completed 2 standardized PROs for depression and anxiety (PHQ9, GAD7 [0–21 score]).Results PWH: 213 men and 86 women responded to the survey. Median age of participants was 29 years (range 18–70 years). Severity was self-reported as mild/moderate/severe/inhibitor (74/189/32/4). Comorbidities associated with hemophilia were arthritis (48%), osteoporosis/fractures (43%/11%), pain (acute/chronic: 29%/13%), anxiety (23%), and depression (22%). Most were educated past high school (87%), employed (81%), and married/in a long-term relationship (54%). Despite the preponderance of mild/moderate PWH, most PWH had some pain (EQ5D-5L) and nearly all had problems with usual activities, anxiety/depression, mobility, and self-care (Table 1). PWH reported moderate pain severity/interference (median 5/5); higher scores were observed for women (7/7), PWH with moderate hemophilia (6/7), and those on routine infusions (6/6). Based upon PHQ9, at least mild depression was observed in >75% of the PWH respondents and more often in moderate and severe PWH. More women than men had depression, and those treated with routine infusions reported higher depression scores than those treated on demand. While 94% reported some physical activity, two-thirds were categorized as moderate or high activity; unexpectedly, there were more mild PWH reporting low activity and more severe PWH categorized as high. There were no apparent differences in upper and lower extremity functional ability (HAL) domains or composite scores across hemophilia severity or by gender; PWH on routine infusions had worse scores than those treated on demand.Results CG:150 CG participants, all parents, included fathers/mothers (34/116) with median age 35 years (range 21–53 years) describing their oldest children <18 years (boys/girls: 121/29; median age 10 years, range <1–18 years), with mild/moderate/severe/inhibitor (27/84/33/6). Most CG were educated past high school (86%), employed (86%), and married/in a long-term relationship (89%). Based on PHQ9 results, more than half of CG reported at least mild depression; just under half reported mild anxiety according to the GAD7 scores (Table 2). Compared with the PWH results, the differences in depression and anxiety were much more pronounced in CG of children with moderate hemophilia and in mothers. CG of CWH treated with routine infusions vs. on demand reported more depression and anxiety.Limitations: Voluntary response bias may limit generalizability of these findings as PWH/CG with greater impact may have been more likely to participate.Conclusions: These findings indicate that pain, functional impairment, and depression/anxiety may contribute to the impact of hemophilia B on education, work, activity, and relationships described in prior reports from B-HERO-S. This is the first study to examine HRQoL in PWH of both genders and CG of affected CWH with mild-to-severe hemophilia B using multiple PRO instruments. These results suggest unmet needs particularly in mild/moderate PWH and women. Comparisons between known groups and analysis of HRQoL predictors are underway. [Display omitted] [Display omitted] DisclosuresBuckner:Genentech: Consultancy; Novo Nordisk: Consultancy; Baxalta: Consultancy. Witkop:Novo Nordisk: Consultancy, Other: Advisory Boards, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; BioEmergent: Consultancy, Speakers Bureau; Baxalta: Consultancy. Guelcher:Novo Nordisk: Other: Advisory Boards, Speakers Bureau; Biogen Idec: Other: Advisory Boards; Baxter/Baxalta: Other: Advisory Boards, Speakers Bureau; Octapharma: Other: Advisory Boards; Grifols: Other: Advisory Boards; Solution Sight: Speakers Bureau. Sidonio:Biogen: Honoraria, Research Funding; CSL Behring: Honoraria; Baxalta: Honoraria, Research Funding; Novo Nordisk: Honoraria; Pfizer: Honoraria; Emergent Solutions: Honoraria. Walsh:Novo Nordisk: Consultancy; Baxalta: Consultancy; Bayer: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy. Kessler:Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; Pfizer: Consultancy; LFB: Other: Member of DSMB; Baxalta: Consultancy, Research Funding. Owens:Haplomics Inc.: Consultancy, Equity Ownership. Iyer:Novo Nordisk: Employment. Cooper:Novo Nordisk: Employment.

Modelling FVIII Levels for Prediction of Zero Spontaneous-Joint Bleeding in a Cohort of Severe Hemophilia a Subjects with Target Joints Initiated on Tertiary Prophylaxis

BackgroundProphylaxis is increasingly the standard of care for adults with severe hemophilia A (SHA), however the optimal dose and treatment regimen when initiating tertiary prophylaxis is unknown. The relationship between factor level and risk of bleeding is not established, particularly in patients with joint disease. A post hoc analysis was conducted on a cohort of adult SHA patients who switched to prophylaxis from on demand therapy.MethodsThe cohort included 63 subjects with measured factor VIII (FVIII) levels of <1 IU/dL, aged 7 to 59 years, receiving on-demand treatment and with a minimum of eight joint hemorrhages in the 12 months prior to enrollment. After 6 months observation of on demand treatment and a full pharmacokinetic (PK) analysis, subjects were randomized to 12 months of either standard prophylaxis (20-40 IU kg−1 every 2nd day) or PK-tailored prophylaxis (20-80 IU kg−1 every 3rd day) targeting FVIII trough levels ≥1 IU/dL.Subjects had a median age of 28 years, and median weight of 71Kg. At study start, 95.2% of subjects had ≥1 target joints (median 3). During on demand treatment before randomization, the median number of spontaneous-joint bleeds was 29.9/year (range: 0 to 91.3). During prophylaxis, the median number of spontaneous-joint bleeds was 0/year (range: 0 to 10.2) in the combined prophylaxis groups.A PK model was fitted to the FVIII activity levels collected during the PK analysis for each subject independently. These individual models were used to predict the FVIII activity level at the time of bleed on the assumption of linear pharmacokinetics and no inter-occasion variability. For each subject the highest FVIII activity level associated with a spontaneous-joint bleeding event was considered as the minimally effective level to prevent spontaneous-joint bleeds. A Kaplan-Meier estimate for the proportion of subjects with no spontaneous-joint bleeds above FVIII activity level was carried out. For subjects who had no spontaneous-joint bleeding events an assumption was made that they would have bled only at 0 IU/dL, even in situations where the trough levels may have been higher.ResultsThe Kaplan-Meier curve for proportion of the cohort without spontaneous-joint bleeds as function of predicted FVIII level is presented in Figure 1. The corresponding estimates are presented in Table 1. Based on this analysis in this cohort, the majority of patients (63%) would not be expected to have spontaneous-joint bleeds while maintaining a trough level of 1 IU/dL with more marginal improvements in response to higher FVIII levels. These results indicate that, in subjects with multiple target joints starting tertiary prophylaxis, most experience no spontaneous-joint bleeds for a predicted FVIII level ≥1 IU/dL, however, bleeds occurred at much higher predicted FVIII levels in some subjects. This is within the range of FVIII levels associated with hemophilia (0-40%) (White GC, et al. Thromb Haemost. 2001 Mar; 85(3):560).ConclusionThe results of the model and the present post-hoc analysis support current trends to personalize prophylaxis based on individual variations in bleeding phenotypes, despite similar FVIII levels. To prevent all spontaneous-joint bleeds, some patients may require higher levels, findings which are congruent with those published on the natural history of joint bleeding in mild, moderate, and severe hemophilia patients (Den Uijl IE et al. Haemophilia. 2011;17(6):849-853). [Display omitted] [Display omitted] DisclosuresFischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Chowdary:Sobi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria; Bayer: Honoraria. Collins:NovoNordisk: Consultancy; Sobi: Consultancy; CSL Behring: Consultancy, Research Funding; Shire: Consultancy, Speakers Bureau. Cotterill:Shire: Employment. Pipe:UniQure: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; Biogen: Consultancy; CSL Behring: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy, Other: Grant funding. Wolfsegger:Shire: Employment, Equity Ownership. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Goldstine:Shire: Employment. Valentino:Shire: Employment. Spotts:Shire: Employment.

Factor XIII Contributes to Clot Formation and Thrombin Generation

BackgroundFactor XIII (FXIII) stabilizes fibrin clots, minimizing the amount of thrombin generation required to stop bleeding. It also has a long half-life (>7 days) and supratherapeutic levels are not associated with thrombosis making it an attractive therapeutic agent to augment factor replacement in hemophilia. FXIII is a transglutaminase that cross-links fibrin and localizes alpha 2-antiplasmin to fibrin inhibiting fibrinolysis. It also interacts with numerous other proteins, most of which have not been well studied and their physiologic significance is unknown. FXIII is classically considered to be activated by thrombin, which may limit its utility in low thrombin states such as hemophilia. However, activation also occurs physiologically through other mechanisms including calpain, neutrophil elastase and calcium influx. In addition, low levels of thrombin are generated by Factor Xa in the absence of the Factor VIII (FVIII)/Factor IX (FIX) complex that may contribute to both FXIII activation and clot formation. Thus, it is not clear if thrombin generated through the participation of FVIII and FIX is necessary for FXIII activation.HypothesisWe hypothesize that FXIII (recombinant FXIII-A2) may contribute to both clot formation and thrombin generation in hemophilia.MethodsAnimal models include Exon 16-deleted FVIII-deficient mice (FVIII-KO), wild-type mice (WT), and exon 16-deleted Factor VIII deficient/GP1bα-FVIII knock-in mice (PF). The PF mice are FVIII-deficient mice expressing human FVIII driven from the glycoprotein 1bα promoter resulting in approximately 3% circulating FVIII.Various combinations of factors were given via tail-vein injection. Citrated blood was collected by cardiac puncture 1.5 - 4 hours post-injection, depending on the factor type. Clotting was characterized using thromboelastography (TEG). Thrombin generation was measured on a fluorescence reader using a reagent comprised of a low concentration of phospholipid micelles containing tissue factor in HEPES buffer.ResultsTEG characterization shows differences in clotting times (R), speed of clot formation (K), and the kinetics of the formation of the clot (α angle) between the various groups without changes in overall clot stability (MA) or degree of fibrinolysis (LY30). R, K, and α angle are all measurements of clot formation, with prolongation of R and K and reduced α angle characteristic of hemophilia. PF mice have similar R, K, and α angle compared to FVIII-KO (p = 0.5, 0.68, and 0.89, respectively), and elongated R and K, and reduced α angle compared to WT (p = 4.0E-3, 2.0E-3, and 1.37E-6, respectively). Giving supratherapeutic FXIII to PF mice results in normalization of these values compared to WT, with a trend towards elongated K and α angle (p = 0.21, 0.08, and 0.13, respectively), and differences compared to FVIII-KO (p = 8.1E-3, 7.4E-3, and 2.1E-3, respectively). Administering FXIII to FVIII-KO mice did not alter R, K, and α angle compared to untreated FVIII-KO mice (p = 0.25, 0.37, and 0.67, respectively).PF mice have similar peak thrombin generation compared to FVIII-KO (p = 0.56) and reduced peak thrombin generation compared to WT (p = 6.69E-5). Giving supratherapeutic FXIII to the PF mice results in peak thrombin generation similar to that of WT (p = 0.97). In contrast, giving supratherapeutic FXIII to FVIII-KO mice did not alter peak thrombin generation levels compared to untreated FVIII-KO mice (p = 0.72). The administration of a cocktail containing both FVIII (2.5 U/kg) and FXIII resulted in a trend for improved peak thrombin generation when compared to an injection of FVIII alone (p = 0.12).ConclusionsThe function of FXIII has classically been considered to be secondary to its transglutaminase activity. With a direct impact on early clot formation and thrombin generation, these data suggest that FXIII has other roles beyond its known activities. The implication of these findings is that FXIII may be an effective hemostatic agent in mild and moderate hemophilia. DisclosuresTaylor:Novo Nordisk: Research Funding; Kedrion: Research Funding; Baxalta/Shire: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding.