Moderate Hemophilia A Research Articles

Real-World Use of Emicizumab in Patients with Hemophilia with and without Inhibitors

Introduction Emicizumab is a recombinant humanized monoclonal antibody that bridges factor IXa and Factor Xa and is administered via subcutaneous injection. After initial FDA approval for patients with hemophilia A (HA) and inhibitors, it was approved in October 2018 for prophylaxis in patients with HA without inhibitors of all ages. In clinical trials of subjects without inhibitors, emicizumab was studied only in those >12 years of age. The primary objective of this study was to report our "real-world", post-licensure experience with emicizumab across a more heterogenous patient population, comparing annualized bleeding rates prior to and after initiating emicizumab. Secondary objectives included evaluating for serious adverse events including death, thrombosis or drug discontinuation. Methods We conducted a multi-center observational study at 3 federally funded Hemophilia Treatment Centers: Children's Hospital of Philadelphia, Virginia Commonwealth University and Children's National Health System. Inclusion criteria included patients with HA initiated on emicizumab prior to May 15th 2019. Data extraction included: demographics, diagnosis, prior HA history (inhibitor, prophylaxis treatment regimen), emicizumab dosing data, bleeding events (all bleeds, treated bleeds, joint bleeds, traumatic bleeds) and thrombotic events from the 6 months prior to emicizumab until July 15th 2019. Annualized bleeding rates (ABR) were calculated to account for variable follow up. Wilcoxon Sign-Rank Difference Test was used to test the difference in number of bleeds and McNemar's test was used to test the difference in proportions of patients with ABR=0. Results Ninety-two patients met inclusion criteria: 89 male and 89 with severe HA (3 moderate HA) (Table 1). Age at initiation of emicizumab ranged from 5 weeks to 55 years; median 8.6 yrs (IQR 4.8-13.5 yrs). Nineteen patients had an active inhibitor at the time of starting emicizumab; the remaining 73 did not have an inhibitor, and most (86%) were on prophylaxis prior to emicizumab. Sixty-two patients were < 12 years of age (13 with inhibitors). Median duration of emicizumab therapy was 48 weeks (inhibitors) and 22 weeks (non-inhibitors), with a total follow up of 53.3 patient years. In patients with inhibitors, the ABR (treated bleeds) prior to emicizumab was 6.2 events (95% CI, 0.98 to 11.4) compared to 0.3 events (95% CI, 0 to 0.73) on emicizumab, p=0.002. In subjects without inhibitors, the ABR prior to emicizumab was 1.8 events (95% CI, 0.66 to 2.96) compared to 0.22 events (95% CI, 0.05 to 0.39) on emicizumab, p<0.001. Additional data on bleeding events is provided in Table 1. The proportion of patients with ABR=0 increased in both inhibitor (from 46% to 74%, p=0.06) and non-inhibitor subjects (from 60 to 78%, p=0.015). All patients received 1.5 mg/kg weekly x 4 loading doses, followed by either weekly (27%), every other week (70%), or monthly (3%) dosing; patients with inhibitors were more likely to receive weekly dosing. No patients who initiated emicizumab discontinued the drug or developed a neutralizing antibody to FVIII or emicizumab, although patients have not been consistently screened for these antibodies. No thrombotic or thrombotic microangiopathy events or death have occurred. Conclusions Our favorable clinical experience with emicizumab post-licensure in patients with HA is similar to that reported in the clinical trials. Although excluded from the clinical trials, patients with HA without inhibitors < 12 years accounted for the majority (67%) of our cohort. As anticipated, these younger patients appear to experience the same benefit as patients > 12. No serious drug-related adverse events were reported, although the overall study period is relatively short. Ongoing follow up of these patients, and others, will be important to assess the ongoing safety and efficacy profile of this novel therapy. Updated data on this cohort will be presented at the ASH meeting Disclosures Guelcher: NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board; Takeda: Other: Advisory Board; Genetech: Other: Advisory Board. Butler:pfizer: Other: Advisory board; Hema-Biologics: Consultancy; genetech: Other: Advisory board. Guerrera:Genetech: Other: Advisory Board; Kendrion: Other: Advisory Board; Shire: Other: Advisory Board; Bayer: Other: Advisory Board; Bioverativ: Consultancy; Pfizer: Other: Advisory Board; Novo Nordisk: Consultancy. Raffini:Roche: Other: Advisory Board; Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board.

Current dosing practices for perioperative factor VIII concentrate treatment in mild haemophilia A patients result in FVIII levels above target.

In patients with haemophilia A (HA) perioperative dosing of factor VIII (FVIII) concentrate is based on body weight, historical FVIII level, in vivo recovery and FVIII level target values. In moderate and severe HA patients, this dosing regimen frequently leads to perioperative FVIII levels below and above target. This has not yet been evaluated in mild HA patients. To evaluate perioperative FVIII concentrate treatment in mild HA patients and to assess the frequency of FVIII levels below or above target. This retrospective single-centre study collected data from medical files of mild HA patients undergoing surgery and treated with FVIII concentrate. FVIII levels were compared to their target ranges and predictive factors for levels outside the target ranges were determined by logistic regression. Fifty surgeries performed in 34 patients were evaluated. Median age was 47years and median historical FVIII level was 0.14IU/mL. Preoperative peak FVIII level was above or below the target range in 80% and 6.7% of surgeries, respectively. Postoperatively, the percentages above and below target trough ranges were 55.8% and 12.8%. Patients with blood group 0 had the highest risk on the preoperative peak FVIII level being above target. In addition, patients who had a preoperative baseline FVIII level of >0.10IU/mL higher than their historical FVIII level had a higher preoperative peak FVIII level than patients without this increase. Dosing above FVIII target ranges with FVIII concentrates occurs frequently during perioperative treatment of mild HA patients. These results underline the necessity for better patient-tailored treatment.

Bayesian pharmacokinetic-guided prophylaxis with recombinant factor VIII in severe or moderate haemophilia A

IntroductionPersonalised pharmacokinetics (PK) using Bayesian analysis with limited sampling is assumed to help to optimise prophylaxis in haemophilia A (HA) patients. Materials and methodsOur prospective, observational study analysed the influence of PK parameters on clinical variables (bleeding rates, joint status, adherence, and consumption) using myPKFiT® in a cohort of twenty-one severe and moderate HA patients on prophylaxis with recombinant FVIII (Advate®) in two periods of one year, the first before PK-based tailoring and the second after PK-guided prophylaxis. Intra-individual and inter-individual coefficients of variation (CV) of half-life (t1/2) were calculated. ResultsA total of 73 PK estimations were performed in both periods, resulting in 17.2% inter-individual CV in mean t1/2, and 4.9% intra-individual CV. Before PK-based tailoring a significant association between joint bleeds and t1/2 was found (P = 0.010), especially in patients with short t1/2. This finding was reproduced (P = 0.013) after withdrawal of two patients with bleeding phenotype related to their advanced arthropathy but normal t1/2 and trough levels. Patients with joint bleeds weighed less (P = 0.039) and required higher doses (P = 0.032) than patients with zero joint bleeds. These associations were not observed in the second period after the adoption of PK-guided prophylaxis. There were no differences between the two periods, although a tendency to fewer spontaneous bleeds was suggested after PK-based tailoring. ConclusionsPK-guided prophylaxis facilitates an adequate level of bleeding control in patients with HA, maintaining clinical variables and patient convenience in an integrative manner, without increasing FVIII consumption.

Understanding Disease Burden Among Persons with Hemophilia Α without Inhibitors

Abstract Introduction Previous studies have reported significant disease burden in persons with hemophilia A (PwHA) who develop inhibitors to factor VIII. However, disease burden in PwHA without inhibitors (PwHA-WO) is not well understood across severities. The CHOICE Project was conducted in partnership between the US Centers for Disease Control and Prevention and the Hemophilia Federation of America to survey persons with bleeding disorders of varying severity, male and female, in the US. Participants in the CHOICE Project included both patients receiving care at federally funded hemophilia treatment centers (HTC) and those who do not receive care at HTCs. The objective of the study was to assess and characterize self-reported clinical outcomes, care, and quality of life (QoL) of PwHA-WO across all disease severities. Methods A retrospective analysis was conducted of data collected through the CHOICE Project, a cross-sectional survey, from April 2013 to July 2015. Adults (≥18 years) and caregivers of children with hemophilia A (HA) were recruited to take the 20-minute CHOICE survey, online or on paper, in English or Spanish. The overall response rate to survey questions was approximately 87%, but it varied by survey item, as participants could opt not to respond to certain questions. PwHA-WO were defined as HA persons that reported no current or past factor VIII inhibitors. In this analysis, self-reported demographics, bleed- and joint-related outcomes, treatment, and QoL among PwHA-WO were descriptively analyzed by self-reported disease severity. Results Of the total 429 PwHA surveyed, 328 (76%) reported no current or past inhibitors (PwHA-WO). The majority of PwHA-WO were adults (59%), males (80%), non-Hispanic (76%), or white (63%) and had commercial insurance (68%). More than a quarter reported depression or anxiety, while 13% and 23% reported diagnosis of human immunodeficiency virus and hepatitis C, respectively. Most patients reported seeking care from a hematologist (96%) or at an HTC (63%). Among PwHA-WO, a higher proportion reported having severe HA (severe, 63%; moderate, 15%; mild, 22%). Overall, 94% of PwHA-WO reported they had ever experienced a bleed (severe, 96%; moderate, 96%; mild, 88%; p=0.42), and more than 85% reported they had ever had a joint bleed (severe, 88%; moderate, 91%; mild, 72%; p=0.006). In the last 12 months, approximately 73% reported a joint bleed (severe, 76%; moderate, 78%; mild, 56%; p=0.025) and 65% reported a bleed in another location (severe, 70%; moderate, 62%; mild, 51%; p=0.17). About 15% and 22% of PwHA-WO reported a history of synovectomy (severe, 18%; moderate, 7%; mild, 11%; p=0.30) or joint replacement surgery (severe, 28%; moderate,19%; mild, 5%; p=0.015). Over 28% of PwHA-WO reported having joint problems such as pain, stiffness, and loss of motion "always" or "frequently" (severe, 32%; moderate, 29%; mild, 15%; p=0.23). About a quarter responded that these problems "always" or "frequently" limited their daily work/school, recreational, and/or self-care activities (severe, 29%; moderate, 24%; mild, 20%; p=0.46). On average, PwHA-WO reported 16 missed days from work, school, or usual activities due to their disease (severe, 12; moderate, 30; mild, 16; p=0.014). Nearly 66% of PwHA-WO reported using over-the-counter pain medication in the last 30 days (severe, 62%; moderate, 80%; mild, 67%; p=0.31) and over a third reported using prescription pain medication over the same period (severe, 44%; moderate, 30%; mild, 11%; p=0.01). Conclusions This study suggests that considerable clinical, emotional, and day-to-day disease burden exists in PwHA-WO, even among those with mild and moderate severity. Although joint bleed-related outcomes varied by severity, patients with moderate HA reported joint-related outcomes comparable to those with severe HA. However, limitation of daily activities did not differ by severity. PwHA-WO with mild, moderate and severe HA reported limitation in physical activities, which can impair their QoL. Better understanding of disease burden by severity among PwHA-WO will help in planning future interventions to address these burdens and improve health outcomes. Disclosures Owens: Divitius LLC: Employment; Genentech Inc.: Consultancy; HFA: Consultancy. Cyhaniuk:Independent Contractor: Consultancy; HFA: Employment; AC Analytical Solutions, LLC: Employment. Patel:Genentech Inc: Employment. Raimundo:Genentech Inc: Employment, Other: Ownership interests PLC. Chan:Hemophilia Federation of America: Employment. Ko:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC.

A Genotype-Phenotype Correlation of Haemophilia a in Victorian Patients with a Description of Novel Mutations

Aim:Hemophilia A (HA) is caused by abnormalities in the Factor VIII gene. Certain abnormalities correlate with disease severity. Here, we report the genotype-phenotype correlation for all Victorian HA patients.Methods:Using the Australian Bleeding Disorders Registry, Victorian HA patients were identified. All genetic testing was conducted at Southern Health. The testing algorithm is summarized in Figure 1.Mutations were compared with the list of known Factor 8 mutations on the Champ and EAHAD F8 Variant Databases. A PubMed search was undertaken for any mutations not on either database. If this too was unrevealing, the mutation was designated novel. In-silico analysis was conducted on all novel mutations using three open-access, online prediction tools: a) Mutation Taster; b) Poly-Phen 2; c) Human Splice Site Predictor.Results:318 patients with matched clinical and genetic records were identified. 275 had known FVIII mutations and 36 novel FVIII mutations were discovered. Eight patients (3%) had no mutations identified. (Table 1)In severe HA the intron-22 inversion was the most common mutation (47/122, 38%). Missense mutations predominated in mild and moderate HA. Inhibitors were present in 44/318 patients, the majority of whom had 26/44 (59%) severe HA.20/36 novel mutations (55%) were associated with severe HA, 12/36 (33%) with mild HA and 4/36 (11%) with a moderate HA. Novel mutations associated with non-severe phenotypes were mostly missense mutations (15/16); More diversity was seen in the novel mutations causing a severe HA with a fairly even distribution of mutations: missense (7/20), nonsense (4/20) and small deletions and insertions (8/20). One large deletion involving a 6.5kb region of exon 26, as well as one duplication of exons 7 to 9 - was seen in the severe group. In-silico analysis predicted that all novel severe HA mutations were likely to be pathogenic.Inhibitors were seen in 7 patients with novel mutations.Of the 36 novel mutations we described, 9/36 (25%) were seen in other family members - often female carriers. All 9 mutations caused a severe phenotype which is not unexpected given that the screening and testing of family members would be unlikely to take place in patients who have a mild phenotype and rarely require supportive medical careConclusion:This study adds 36 novel mutations to the currently known FVIII haemophilic mutations. It also confirms that the frequency and correlative clinical severity of known genetic mutations in the Victorian HA cohort is similar to that described internationally. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Successful of Immune Tolerance Induction (R-ITI) with Simoctocog Alfa (rhFVIII) in Hemophilia a Patients and High-Titer Inhibitors

Backgroud: The appearance of inhibitors (INH) is the most serious complication in hemophilia A (HA) patients. The primary objective is their eradication. Usually the primary ITI was performed with the same concentrate causing INH development, but which replacement factor to be use in case of ITI-R is still debatable. We report two successful cases of ITI-R with simoctocog alfa (rhFVIII) performed in two different Italian Hemophilia Centers, while three other cases are still ongoing. Case Report: Case-1: Adult man with moderate HA who developed INH after surgery and concomitant switch to another concentrate (octocog-alfa 2nd gen). The patient refused the ITI treatment immediately after the inhibitors appearance, and was then put on prophylaxis with bypassing agents for several months. First ITI was then started with pdFVIII/vWF at 200 IU/kg/day, inhibitor titer reached its historical peak (134 BU/ml) two months later and progressively decreased to 15 BU/ml, but without ever disappearing. This ITI was stopped after nineteen months. A second ITI was then tried with high dose regimen of morocotocog-alfa, but also in this case the mean INH titer remained steadily high (21 BU/ml) and this treatment was considered failed after fifteen months from the onset. A new ITI-R was then started when the INH titer was 74 BU/ml, with simoctoctocog-alfa (rhFVIII), at 200 IU/kg/day. INH progressively decreased and 7 months later disappeared ( Disclosures No relevant conflicts of interest to declare.

Antithrombotic Therapy Management in Patients with Inherited Bleeding Disorders and Ischaemic Heart Disease: A Single-Center Experience

Introduction: In the last decades, the life expectancy of patients with hemophilia A (HA), hemophilia B (HB) and von Willebrand disease (VWD) has substantially improved. As a result, these patients experience age-related comorbidities, especially ischaemic heart disease. Safety and efficacy of antiplatelet drugs in patients with inherited bleeding disorders remain unclear, while there is no evidence-based guideline for the antithrombotic management in this population. The aims of our study were to describe the management of patients with HA, HB and VWD at the occurrence of ischaemic heart disease in our regional referral center; to compare this management to experts' recommendations; and to evaluate the safety and the efficacy of antiplatelet drugs in this population.Methods: The source of population was the 2008-2018 cohort of patients with HA (n=565), HB (n=115) and VWD (n=618) followed at Toulouse University hospital (France). Their follow-up is recorded in electronic medical files. We retrospectively identified the patients who experienced an ischaemic heart disease treated by antiplatelet therapy. Ischaemic heart disease included ST- and non-ST-segment elevation acute myocardial infarction, stable and unstable angina, and silent coronary artery disease. We described the reperfusion therapy, the use of antiplatelet drugs and replacement factors, and the occurrence of bleeding or thrombotic complications during the follow-up.Results: Eight patients had an ischaemic heart disease: 5 HA, 1 HB and 2 VWD patients. Four of the haemophilic patients had minor hemophilia; the two others had moderate hemophilia. VWD patients were one type 1 (FVIII 26%, VWF:Ag 13%) and one type 2B (FVIII 29%, VWF:Ag 75%, VWF :Act 24%, low platelet count). Age at the time of the cardiac event ranged from 49 to 80 years. All patients were men except the patient with type 2B VWD. Cardiovascular risk factors were frequent (overweight, n=5; hypercholesterolemia, n=4; smoking, n=4). Four patients were investigated because of cardiac symptoms (unstable angina, angina, dyspnea, palpitations, n=1 each), and one patient because of family history. The last 3 patients were investigated as part of a screening program including patients with a high cardiovascular risk estimation.The initial management was as follows: 4 patients underwent a percutaneous coronary intervention (PCI) and 4 had a triple coronary artery bypass grafting (CABG). All patients treated with PCI had dual antiplatelet therapy for one month, then low-dose aspirin. CABG patients were initiated with low-dose aspirin. FVIII exposure was lower in PCI patients than in CABG patients (13 ± 10.42 versus 19 ± 9.35 cumulative exposure days to FVIII).Four patients were managed with differences from current guidelines1-3: first, the woman with type 2B VWD was treated with two drug-eluting stents whereas bare-metal stents are recommended. Dual antiplatelet therapy was then initiated but stopped at one month because of microcytic anemia. She was then treated with acid acetylsalicylic, 160mg per day instead of 75mg, and presented a severe gastrointestinal bleeding. Second, the patient with HB (FIX 34%) received no replacement therapy during PCI and no proton pump inhibitors while treated by antiplatelet drug, but he experienced no bleeding. Third, a HA patient (FVIII 6%) had a trough level of FVIII slightly lower than recommended (FVIII 37% versus > 50%) at day 7 after CABG. He presented a hemopericardium the next day, complicated with cardiac tamponade. Lastly, a moderate HA patient had no long-term antiplatelet therapy after CABG. However, he did not experience any new cardiovascular event during the following 4 years.During the follow-up (median: 24,5 months), only one HA (FVIII 20%) patient had a new cardiovascular event: a critical lower limb ischemia complicated with an arterial ulcer at the age of 91 years, 11 years after CABG. In contrast, 3 patients experienced a severe bleeding while treated by dual or low-dose aspirin: one hemopericardium, one gastrointestinal bleeding and one intracranial bleeding at J7 post-CABG, 13 months and 11 years after the cardiac event, respectively.Conclusion: This series of 8 patients confirms the significant risk of severe bleeding complications when antiplatelet drug is initiated in patients with hemophilia or VWD. In 1/3 cases, the severe bleeding occurred despite strict adherence to current recommendations. DisclosuresNo relevant conflicts of interest to declare.

Impact of Mhealth and Ehealth Applications on Hemophilia Treatment Management

Objective:To evaluate the effect of the implementation of a smart-phone based therapy management application over the monitoring of the hemophilia A (HA) and B (HB) patients in home-care setting.Setting:Since 2016 our hospital is using a mobile app and real time therapy management system for hemophilia patients (Haemoassist™, StatConsult) as a new tool of hemophilia patients care management complementing the existing health charts.Methods:A retrospective research conducted at one hemophilia treatment center covering four islands. HA and HB patients using the mobile app with at least 6-month follow-up period were included. Data on socio-demographics, clinical and therapy were collected before and after 6-month period of the app introduction. Sources of information were the electronic medical history (Millenium-Cerner™), pharmacy outpatient delivery program (Hospiwin™) and the above mentioned smart-phone app.The adherence was estimated calculating real factor consumption divided by the theoretical factor consumption according to prescribed prophylactic regimen for each study period. The extra doses for bleeding episodes were collected only after the intervention, due to unavailable reliable reports for mild and moderate bleeding events before the incorporation of the app.Results:A total of 28 patients with severe and moderate HA and HB on prophylactic treatment were included. The median age was 25 years (range 3-57). The median of the first period adherence was 72.7 % (range 30.77-100%) and of the second was 100% (range 51.88-100%). The median of the difference between periods was 15% (see chart 1 for more detailed information). In the post-intervention period, 12 (43 %) patients had a median of 3 bleeding events (range 1 -7) and needed extra-infusions with a median of 7 doses (range 3-17).Conclusions:The adherence to prophylactic treatment is crucial to reduce joint bleedings (Manco-Johnson MJ et al. NEJM. 2007). The use of therapy management mobile app has contributed to increase adherence in our patients allowing a precise monitoring of the administered factor and bleeding events in real time. DisclosuresNo relevant conflicts of interest to declare.

Australian multicentre study of current real-world prophylaxis practice in severe and moderate haemophilia A and B.

With the emergence of novel treatment products for haemophilia and an increasing focus on the benefits of pharmacokinetic driven individualized prophylaxis, robust national data with regard to current patterns of factor consumption and adherence are required. To characterize current Australian practice with regard to use of prophylactic clotting factor infusions in patients with moderate or severe haemophilia A (HA) and haemophilia B (HB). This was a retrospective, non-interventional study utilizing Australian Bleeding Disorder Registry (ABDR) data collected over a 12month period. Registered and consented patients with moderate or severe HA or HB without inhibitors were included. A total of 718 HA (551 severe, 167 moderate) and 166 HB (87 severe, 79 moderate) patients were included. Regular prophylaxis was prescribed in 453 patients (82%) with severe HA, 42 patients (25%) with moderate HA, 66 patients (75%) with severe HB and 11 patients (14%) with moderate HB. Near universal prophylaxis was achieved in the paediatric subgroup. The mean weekly dose of factor VIII in severe HA was 84 international units/kg/wk (IU/kg/wk) vs 71 IU/kg/wk of factor IX in severe HB. Most patients on prophylaxis were treated ≥3times/wk (HA) or 2times/wk (HB). Non-adherence peaked in the 20-29year age group. Older individuals on regular prophylaxis used more factor than was expected for their prescribed regimen. Prophylaxis rates in severe haemophilia are comparable with other developed nations. The benefit of a national registry is demonstrable. Furthermore research into the underlying reasons for non-compliance in young adults with haemophilia is required.

Retrospectively analysis of the difference of bleeding frequency and hemophilic arthropathy between hemophilia A and hemophilia B patients

目的分析血友病A（HA）和血友病B（HB）的出血频率和X线分级情况、X线分级进展的危险因素及差异。方法回顾性分析2007年1月至2010年12月中国医学科学院血液病医院收治的211例血友病患者的临床资料，随访部分患者出血关节的X线Arnold-Hilgartner诊断分级结果。结果211例患者均为男性，其中HA 150例，HB 61例。HA组总体中位年均总出血次数、中位年均关节出血次数分别为20.5（0~48）、13.5（0~38）次，HB组总体中位年均总出血次数、中位年均关节出血次数分别为13（1~40）、8（0~33）次，中间型HA患者中位年均总出血次数和中位年均关节出血次数高于中间型HB患者[26（1~48）次对12（1~36）次，P<0.001；18（0~36）次对7.5（0~26）次，P=0.001]，而重型HA和HB患者中位年均总出血次数和中位年均关节出血次数比较差异无统计学意义[33（1~41）次对26（1~40）次，P=0.702；22（0~36）次对18（0~33）次，P=0.429]。108例HA、54例HB患者入院时行出血关节普通X线检查，HA患者血友病严重程度与关节X线Arnold-Hilgartner诊断分级呈正相关（r=0.063，P=0.004）；HB患者严重程度分级与关节X线Arnold-Hilgartner诊断分级无相关性（r=0.045，P=0.082）；36例HA和19例HB患者5年后复查病变关节X线片，总体HA与HB患者X线进展程度比较差异无统计学意义（z=1.941，P=0.052），但中间型HA患者进展程度高于中间型HB患者（z=0.076，P=0.002），重型HA和重型HB患者比较差异无统计学意义（z=3.139，P=0.945）。多因素分析显示关节出血次数[P<0.001，OR=1.166（95%CI 1.097~1.239）]和外伤[P=0.018，OR=2.842（95%CI 1.196~6.755）]是血友病患者关节X线Arnold-Hilgartner诊断分级进展的独立危险因素。结论HB患者出血频率低于HA患者，中间型患者差异尤其明显。中间型HB患者关节X线分级进展较中间型HA患者慢。关节出血次数和外伤是血友病患者关节X线Arnold-Hilgartner诊断分级进展的独立危险因素。

Clinical Joint Outcome after Joint Bleeds in Patients with Von Willebrand Disease Is Comparable to Moderate and Severe Hemophilia A Despite Fewer Joint Bleeds

BackgroundRecurrent joint bleeds are the main cause of joint deterioration (hemophilic arthropathy) in patients with hemophilia. To what extent arthropathy occurs following joint bleeds in patients with Von Willebrand disease (VWD) compared to hemophilia has never been studied.ObjectivesThe primary objective was to compare joint outcome by physical examination between adults with VWD and moderate and severe hemophilia A (HA). The main secondary objectives were to compare joint bleed frequency, radiological joint damage and self-reported functional limitations between VWD and moderate and severe HA.MethodsWe selected adult patients with VWD (VWF activity <30%) and moderate or severe HA, who had a medical history of treatment for joint bleeds, for this post hoc analysis. To compare joint outcome we used the Hemophilia Joint Health Score (HJHS range 0-124, obtained by physical examination), X-ray Pettersson scores of ankles, knees and elbows (PS range 0-13 per joint) and Hemophilia Activities List scores, a patient administered questionnaire measuring functional limitations (HAL range 0-100). Univariate analyses were performed using Mann Whitney U and Chi2. For multivariate analysis we used negative binomial regression analysis (HJHS) and logistic regression (dichotomized PS>3 and HAL<95) adjusted for age. We performed a subgroup analysis of the patients with type 3 VWD.ResultsWe included 48 patients with VWD, 39 with moderate and 59 with severe HA. The mean age was 45, 38 and 26 years, respectively. Fewer patients with VWD than HA had a lifetime history of more than 5 joint bleeds (56% VWD vs. 77% moderate HA vs. 98% severe HA, p<0.001). Joint dysfunction at physical examination was comparable between the patients with VWD and moderate HA (median HJHS 5 vs. 5.5, p=0.65) but slightly better in VWD compared to severe HA (median HJHS 5 vs. 9, p=0.02). Apparent joint damage on X rays (PS>3 of one or more joints) occurred in 12/46 patients with VWD compared to 27/40 patients with severe HA (26% vs. 68%: OR 0.09; 95%CI 0.03-0.34, p<0.001). In moderate HA insufficient X rays were available for analyses. Functional limitations according to the HAL were comparable between patients with VWD and moderate and severe HA (VWD median HAL total score 88 vs. 95 in both moderate and severe HA, p=0.35).The subgroup analysis of joint dysfunction in patients with type 3 VWD (n=19, median age 40) showed clinical changes comparable to severe HA (median HJHS 14 vs. 9, p=0.83). We found a trend towards less radiological joint damage in type 3 VWD compared to severe HA (PS>3: 47% vs. 68%, OR 0.28; 95%CI 0.07-1.12, p=0.07). However, patients with type 3 VWD reported more functional limitations compared to those with moderate or severe HA (median HAL total score 77 vs. 95, p=0.01; adjusted for age OR 0.38; 95%CI 0.1-1.2, p=0.10).ConclusionsDespite fewer joint bleeds, joint function according to the HJHS was comparable between adult patients with VWD and moderate HA with a history of treatment for joint bleeds. Apparent X ray joint damage occurred less often in patients with VWD compared to those with severe HA. The HJHS of patients with type 3 VWD was comparable to those with severe HA, but the patients with type 3 VWD reported more functional limitations, partly explained by their higher age. Knowledge of similarities and differences in joint outcome between VWD and hemophilia can be helpful to improve the awareness and treatment of joint bleeds in VWD to prevent arthropathy and functional limitations. Disclosuresvan Galen:Bayer: Research Funding; CSL Behring: Research Funding; Baxter: Research Funding. Leebeek:CSL Behring: Research Funding; Baxter: Research Funding. Schutgens:Sanquin: Research Funding; CSL Behring: Research Funding. Fischer:Baxalta/Baxter: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Wyeth: Research Funding; Biogen: Consultancy; Biotest: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy. Mauser-Bunschoten:CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Griffols: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Biovitrum: Research Funding; Saquin: Research Funding.

Improved Clinical Outcomes and Replacement FVIII Consumption in Patients with Hemophilia a after Prophylaxis Adjustment Using a FVIII Pharmacokinetics Estimation Based on Bayesian Models

INTRODUCTIONCurrent guidelines recommend that subjects with severe hemophilia A (HA) receive prophylaxis in order to prevent severe bleeding and recurrent hemarthrosis that lead to the development of arthropathy, an extremely painful and disabling condition. Success of this approach greatly depends on treatment individualization, and the pharmacokinetics (PK) of factor VIII (FVIII) replacement therapy in a given patient is a crucial consideration.Standard PK studies require extraction of 6 to 10 samples, a procedure that takes several hours and causes adult patients and the parents of pediatric patients to miss work and children to miss school. This represents a significant barrier for routine performance of PK tests, and more rapid methods are needed in order to universalize PK-based adjustment in clinical practice.Björkman et al. developed a method to estimate PK parameters of factor FVIII using Bayesian models (Haemophilia 2010, 16(4):597-605). This approach requires only 2-3 blood extractions between 4 and 48 h after infusion, and may help introduce PK-based tailoring in hemophilia clinics. Based on this methodology, an online tool was developed to perform PK estimates in patients using the FVIII product Advate® (myPKFiT®, www.mypkfit.com; Baxter Healthcare Corporation; Haemophilia 2014, 20 (Suppl.2):15).This report describes the impact of using this tool to adjust prophylaxis regimens in clinical practice, in terms of clinical bleeding and joint bleeding rates and FVIII consumption, in subjects with HA receiving prophylaxis.METHODSThis is an observational case series of 3 Spanish centers. Thirty-four patients were evaluated (30 severe and 4 moderate HA) aged 7-52 years (median 22 years). All were receiving prophylaxis, and all received Advate® as replacement factor.myPKFiT® was used for estimations in 2014-2015. FVIII trough levels were adjusted between 1% and 2%. We evaluated the annual bleeding rate (ABR), the annual joint bleeding rate (AJBR) and annual FVIII use before and after PK adjustment of prophylaxis using the study tool.RESULTSOf the 34 patients,16 had not previously undergone a PK study (NPAP group), while 18 had already had their therapy previously adjusted by trough FVIII levels determination (PAP group). Most patients (n = 23) were following an M/W/F infusion schedule before myPKFiT® study. Median weight was 60 kg (interquartile range [IQR] = 32-78). Two samples were used for determinations in 27 patients, 3 in 5, and 4 in 2. Median FVIII half-life calculated with the study tool was 11.95 h (IQR = 10.13-14.33); median clearance was 0.035 dl/h/kg (IQR = 0.027-0.042), and median time until FVIII level 1% was 59.5 (IQR = 50.8-72.0).FVIII use, ABR and ABJR before and after adjustment with the parameters provided by myPKFiT® are summarized in Table 1. Adjustment had an impact in the individual factor consumption of most patients: in 14 cases, the annual amount was reduced (mean −34824 ± 49925 IU/year), and in 16 it was increased (mean +60605 ± 43517 IU/year). However, this did not have a significant impact in the mean amount used in the whole series compared to that used the year prior to myPKFiT-adjusted prophylaxis (p = 0.196). Regarding clinical outcome, ABR and AJBR were both significantly reduced in the NPAP group, where 68.7% and 62.5% of patients reduced their ABR (p = 0.008) and AJBR (p = 0.008), respectively, after adjustment. These rates were generally maintained after myPKFiT-based personalization in the PAP group.CONCLUSIONSClinical experience in this series suggests that PK-adjusted prophylaxis by means of a tool such as myPKFiT® may have a favorable impact on the prophylaxis regimens of HA patients. Clinical benefit can be achieved in patients whose therapy has not previously been adjusted using PK-based methods, and this personalized approach can reduce bleeding rates without significantly increasing the overall cost of FVIII therapy. Furthermore, the maintenance of bleeding rates in patients with prophylaxis previously adjusted by determination of trough levels suggests that outcomes with this method might be comparable. DisclosuresMingot-Castellano:Amgen: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy; Bayer: Consultancy, Research Funding. Parra:Baxalta: Consultancy.

Study on risk factors and follow-up of 26 hemophilia A children with inhibitors

目的探讨中国血友病A(HA）患儿凝血因子Ⅷ（FⅧ）抑制物发生的危险因素、治疗及转归以及抑制物对HA患儿出血特征的影响。方法回顾性分析2010年1月至2014年12月445例HA患儿的临床资料。采用病例对照研究方法分析抑制物发生的危险因素。结果在纳入研究的445例HA患儿中，重型患者82例（18.4%），中间型患者269例（60.5%），轻型患者94例（21.1%）。抑制物阳性26例（5.8%，失访3例），低滴度抑制物9例，高滴度抑制物17例，其中重型、中间型患者各13例。高强度替代治疗是抑制物产生的危险因素[P=0.030，HR值为4.435(95% CI 1.150~17.094）]；抑制物产生后2例患者接受小剂量利妥昔单抗清除抗体治疗，其中1例联合免疫耐受治疗3个月。出血时65.2%（15/23）的患者选择凝血酶原复合物治疗，8.7%（2/23）选择制动、冰敷、抬高患肢等保守治疗措施，26.1%（6/23）选择间断输注小剂量FⅧ治疗。未接受抗体清除治疗的患者中，87.5%（7/8）低滴度抑制物转阴，抑制物中位持续时间为3(1~3）个月，84.6%（11/13）的高滴度抑制物随时间呈下降趋势，在未进行抗体清除治疗的情况下持续12~48个月仍未转阴，7.7%（1/13）的高滴度抑制物2年后转阴。抑制物产生前后患儿关节年出血率、非关节年出血率、自发年出血率、创伤性年出血率差异无统计学意义。结论高强度替代治疗是HA患儿抑制物产生的危险因素；抑制物并不能增加HA患儿出血频率。

Generic and disease-specific quality of life among youth and young men with Hemophilia in Canada.

BackgroundThis study was undertaken to explore the longitudinal patterns of health-related quality of life (HRQoL) among youth and young adults with Hemophilia A (HA) over a 3-year period. This report presents the baseline characteristics of the study cohort.MethodsMales, 14 to 29 years of age, with predominantly severe HA were recruited from six treatment centres in Canada. Subjects completed a comprehensive survey. HRQoL was measured using: the CHO-KLAT2.0 (youth), Haemo-QoL-A (young adults) and the SF-36v2 (all).Results13 youth (mean age = 15.7, range = 12.9-17.9 years) and 33 young adults (mean age = 23.6; range = 18.4 -28.7 years) with moderate (7 %) and severe (93 %) HA were enrolled. All were on a prophylactic regimen with antihemophilic factor (Helixate FS®) during the study. The youth had minimal joint damage (mean HJHS = 5.2) compared to young adults (mean HJHS = 13.3). The mean HRQoL scores for youth were: 79.2 (SD = 11.9) for the CHO-KLAT, and 53.0 (5.5) and 52.3 (6.8) for the SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores respectively. The mean HRQoL scores for young adults were: 85.8 (9.5) for the Haemo-Qol-A, and 50.8 (6.4) and 50.9 (8.8) for PCS and MCS respectively. PCS and MCS scores were comparable to published Canadian norms, however significant differences were found for the domains of Physical Functioning and Bodily Pain. The disease-specific HRQoL scores were weakly correlated with the PCS for youth (CHO-KLAT vs. PCS r = 0.28, p = 0.35); and moderately correlated for the MCS (r = 0.39, p = 0.19). Haemo-QoL-A scores for young adults were strongly correlated with the PCS (r = 0.53, p = 0.001); and weakly correlated with the MCS (r = 0.26, p = 0.13). Joint status as assessed by HJHS was correlated with PCS scores. A history of lifelong prophylaxis resulted in better PCS but worse MCS scores.ConclusionDespite having hemophilia, the youth in this cohort have minimal joint disease and good HRQoL. The young adults demonstrated more joint disease and slightly worse HRQoL in the domains of physical functioning and pain. The data presented here provide new information to inform the selection of Health Related Quality of Life (HRQoL) instruments for use in future clinical trials involving persons with hemophilia.Trial registrationClinicalTrials.gov : NCT01034904. Study funded by CSL Behring Canada.Electronic supplementary materialThe online version of this article (doi:10.1186/s12878-016-0052-x) contains supplementary material, which is available to authorized users.

Low-dose continuous infusion of factor VIII in patients with haemophilia A.

Patients with haemophilia A (HA) or B (HB) can be given prophylactic or on-demand treatment administered by continuous infusion or bolus injections of factor VIII (FVIII) or IX (FIX). In this study we evaluated the efficacy and safety of low-dose continuous infusion of FVIII or FIX. We studied all eligible patients with HA or HB treated with continuous infusion of factor concentrates over an 18-year period in a single Slovenian Haemophilia Comprehensive Care Centre. Treatment started with a bolus injection of FVIII or FIX, followed by continuous infusion at the initial rate of 2 IU/kg/h of FVIII in HA patients and 4.5 IU/kg/h of FIX in HB patients. The infusion rate was subsequently adjusted according to the indication for therapy. A total of 66 continuous infusions (40 in major surgery, 10 in minor surgery and 16 with bleeding episode) in 46 HA patients and 16 (15 in severe and 1 in mild HA) in eight HB patients were included in the study. During the first week of treatment, the median continuous infusion rates in HA patients undergoing major surgery, minor surgery and a bleeding event were 2.18 (0.75-3.68), 1.48 (1.0-2.54) and 2.24 (1.33-3.93) IU/kg/h, respectively. The median FVIII activities were 0.69 (0.37-1.19), 0.47 (0.39-0.84) and 0.52 (0.36-1.06) IU/mL. After the first week of treatment, even lower doses of FVIII were needed. Red blood cell transfusions had to be administered to three patients (2 with severe and 1 with moderate HA) during the continuous infusion and inhibitors developed in five patients. In HB patients, the median continuous infusion rate was 1.85 (1.07-2.94) IU/kg/h and the median FIX activity was 0.62 (0.30-1.04) IU/mL. Red blood cell transfusions were not required, and thrombophlebitis and inhibitors did not appear. Overall, low-dose continuous infusion was shown to be an effective and safe way of treating patients with HA. The protocol used also proved efficient and safe in all HB patients.

Mutations in Intron 1 and Intron 22 Inversion Negative Haemophilia A Patients from Western India

Despite increased awareness and diagnostic facilities, 70–80% of the haemophilia A (HA) patients still remain undiagnosed in India. Very little data is available on prevalent mutations in HA from this country. We report fifty mutations in seventy one Indian HA patients, of which twenty were novel. Ten novel missense mutations [p.Leu11Pro (p.Leu-8Pro), p.Tyr155Ser (p.Tyr136Ser), p.Ile405Thr (p.Ile386Thr), p.Gly582Val (p.Gly563Val) p.Thr696Ile (p.Thr677Ile), p.Tyr737Cys (p.Tyr718Cys), p.Pro1999Arg (p.Pro1980Arg), p.Ser2082Thr (p.Ser2063Thr), p.Leu2197Trp (p.Leu2178Trp), p.Asp2317Glu (p.Asp2298Glu)] two nonsense [p.Lys396* (p.Lys377*), p.Ser2205* (p.Ser2186*)], one insertion [p.Glu1268_Asp1269ins (p.Glu1249_Asp1250)] and seven deletions [p.Leu882del (p.Leu863del), p.Met701del (p.Met682del), p.Leu1223del (p.Leu1204del), p.Trp1961_Tyr1962del (p.Trp1942_Tyr1943del) p.Glu1988del (p.Glu1969del), p.His1841del (p.His1822del), p.Ser2205del (p.Ser2186del)] were identified. Double mutations (p.Asp2317Glu; p.Thr696Ile) were observed in a moderate HA case. Mutations [p. Arg612Cys (p.Arg593Cys), p.Arg2326Gln (p.Arg2307Gln)] known to be predisposing to inhibitors to factor VIII (FVIII) were identified in two patients. 4.6% of the cases were found to be cross reacting material positive (CRM+ve). A wide heterogeneity in the nature of mutations was seen in the present study which has been successfully used for carrier detection and antenatal diagnosis in 10 families affected with severe to moderate HA.

Similarity in joint function limitation in Type 3 von Willebrand's disease and moderate haemophilia A

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.

Hydrolysis of factor VIII mediated by catalytic antibodies occurs in haemophilia A patients with or without factor VIII inhibitors

The major complication of the substitutive treatment of haemophilia A (HA) is the development of antifactor VIII (FVIII) antibodies. Most of these antibodies neutralize FVIII procoagulant activity, and are identified as FVIII inhibitor. A subgroup of these antibodies, 'catalytic antibodies', catalyses the FVIII hydrolysis. We investigated the frequency and the activity of catalytic antibodies, according to the phenotype of HA and the presence or absence of FVIII inhibitor. IgG from 16 patients with inhibitor and 17 patients without inhibitor were purified. Rates of FVIII hydrolysis and inhibitor titres were evaluated. Anti-FVIII catalytic antibodies were detected in 63.6% of patients with HA, irrespective of the HA phenotype and the presence of FVIII inhibitor. The frequency was significantly higher for severe HA patients (73.3%) and patients with inhibitor (87.5%), but their FVIII-proteolytic activity was not significantly different from patients with mild or moderate HA and patients without inhibitor. The evolution of both catalytic and inhibitory activities was studied for 11 patients with FVIII inhibitor. We observed two profiles. In the profile 1, 18.2% of patients, the catalytic activity and the inhibitor titre coevolved. In contrast, a dissociated evolution of these two parameters was observed in 72.8% patients in profile 2. These data confirm the importance of anti-FVIII catalytic activity in patients with severe, moderate and mild HA. Interestingly, most of the patients presented a dissociated profile, suggesting that anti-FVIII antibodies might not systematically act as FVIII inhibitors.

Presence and Evolution of a Catalytic Activity in Patients with Severe, Mild or Moderate Hemophilia A

Abstract 1211The development of neutralizing anti-Factor VIII (FVIII) antibodies is the major complication of the treatment of patients with hemophilia A (HA). Several mechanisms of inhibition have been described: steric hindrance, immune complex formation and catalytic antibodies. Anti-FVIII catalytic antibodies act like enzymes and lead to the hydrolysis of FVIII. Lacroix-Desmazes et al. had shown the presence of catalytic antibodies in the plasma of patients with severe HA who had developed inhibitors (13/24) (Lacroix-Desmazes et al, NEJM, 2002). Previous studies on catalytic antibodies reported results for patients with severe HA at one time point, exclusively. Thus, we proposed to extend the analysis of catalytic antibodies to patients with a mild or moderate HA and to follow over their lifetime patients who develop inhibitor.We studied plasma samples from 33 patients with HA. Sixteen were patients with severe HA, including 8 patients with inhibitor (Inh+) and 8 patients without inhibitor (Inh-), and 17 were mild or moderate HA patients (7 Inh+ and 10 Inh-). Among Inh+ patients, 6 were treated on-demand (3 severe and 3 moderate HA patients) and 9 were submitted to an immune tolerance induction (ITI) protocol (4 severe and 5 mild or moderate patients with HA). A therapeutic preparation of pooled normal IgG (IVIg) from healthy donors was used as a source of normal IgG. We also used plasma from 13 male healthy donors. As described previously [2], IgG were purified from plasma by affinity-chromatography on protein G followed by a size-exclusion chromatography in presence of urea. Then, catalytic activity was evaluated by the hydrolysis of FVIII after incubation with purified IgG (Lacroix-Desmazes et al, Nature, 1999). Inhibitor titer is measured by modified Bethesda test.Mean FVIII-hydrolyzing rates were determined for healthy donors, HA patients and IVIg, used as control. Catalytic activity of HA patients IgG was significantly higher than those of healthy donors or IVIg (p<0.01 and p<0.001, respectively). Sixty four per cent of patients with HA had catalytic antibodies, regardless the phenotype nor inhibitor presence. In addition, prevalence of FVIII-hydrolyzing antibodies for Inh+ and Inh- HA patients was 94% and 47%, respectively. However, the mean FVIII-hydrolysis rate was comparable for both groups (0.23 ± 0.06 mmol/min/mol). Surprisingly, we showed that the mean catalytic activity of mild or moderate HA patients were significantly lower than those of severe HA patients (0.17 ± 0.05 versus 0.31 ± 0.07). Interestingly, we were able to study the evolution of both catalytic and inhibitory activities for patients who developed inhibitor. We observed 2 profiles: in the first case, FVIII-hydrolysis rate and inhibitor titer followed the same trend, but in the second case, these two parameters showed a dissociated evolution. These results were independent of the type of treatment (on-demand or ITI).For the first time, we studied catalytic activity for patients with mild or moderate HA. In comparison with patients with severe HA, catalytic activity is much lower for patients with mild or moderate HA. In addition, most of patients with severe HA had FVIII-hydrolytic antibodies (88 %), in contrast with previous studies (50%) (Lacroix-Desmazes et al, NEJM, 2002). In the same way, we showed the presence of catalytic antibodies in patients without inhibitor. Moreover, we studied the evolution of catalytic activity and inhibitor titer over the time for patients with inhibitor and showed that catalytic activity did not necessarily follow the same trend as inhibitory activity. The results suggested that catalytic antibodies could not act like neutralizing antibodies. Disclosures:No relevant conflicts of interest to declare.

Long-Term Investigation on Age-Dependent Variations of Coagulation Factors in Patients with Von Willebrand Disease and Hemophilia,

Abstract 3321▪▪This icon denotes a clinically relevant abstract Aim:Age dependent variations of coagulation factors are well known in the general population. This investigation studies the long/term, age-dependent variations of coagulation factors in patients with hemophilia A (HA) and von Willebrand disease (VWD) in correlation to the co-morbidity. Methods:In this retrospective, single center cohort study, the median observation time was 14 years (5–43). Technical equipment did not change during the observation time. We compared FVIII:C, vWF:Ag and vWF:RCo levels of 65 pt with HA (mild n=48, moderate n=10, severe n=7; median age 28 years at first blood withdrawal, 47 years at last withdrawal), 84 pt with VWD (54w, 30m; type 1 n=57, type 2 n=15, type 3 n=10, type not specified n=2; median age 30,5 years at first blood withdrawal, 47,5 years at last withdrawal) and 23 conductors of HA (median age 36 years at first blood withdrawal, 42 years at last withdrawal). Results:FVIII:C levels collected from pt with mild HA displayed a significant median increase of 6,5% (−15 – 31%) with proceeding age from 14,5% (5,3 – 47%) to 19% (4,8 – 76%) (p=0,001335). For pt with moderate HA a non significant median increase of 1,05% (−3,6 – 16%) from 4,95% (2,8 – 11%) to (3 – 20%) was found. Eight pt showed FVIII:C levels during the last blood withdrawal, that indicated a change of severity from moderate to mild HA. Conductors of HA showed a non significant median increase of 8% (−52 – 95%) from 59% (21 – 118%) to 55% (33 – 145%). The course of FVIII:C levels in pt with severe HA did not vary. FVIII:C levels of pt with mild HA and conductors of HA showed a non significant tendency to higher increase at higher age. Also, a stronger increase at higher initial FVIII:C levels (assessed at first blood withdrawal) was found. Neither cardiovascular diseases nor hepatitis status correlated significantly to the age dependant increase of FVIII:C.FVIII:C levels of patients with VWD displayed an age-dependant significant median increase of 7,5% (−39 – 54%) from 62% (1 – 98%) to 68% (1 – 138%) (p = 0.010038). Additionally, a significant median increase of vWF:Ag of 7% (−61 – 67%) from 49% (0 – 112%) to 57% (3 – 105%) (p = 0.000072) and a non significant median increase of VWF:RCo of 2,5% (−42 – 82%) from 50% (0 – 90%) to 49,5% (0 – 143%) (p = 0.867876) were observed. The type of VWD (1, 2, 3), BMI, smoking status, treatment preparation, and co-morbidity (CHD, thrombosis, hypertonus, malignant disease and smoking) did not correlate to the observed increases. Conclusion:Pt with mild HA/VWD showed a significant increase of FVIII:C levels parallel to the ageing process. This increase was not significant in pt with moderate HA and conductors of HA. The course of FVIII:C levels in pt with severe HA did not vary. Pt with VWD additionally showed a significant increase of VWF:Ag and a non significant increase of VWF:RCo at proceeding age. No correlation to lifestyle factors or co-morbidity could be found. Disclosures:No relevant conflicts of interest to declare.