Comprehensive Haemophilia Treatment Centres Research Articles

Hereditary Hemorrhagic Telangiectasia May be the Most Clinically Significant and Morbid Inherited Bleeding Disorder of Women

Background Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder (1 in 5000 people) behind von Willebrand disease (VWD) and has no FDA- or EMA-approved therapies. HHT causes serious bleeding resulting in severe iron deficiency anemia, major psychosocial complications, and visceral arteriovenous malformations in brain, lung, and liver that can cause life-threatening hemorrhage, stroke, and other morbid complications. While HHT prevalence is equal in men and women, manifestations may be worse in women (as evidenced by a female predominance in HHT clinical trials). Due to the focus on hemophilia (an X-linked disease nearly exclusive to men) in the hemostasis research community, no study has examined the relative morbidity of the most common inherited bleeding disorders in women: HHT and VWD. Methods We performed an observational cohort study of women with HHT or VWD cared for at our institutional Comprehensive Hemophilia and Von Willebrand Disease Treatment Center or HHT Center of Excellence. Using an electronic patient data registry, a representative sample of 100 randomly selected women with HHT were age-matched to 100 randomly selected women with VWD for analysis. All data was extracted and confirmed using manual chart review; we quantified and compared bleeding and healthcare utilization outcomes. Results Patient Population. The mean (range) age in both groups was 49 (14-87) years. Mean BMI was 27 in both groups, and racial/ethnic breakdown was similar in both groups. Mean follow-up durations were 9.07 years (HHT) and 14.83 years (VWD) per patient. The VWD group included 86 patients with type 1 VWD and 14 with type 2 VWD. Bleeding Outcomes. Bleeding outcomes are detailed in TABLE 1. In women with HHT compared with VWD, recurrent epistaxis and GI bleeding were more likely (odds ratio [OR] [95% CI] = 32.73 [13.81-71.80], P<0.0001 and 5.69 [2.59-12.89], P<0.0001, respectively), and heavy menstrual bleeding was less likely (OR 0.32 [0.18-0.57], P<0.0001). Iron deficiency anemia was significantly more likely, and lowest hemoglobin significantly lower, in HHT versus VWD. Requirements for IV iron and RBC transfusion were significantly more likely in HHT versus VWD. Women with HHT had 17-fold higher odds of iron infusion dependence and 8-fold higher odds of requiring hemostatic surgical procedures than women with VWD. Healthcare Utilization for HHT or VWD Management. Healthcare utilization is detailed in TABLE 2. In women with HHT compared with VWD, emergency department (ED) visits and hospital admissions specifically to manage disease complications were significantly more likely (OR [95% CI] = 3.83 [1.67-8.48], P=0.001 and 7.33 [3.57-14.73], P<0.0001, respectively). Rates of ED visitation, admission, and outpatient encounters specifically for HHT or VWD management were significantly higher in women with HHT vs. women with VWD: ED visits, 10.3 per 100 patient-years (pt-yrs) vs. 0.74 per 100 pt-yrs, P=0.001; admissions, 14.4 per 100 pt-yrs vs. 1.0 per 100 pt-yrs, P<0.0001; outpatient encounters, 386.5 per 100 pt-yrs vs. 43.7 per 100 pt-yrs, P<0.0001. Adjusting these rates for the prevalence of HHT (1 in 5000) and VWD (1 in 1000) at the population level, all rates were still higher in the HHT group. Infusion visits, radiology encounters, and nearly all subspecialty provider visit types were much higher in women with HHT ( TABLE 2). Conclusions Analyzing matched populations of women at a health system that serves as a tertiary referral center for both diseases, HHT, a historically neglected bleeding disorder, was responsible for much higher morbidity and healthcare utilization in women than VWD, certainly at the individual patient level and possibly at the population level (prevalence-adjusted). Overall incidence of disease complications in each group was consistent with the published literature for both HHT and VWD, supporting the generalizability of our findings. These findings are critically important in achieving gender equity in the hemostasis field, given that both government and industry funding for VWD research is many times greater than for HHT research and such funding for hemophilia research, a disease of men, is at least 10-fold greater than for HHT research. Continued neglect of funding for clinical care and research of HHT within the hemostasis academic community and industry will only sustain and exacerbate gender inequities in hematology.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities in health services; diversity, equity, and inclusion; and implementation science

ABSTRACT Background The National Hemophilia Foundation (NHF) conducted extensive all-stakeholder inherited bleeding disorder (BD) community consultations to inform a blueprint for future research. Sustaining and expanding the specialized and comprehensive Hemophilia Treatment Center care model, to better serve all people with inherited BDs (PWIBD), and increasing equitable access to optimal health emerged as top priorities. Research Design and Methods NHF, with the American Thrombosis and Hemostasis Network (ATHN), convened multidisciplinary expert working groups (WG) to distill priority research initiatives from consultation findings. WG5 was charged with prioritizing health services research (HSR); diversity, equity, and inclusion (DEI); and implementation science (IS) research initiatives to advance community-identified priorities. Results WG5 identified multiple priority research themes and initiatives essential to capitalizing on this potential. Formative studies using qualitative and mixed methods approaches should be conducted to characterize issues and meaningfully investigate interventions. Investment in HSR, DEI and IS education, training, and workforce development are vital. Conclusions An enormous amount of work is required in the areas of HSR, DEI, and IS, which have received inadequate attention in inherited BDs. This research has great potential to evolve the experiences of PWIBD, deliver transformational community-based care, and advance health equity.

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.

Occurrence rates of von Willebrand disease among people receiving care in specialized treatment centres in the United States.

In the network of U.S. comprehensive haemophilia treatment centres (HTCs), von Willebrand disease (VWD) is the most common bleeding disorder other than haemophilia. Estimates of the size and characteristics of the VWD population receiving treatment are useful for healthcare planning. Estimate the prevalence and incidence of VWD among males and females receiving care at U.S. HTCs (HTC-treated prevalence and incidence). During the period 2012-2019, de-identified surveillance data were collected on all VWD patients who visited an HTC including year of birth, sex, race, Hispanic ethnicity, VWD type, and laboratory findings and used to calculate period HTC-treated prevalence by VWD type and sex. Data from patients born 1995-1999 were used to estimate HTC-treated incidence rates. During the period, 24,238 patients with a diagnosis of VWD attended HTCs; for 23,479 (96.9%), VWD type was reported or could be assigned. Age-adjusted HTC-treated prevalence was 8.6 cases/100,000 (7.2/100,000 for Type 1, 1.2/100,000 for Type 2 and 1.7/million for Type 3) and was twice as high in women as men (4.8 vs. 2.4 cases/100,000) for Type 1 and similar by sex for Type 2 and Type 3. HTC-treated Type 1 incidence increased over the period, averaging nearly threefold higher for women than men (26.2 vs. 9.9/100,000 live births). Sex differences were less for Type 2 (2.2 vs. 1.4 cases/100,000 births) and slight in Type 3. Prevalence and incidence of HTC-treated VWD differ by sex and type and are likely strongly influenced by differences in rates of diagnosis.

Real-world evidence on health resource use among patients with haemophilia and inhibitor exhibiting severe bleeding episodes.

This study aimed to explore real-world evidence on health resource use (HRU) spending on patients with haemophilia and inhibitor. Medical records from 1990 to 2019 of patients with haemophilia and inhibitor from three comprehensive haemophilia treatment centres were retrospectively retrieved. In all, 31 patients with haemophilia (A=30, B=1) and inhibitor ≥5 BU were included. The mean initial inhibitor of 95.4 BU was detected at the mean age of 6.7years. The mean number of annual hospitalisations was 3.9. A total of 795 bleeding episodes (major =125, minor =670) were evaluated. The treatment included bypassing agents or plasma exchange before administering high-dose factor VIII concentrate and intervention or surgery. Six patients succumbed to bleeding at the mean age of 17.2years. Nineteen surviving patients experienced multiple morbidity except six patients with successful and partially successful immune tolerance induction (ITI). The mean (SD) annual total medical consumption for episodic treatment and successful ITI per patient with haemophilia A were 30,804 (81,332) USD and 55,531 (100,566) USD, respectively. Only episodic treatment was paid by the government budget for limited amounts of bypassing agents. Management for patients with haemophilia and inhibitor exhibiting severe bleeding is challenging for medical personnel in countries having limited resources over decades. The real-world data will be used to negotiate with the government to increase budget for adequate bypassing agents or nonreplacement therapy and to include ITI in the national haemophilia treatment.

Occurrence rates of haemophilia among males in the United States based on surveillance conducted in specialized haemophilia treatment centres.

Estimates of the size and characteristics of the US haemophilia population are needed for healthcare planning and resource needs assessment. A network of comprehensive haemophilia treatment centres (HTCs) located throughout the United States receives federal support for diagnosis and management of haemophilia and other rare bleeding disorders. Estimate the incidence and prevalence of haemophilia among US males using the HTC network. During the period 2012-2018, de-identified surveillance data were collected on all males who visited an HTC that included year of birth, gender, race, Hispanic ethnicity, residence zip code, haemophilia type and severity. Data from all patients were used to calculate period prevalence by haemophilia type, severity and state of residence. Data from a subset of patients born 1995-2014 were used to estimate incidence rates over the 20-year period. During the period, 21748 males with haemophilia visited the HTCs resulting in an age-adjusted prevalence of 15.7 cases per 100000 males (12 for haemophilia A and 3.7 for haemophilia B). Prevalence was higher among whites (15.1) than blacks (12.4) or Hispanics of either race (12.4). State-specific prevalence varied from 1.6 to 23.3 cases per 100000. Based on 9587 males born during the index period, the average haemophilia incidence was 1 case per 4334 live male births. Based on these data, we estimate that there are between 29 761 and 32 985 males with haemophilia living in the United States today, the majority of whom receive comprehensive care in specialized clinical centres.

Hemostatic prophylaxis and colonoscopy outcomes for patients with bleeding disorders: A retrospective cohort study and review of the literature.

IntroductionHemostatic prophylaxis (HP) is recommended for patients with bleeding disorders (PWBD) before invasive procedures. However, evidence‐based guidelines are needed to determine optimal HP strategies.AimTo determine outcomes of HP for PWBD undergoing colonoscopy.MethodsWe undertook a retrospective cohort study of HP and outcomes of colonoscopy procedures performed between 9 November 1993 and 13 February 2018 for PWBD who received care in the Mayo Clinic Comprehensive Hemophilia Treatment Center.ResultsDuring the study period, 73 PWBD (58 with milder phenotypes: haemophilia, von Willebrand disease [subtypes 1 and 2; II, VII and XI deficiency]) underwent 141 procedures. Preprocedural HP was given to 61%, and interventions were performed in 47%. Of the 39% without preprocedural HP, postprocedural HP was given for 11%. One major (0.7%; 6 days postprocedure despite HP) and 10 minor (7%) bleeding complications occurred, which tended to be in patients with severe disease and/or after excision of larger polyps. There was no significant difference in the rate of bleeding complications with or without preprocedural HP (8.1% vs 5.5%, respectively; P = .74, Fisher's exact test).ConclusionThe low bleeding rates in our cohort suggest that preprocedure HP may be withheld for patients with mild bleeding disorders who undergo colonoscopy with a low likelihood of requiring an intervention or who require only low‐risk intervention. This strategy may be best used in experienced centres, provided optimal local hemostasis measures are undertaken and postprocedural HP is rapidly available if high‐risk intervention is required. Further studies are needed to determine optimal evidence‐based HP strategies for PWBD undergoing colonoscopy.

Management of Major Surgical Procedures in Patients with Hemophilia: A Single-Center Experience of 49 Procedures

Background: Management of surgical procedures in people with hemophilia (PwH) has always been a major concern. Insufficient hemostatic control might be an important cause of morbidity and mortality. However, the success of surgical procedures does not only depend on appropriate replacement of the missing factor. Pre- and post-operative interventions, laboratory monitoring, care and rehabilitation of the patient are important. Therefore, surgical procedures in hemophilia patients should be performed in full-fledged hospitals capable of providing a multidisciplinary approach as a "Comprehensive Hemophilia Treatment Center". The aim of our study is to evaluate the outcomes of major surgical procedures (MSPs) among PwH who were followed at Cerrahpasa Medical Faculty. Methods: All MSPs performed on PwH between 2004 and 2017 were included. Baseline activated partial thromboplastin time (aPTT)and factor levels prior to MSP, inhibitor screening and (if any) the inhibitor titration results together with complete blood count, blood group and liver function tests were retrospectively obtained from patient files. The type of MSP, amount of factor concentrates given prior to, during and after the operation, the factor levels and aPTT results following factor replacement; complications developing during or after surgery, and information on the type of treatment modality prior to surgery (on demand vs. prophylaxis) were noted. The amount of factor concentrates administered to patients was determined in units per kilogram. Results: Of the 39 patients included in the study (37 hemophilia A and two hemophilia B) 20 were severe, 7 were moderate and 12 were mild hemophilia (Table 1). The median age at the time of MSP was 37 (20-61) years. A total of 49 MSPs were performed, two patients had 3 surgeries, six patients had 2 surgeries, and 30 patients had one surgery. Fifteen surgical procedures were performed in two, one surgical procedure was performed in three, and 33 operation procedures were performed in one operation area. There were no significant differences in complication rates between hemophilia types (A vs. B), severities (severe vs. moderate vs. mild) and number of operated regions (1 vs. >1). In our study, general surgery (n=15) and orthopedic (n=10) operations were the most frequently performed MSPs (Table 2). There was no significant difference in complication rates among surgical branches. Complications were observed in a total of 6 (12%) MSPs, and one patient was deceased due to sepsis. Complication rates were 16% and 11% for MSPs done in PwH with and without inhibitors, respectively (p=non-significant). Factor consumption (U/kg) was highest in patients undergoing orthopedic surgery, followed by cardiovascular and neurosurgical operations. Factor utilization was significantly less for operations done in general surgery, urology and ear, nose and throat departments (p<0.001). There was a significant positive correlation between factor consumption and duration of hospitalization (r = 0,690; p <0.001). The data on the type of factor were available in 36 MSPs. Surgical procedures were carried out using plasma-derived and recombinant factor concentrates only in 26 and 5 patients, respectively. In the remaining 5, plasma-derived and recombinant factor concentrations were alternately applied. No statistically significant difference was noted with regard to the type of the factor used (plasma-derived, recombinant and plasma-derived/recombinant) and the duration of hospitalization or the complication rate. Number of days spent in the hospital were significantly higher in patients with complications than those without (16 vs. 9.5 days; p=0.003). Conclusion: The results of our retrospective study, being consistent with the current literature, clearly demonstrates that, in experienced comprehensive care centers MSPs can effectively and successfully be performed in PwH, even in those with inhibitors. Disclosures No relevant conflicts of interest to declare.

Outcomes Of Colonoscopies In Patients With Bleeding Disorders

BackgroundBased on data from the CDC, over the next 20 years, approximately 12,500 patients (pt) with bleeding disorders will require a screening colonoscopy. For a 75 kg adult receiving an average factor dose of 35 units/kg, this translates into utilization of approximately 30 million units over this time period which will vary with pt weight and disease severity. In the absence of evidence based guidelines, current practice is to provide prophylactic clotting factor concentrates to all such pt. Herein we report our institutional experience. Materials and MethodsRetrospective chart review of Mayo Comprehensive Hemophilia Treatment Center pt undergoing colonoscopies. Eligible pt had congenital von Willebrand disease (VWD), hemophilia A (HA) and B (HB). Data collected included pt demographics, factor concentrate and antifibrinolytic agent use, biopsy and polypectomy procedures, and bleeding complications (up to 1 month). ResultsFrom 1993-2013, 69 pt underwent 130 colonoscopies, 40/69 (58%) were males. Median (range) age at the time of the procedure was 60 years (3 to 87). The distribution of diagnoses were as follows: HA mild n=13, moderate n=5, severe n=5 and severe with inhibitor n=1; symptomatic carrier of HA n=2; HB mild n=6, severe n=1; VWD types 1: n=23, 2A: n=5, 2B: n=5, 2M: n=2; 3: n=3.40/69 (58%) pt had one colonoscopy, the remainder 2 to 8 colonoscopies. The procedures were performed as outpatient in 119 (92%) and as inpatient in 11 (8%). Colonoscopy indications included: GI bleeding (49/130, 38%); screening (32/130, 25%); history of polyps (24/130, 18%); iron deficiency anemia (7/130, 6%); Crohn's disease (5/130, 4%); diarrhea (4/130, 3%); colon cancer followup (3/130, 2%); abnormal imaging (3/130, 2%); family history of colon cancer, diverticulitis, and ulcerative colitis (combined 3/130, 2%).Of the 130 procedures, 25/130 (19%) received no factor or antifibrinolytic treatment, 58/130 (45%) received pre-procedure prophylactic factor only, 1/130 (1%) received post-procedure factor only, 29/130 (22%) received both, 3/130 (2%) received pre-factor and an antifibrinolytic, 3/130 (2%) received post-factor and an antifibrinolytic, 11/130 (8%) received pre and post-procedure factor and an antifibrinolytic. None received an antifibrinolytic alone.Biopsy was performed in only 56/130 (43%) of colonoscopies. Types of biopsies: polyp 37/56 (66%), mucosal 11/56 (20%), mucosal & polyp 5/56 (9%), lesion 1/56 (2%), lesion & polyp 2/56 (4%). Of the pt receiving a biopsy, 39/56 (70%) received pre-procedure factor and 25/56 (45%) received post-procedure factor. The pt most likely to be biopsied were those with an indication of history of polyps 15/56 (27%), GI bleed 13/56 (23%), screening 10/56 (18%), and Crohn's disease/colon cancer follow up/ diarrhea/iron deficiency anemia each 3/56 (5%).Of the total number of procedures, 39/130 (30%) underwent a polypectomy. Of these, 26/39 (67%) received pre-procedure factor and 17/39 (44%) received post-procedure factor. The average number of polypectomies per patient was 2.3 and the average number of polyps removed per procedure was 3.2.Hemorrhagic complications were noted in 26/130 procedures (13/26 procedural only, 4/26 post-procedure only, 9/26 both), of which 8/26 (31%) were major (requiring hospitalization or RBC transfusion) and 18/26 (69%) were minor (requiring factor or observation). Of all the bleeding complications observed, 15/26 (58%) received factor alone (3/15 major bleeds, 12/15 minor bleeds), 3/26 (11%) received nothing (3/3 minor bleeds), and 8/26 (31%) received a combination of factor concentrate and an antifibrinolytic (5/8 major bleeds, 3/8 minor bleeds). There were 14/56 (25%) pt who underwent a biopsy or polypectomy without receiving any pre/post factor or antifibrinolytic. In 3/14 (21%), there was a minor bleeding complication and in 0/14 (0%), there was a major bleeding complication. No pt experienced colonic perforation. ConclusionIn this study, most pt did not receive a biopsy or polypectomy. A risk stratification approach could be taken when deciding on factor concentrate infusions. For low risk pt, factor could be withheld but with post-procedure infusion provided for those undergoing biopsy or polypectomy. For high risk pt, current practices are reasonable. Based on the results presented here and the potential magnitude of impact, this topic deserves further study in a prospective fashion. Disclosures:No relevant conflicts of interest to declare.

Patterns of Bleeding in Males with Von Willebrand Disease

AbstractAbstract 1129 Background:Von Willebrand disease (vWD) is the most common inherited bleeding disorder in the United States, affecting about 1–2 % of the population. It is generally inherited as an autosomal dominant trait and is equally prevalent in males and females. Though this disorder usually manifests as mucosal bleeding, it is well known that there is a wide variation in clinical severity. The symptoms of vWD are usually more obvious in women because of menstruation and labor/delivery; and may be significantly under recognized in men. The pattern of bleeding and presentation at diagnosis in males has previously only been described in a small population of type 1 vWD patients (pts). Patients and Methods:We performed a retrospective chart review of active male pts with vWD receiving care at the Comprehensive Hemophilia Treatment Center. Clinical information such as age at diagnosis, initial symptom prompting the diagnosis and clinical bleeding history was obtained. Invasive procedures were reviewed for bleeding complications and relevant hematological intervention. Relevant laboratory data like PT, PTT, von Willebrand antigen (vWF:Ag), von Willebrand ristocetin cofactor (vWF:RCoF) and factor VIII activity (FVIII:C) was noted. Results:We identified a total of 140 male subjects with the diagnosis of vWD. Of the 140, 85 were evaluable with complete data. The mean age of the pts at the time of the study is 19 years (yrs) (1–79 yrs). 76/85 (89%) are type 1, 6/85 (7%) type 2 and 2/85 (4%) type 3 vWD. The mean age at diagnosis was 9.7 yrs (0.5–60 yrs) with 62/85 (73%) being diagnosed at age ≤ 10 yrs. The most common initial presentations leading to the diagnosis of vWD were epistaxis (25/85; 29%), a positive family history (24/85; 28%), prolonged preoperative (preop) PTT (14/85; 16%), easy bruising (10/85; 12%) and postoperative (postop) bleeding (5/85; 6%) pts. The mean lab values of vWF:Ag 48 IU/dl, vWF:RCoF 45 IU/dl and FVIII:C 62 IU/dl. 25/85 (29%) pts have one of the above parameters measuring < 30 IU/dl. Among those who ever experienced bleeding, the most common manifestations were epistaxis (30/85; 35%), easy bruising (10/85; 12%), postop bleeding (10/85; 8%), hemarthrosis (4/85; 5%), hematuria and oral bleeds (3/85; 4% each). A total of 48 surgical procedures occurred, consisting of 18 dental procedures, 13 tonsillectomy/adenoidectomy (T/A), 7 circumcisions, 5 joint surgeries, 2 port placements and 1 each of cystoscopy, orchiopexy and heart surgery. Bleeding complications were common 10/48 (21%): 5 with dental procedures, 2 each with T/A and circumcision and 1 with cystoscopy; all occurring in the absence of prophylactic treatment and 2/10 (20%) complications requiring transfusion of blood products. Conclusions:In our study which included types 1, 2 and 3 vWD pts, the majority of male subjects were symptomatic at the time of diagnosis, whereas about 40% were brought to attention due to a positive family history or an abnormal preop screening test. As opposed to previous reports, postop bleeding was a rare initial presentation in our larger cohort, possibly due to improved preop screening and earlier diagnosis. The most common pattern of bleeding amongst the symptomatic pts was mucosal, in the form of epistaxis and easy bruising. Bleeding complications can occur with invasive procedures, so aggressive use of DDAVP or clotting factor concentrates is warranted in a pt with known diagnosis of vWD. Disclosures:No relevant conflicts of interest to declare.

Establishment of Carrier Detection and Prenatal Diagnosis Service for Hemophilia in a Developing Country: Experience From International Hemophilia Training Center-Bangkok.

AbstractAbstract 3162 Background:Hemophilia is a hereditary bleeding disorder manifested by prominent bleeding in the musculoskeletal system. Patients with severe and moderate severity require life long administration of factor concentrates to replace the missing coagulation factors, otherwise they may end-up with morbidity and mortality in the early childhood period. Objective:To set-up carrier detection and prenatal diagnosis service for hemophilia all over Thailand. Methods:A study of DNA extraction from EDTA blood sent by surface mail without ice was previously conducted and revealed that the quality and quantity of extracted DNA from EDTA blood was suitable for the genotypic analysis of hemophilia up to 10 days of transportation. Then, the managers who are nurses in 42 registered hemophilia treatment centers located at the provincial, regional and university hospitals all over Thailand attended a two-day short course training on genetic counseling. They learned the clinical aspect of hemophilia, mode of inheritance and identify females at risk for carrier, writing a pedigree, preparing the blood samples, and sending them to the comprehensive hemophilia treatment center in Bangkok. Results:After the accurate diagnosis of moderate or severe hemophilia, genetic counseling was provided by a well-trained health personnel in the comprehensive hemophilia center in Bangkok or their hometown. A ‘family genetic game' was created and used for the counseling. It consisted of pictures of father, mother, sons, daughters, normal X chromosome, X chromosome with hemophilia gene, and normal Y chromosome. A magnet was attached to the back of every individual piece of picture. Different scenarios were demonstrated and discussed interactively. After the family members clearly understood their own risk of being a hemophilia carrier, the nurse took their blood with EDTA anticoagulant and sent to the comprehensive hemophilia center in Bangkok by surface mail without ice. Genotypic analysis of hemophilia A and B family was performed by screening the mutation with the conformation gel electrophoresis followed by sequencing except for those with hemophilia A families, the inversion of intron 22 was initially performed. Also, polymorphisms associated with factor VIII gene (Bcl I, intron 13, intron 22) and factor IX gene (Mse I, Sal I, Nru I, Dde I, Hha I) among the patients and family members were also studied. A pilot study was conducted in 151 patients from 140 families (101 hemophilia A, 39 hemophilia B). For hemophilia A, the inversion of intron 22 was found in 46 families, 19 with identified mutations and 36 on the process of mutation identification. On the contrary, mutations were identified in all 39 families with hemophilia B. Nine novel mutations were found in hemophilia A (p.Asp2108 Val fs*15, p.Ser853*, p.Met1934 fs, p.Leu529Asp fs*6, p.Trp637*, p.Ala469Pro, p.Arg1966*, p.Trp208*, p.Asn1441Ile*5) and 6 novel mutations were found in hemophilia B (p.Trp194Ser, p.Gly317Arg, p.Asp359 Val, p.Gln-45 fs, p.Glu-37 fs, p.Tyr69 fs). Eighty females at risk for carrier were included and half of them were diagnosed with carriers. However, 26 prenatal diagnosis was performed in 21 females (18 hemophilia A, 3 hemophilia B) by chorionic villi sampling, amniocentesis or fetal blood sampling. The results revealed 23 male and 3 female fetuses. Only six male fetuses were diagnosed with hemophilia and the pregnancies were terminated due to the request of the couples at risk. An additional termination of pregnancy was performed in one male fetus with Down syndrome. Only one fetal loss complication was found.The cost of genotypic analysis for each family and the prenatal diagnosis was 100 USD and 75 USD, respectively. Therefore, the total cost of this pilot study was 15,950 USD and six births of new hemophilia patient were prevented. It is highly cost-effective as compared to the cost of treatment. Importantly, the established service is convenient for family members even though they stay far from the advanced comprehensive hemophilia center. Conclusion:A service for carrier detection and prenatal diagnosis is essentially. required for developing countries where adequate treatment of factor concentrates is not available. It should be integrated into the existing infrastructure of health care system. Research for simplifying the advanced technology and training for upgrading the medical knowledge among health personnel are the keys of success. Disclosures:No relevant conflicts of interest to declare.

Physical Functioning in Boys with Hemophilia in the U.S.

Hemophilia is the most common inherited severe bleeding disorder. Although the most frequent complication of repeated hemorrhages is a crippling joint disease that begins in childhood, the extent of resultant joint functional impairment varies widely within the hemophilia population. The goal of this exploratory analysis was to examine a national database that collects information on boys with hemophilia, an X-linked severe congenital bleeding disorder, to determine characteristics associated with increased risk of developing limitations in physical functioning as an outcome of recurrent hemorrhages. A standard set of data is collected annually at ∼130 U.S. comprehensive hemophilia treatment centers (HTCs) in a voluntary surveillance program called the Universal Data Collection (UDC) program. Fifteen potential predictors for poor outcomes of physical functioning related to bleeding were examined for boys (aged ≤ 18 years) from 1998 to 2008. Bivariate and multivariate analyses of these predictors performed in 2009 examined associations with self-reported limitation of activities, absenteeism from work or school, and reliance on assistive devices for ambulation and mobility. Multiple characteristics of underlying hemophilia severity and disease chronicity (in particular, increasing age, presence of joint bleeding, and inhibitor antibodies) were independently associated with increased risk of limitations of physical function. Nonwhite race/ethnicity was associated with each of the poorer functional outcomes in bivariate analyses. After controlling for the potential confounding effects of the multiple population characteristics on race, only African-American race was independently associated with activity restrictions, and African-American and Asian/Pacific Island ethnicity with absenteeism. With the exception of indicators of underlying disease severity, only obesity and medical insurance coverage with Medicaid rather than commercial insurance were independently associated with multiple poor outcomes. Interventions focused on eliminating inhibitors, improving outcomes for African-American children with hemophilia, and maintaining healthy body weight are warranted. In addition, strategies are needed to assure adequate insurance coverage for all people with hemophilia to eliminate economic barriers to optimal functional outcomes.

Web‐enabled registry of inherited bleeding disorders in Portugal: conditions and perception of the patients

Local and national haemophilia registries are powerful instruments to support the healthcare and researchers and improve the communication between Comprehensive Haemophilia Diagnostic and Treatment Centres (HTCs) and patients. Hemo@care is an example of a Local Haemophilia Registry Systems (LHR_Sys) based on the Web, developed in collaboration with a HTC located in Portugal, to support the haemophilia treatments registry, collect and manage the clinical information and provide mechanisms to control the clotting factor concentrates (CFC) stock. To extend this solution (the hemo@care) to other Portuguese HTCs and consequently to meet the preconditions to create a National Haemophilia Registry Systems (NHR_Sys), a study based on a questionnaire was carried out at nationwide. This study aims to assess the conditions and motivations of people with haemophilia (PWH) geographically scattered throughout the country, to use a potential Web-enabled registry with the purpose of replacing the traditional paper-diaries, to understand their judgment about a potential NHR_Sys currently non-existent in Portugal, and at the same time, to characterize demographically and pathologically those people at the nationwide. The results based on the analysis of 168 responses (response rate of 31%) confirmed the high prevalence of the disease in haemophilia A (75%) compared with haemophilia B (11.3%) and a large incidence in the severe levels, or the existence of people with mild severity without diagnosis and treatment. Furthermore, the results also revealed the need, conditions and motivation for using a registry system by PWH; thus it is deemed to justify the extension of the hemo@care to other HTCs in Portugal and consequently to create the NHR_Sys.

The Aging Patient with Hemophilia: Complications, Comorbidities, and Management Issues

Improvements in hemophilia care and antiviral treatments have resulted in increases in median life expectancy for persons with congenital hemophilia A and B. Currently, 2% of hemophilia A and B patients surveyed in US comprehensive hemophilia treatment centers are 65 years of age or older and 15% are 45 years or older. Many of the complications of hemophilia, including intracranial hemorrhage, joint disease, and inhibitor development, increase with increasing age. Hepatocellular carcinoma and end-stage liver disease are increasing in the older hemophilia population due to infection with hepatitis C (HCV) and HCV/HIV coinfection. Older hemophilia patients also now face the same medical conditions associated with aging in the general population, including cardiovascular disease and cancer. Complex hemostatic management, sometimes in conjunction with antithrombotic management, with extensive cross-specialty clinical and laboratory coordination may be required for the care of the older hemophilia patient. Because elderly hemophilia patients currently represent a small portion of the overall hemophilia population, there is little in the way of clinical data to guide recommendations. Registry databases and cooperative group studies are needed for the development of evidence-based guidelines for the older hemophilia population, which is anticipated to expand in the future.

Administration of Vaccines to Infants and Children with Hemophilia. A Survey of the Region III Comprehensive Hemophilia Treatment Centers.

There appears to be variability in both recommendations and practice regarding the route of administration of immunizations to infants and children with hemophilia. The CDC Advisory Committee on Immunizations, the American Academy of Pediatrics Red Book, and the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation all recommend intramuscular vaccination; the risk of bleeding can be minimized by concomitant administration of antihemophilic factor. However, informal discussions among practicing hematologists suggest that common practice is subcutaneous administration.METHODS: To determine the standard practice regarding immunizations a survey was completed by 12 Hemophilia Treatment Centers in Federal Region III (Mid-Atlantic states). The number of pediatric patients followed in each institution ranged from 9 to 182 (average 73).RESULTS: All centers have a policy or standard practice regarding the administration of vaccines and 10 of 12 recommend subcutaneous administration of all vaccines. Of the two centers that recommend following manufacturer guidelines one does and one does not routinely recommend concomitant factor administration. One center, whose policy is subcutaneous administration, recommends simultaneous factor administration if the primary care provider insists on intramuscular administration. Half of the centers do not offer immunizations on site; those that do usually offer only hepatitis A and B vaccines. All but one center have seen hematoma formation following immunizations, but none have seen sterile abscesses, necrosis, or granuloma formation. Hematomas have been seen following both subcutaneous and intramuscular injection. Estimates of hematoma formation are difficult to calculate, but one large program (folowing 182 patients) sees about 1 hematoma per year or an estimated 2–5% incidence.CONCLUSION: Contrary to CDC and MASAC guidelines, it is standard practice at most Hemophilia Treatment Centers in Federal Region III to recommend subcutaneous administration of all vaccines without coverage of factor replacement. Hematoma formation is uncommon and can be seen following either subcutaneous or intramuscular administration. There appears to be little indication for prophylactic factor treatment before vaccine administration.

A model for a regional system of care to promote the health and well-being of people with rare chronic genetic disorders.

People with rare, inherited chronic health conditions, such as hemophilia, face added physical, social, emotional, and fiscal challenges beyond those that are common to more prevalent chronic conditions. In 1975, a partnership among clinicians, consumers, and government agencies created a nationwide regional health delivery system that increased access to clinical care, prevention, and research, thereby improving health outcomes for people with hemophilia in the United States. Today, more than 130 Comprehensive Hemophilia Diagnostic and Treatment Centers in 12 regions serve 70%-80% of the nation's hemophilia patients. Health care leaders and advocates for other rare, expensive, chronic disorders may find that regionalization improves survival and reduces disability among affected populations. However, diverse and stable resources are needed to sustain such a model in our profit-oriented US health care arena.

Prevalence of conditions associated with human immunodeficiency and hepatitis virus infections among persons with haemophilia, 2001-2003

Before the mid-1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV-1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV-seropositive patients, age 13-88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross-sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV-1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV-1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV-1-positive participants had > or = 200 CD4+ cells microL(-1), only 59% were on HAART. HIV-1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti-HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV-1-positive than HIV-1-negative participants (85% vs. 70%, P < 0.0001). HIV-1-positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV-negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self-reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non-Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV-1, HCV or both.

Utilization of care in haemophilia: a resource-based method for cost analysis from the Haemophilia Utilization Group Study (HUGS).

The Haemophilia Utilization Group Study (HUGS) was created 10 years ago to examine the annual utilization and cost of haemophilia-related healthcare services. Retrospective chart reviews for 336 patients with haemophilia A receiving treatment in one of five comprehensive haemophilia treatment centres (HTCs) during 1995 were completed through interview of the provider. This method provided adequate collection of data from patient charts without the abstractor having direct access to patient health information. Utilization data were used to impute the costs of different components of care (e.g. physician visits, factor VIII concentrate, emergency room, hospitalization). The total annual cost of care was 139,102 dollars (SD $304,033). Factor VIII concentrate costs comprised the largest proportion of these costs; mean factor VIII concentrate use was 128,517 units per patient per year. Unbilled physician utilization accounted for 7.8% of the mean total physician costs per annum, while mean allied healthcare costs accounted for 33.5% of the total annual allied healthcare costs per patient. In the ordinary least-squares regression model, higher costs were associated with severe factor VIII deficiency, arthropathy, more comorbid conditions, an inhibitor to factor VIII concentrate, infusing through a port and prophylaxis. Although factor VIII concentrate is the most costly component, the treatment of haemophilia uses many healthcare resources. HUGS has demonstrated that patient clinical characteristics and physician practices predominantly drive the costs of haemophilia care. Specifically, patients with more severe arthropathy had greater healthcare costs. As future funding decisions are made, it is important to provide for all components of care.

Frequency and causes of hospitalization in HIV-negative children and adolescents with haemophilia A or B and its effect on academic achievement.

The aim of the study is to determine the causes and frequency of hospitalization in HIV-negative boys and adolescents with haemophilia and evaluate their impact on academic achievement. One hundred and twenty-six HIV-negative boys and adolescents were followed prospectively from 1989-96, at 14 comprehensive haemophilia treatment centres. One hundred and fifteen participants with haemophilia A or B were included in the investigation. These participants contributed an average of 57.8 months of follow-up. There were 203 hospitalizations in 65 participants and 50 participants were never hospitalized. Haemarthroses and soft tissue bleeds accounted for 46 and 44 causes of hospitalization. Central line infection was the third most common cause. Participants with inhibitor had the majority of central line infections and hospitalizations. Intracranial haemorrhage resulted in five hospitalizations in two participants. Other causes of bleeding accounted for 22% of hospitalizations. The median number of hospitalizations per year was 0.18. Duration of hospital stay was significantly related to lower spelling scores. Acute and chronic joint problems and soft tissue bleeds still account for the majority of hospitalizations. Positive inhibitor status was associated with higher numbers of hospitalizations and central line infections. Academic achievement was affected, to some degree, by length of hospital stay.

The Hemophilia Utilization Group Study (HUGS): determinants of costs of care in persons with haemophilia A.

The main objective of this study was to examine factors associated with utilization and costs for persons with haemophilia. Utilization data and patient characteristics were collected through medical record review of 336 patients receiving treatment for at least 90% of their haemophilia care at one of five comprehensive haemophilia treatment centres in California. The range of factor VIII deficiency in our sample was similar to the distribution among haemophilic patients in the Western United States; 215 (64%) had severe FVIII deficiency. The mean age in our sample was 21.4 (SD = 16.2) years old and 114 (34%) were HIV-positive. In the multivariate model predicting the total cost of health care during 1995 (adjusted R2 = 0.40), total annual costs were significantly (P < 0.05) associated with being HIV-seropositive, infusing FVIII concentrate through a port vs. i.v. infusion, the number of comorbidities, moderate arthropathy (compared with no arthropathy), mild arthropathy, history of inhibitor to FVIII, and current prophylactic FVIII concentrate infusion. As expected, total health-care costs were correlated with comorbid medical conditions, such as HIV and sequelae of haemophilia such as arthropathy. Health policy should consider risk adjustment for the presence of complications such as arthropathy and HIV infection in the financing of haemophilia treatment to promote more equitable delivery of these services.