Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System.

AIM: To describe the prevalence and complications in babies ≤2 years with haemophilia. METHODS: We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). RESULTS: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates. CONCLUSION: Bleeding events in haemophilic babies ≤2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment.

Physical activity and health outcomes in persons with haemophilia B.

Regular participation in physical activity helps to prevent damage and maintain joint health in persons with haemophilia. This study describes self-reported physical activity participation among a sample of people with haemophilia B in the US and measures its association with health-related quality of life (HRQoL). Data on 135 participants aged 5-64 years were abstracted from Hemophilia Utilization Group Study Part Vb. The International Physical Activity Questionnaire assessed physical activity among participants aged 15-64 years, and the Children's Physical Activity Questionnaire abstracted from the Canadian Community Health Survey was used for participants aged 5-14 years. SF-12 was used to measure HRQoL and the EuroQol (EQ-5D-3L) was used to measure health status for participants older than 18 years of age. PedsQL was used to measure HRQoL in children aged 5-18 years. Sixty-two percent of participants in the 15-64 year-old age cohort reported a high level of physical activity, 29% reported moderate activity and 9% reported low activity. For children aged 5-14 years, 79% reported participating in physical activity for at least 4 days over a typical week. Based on the 2008 Physical Activity Guidelines for Americans, 79% of adults achieved the recommended physical activity level. Multivariable regression models indicated that adults who engaged in a high level of physical activity reported EQ-5D Visual Analogue Scale (VAS) scores that were 11.7 (P = 0.0726) points greater than those who engaged in moderate/low activity, indicating better health outcomes. Among children, no statistically significant differences in health outcomes were found between high and moderate or low activity groups.

MASAC Consensus Conference: impediments to conducting clinical research in persons with haemophilia, von Willebrand's disease and rare bleeding disorders.

A consensus conference conducted by the Medical and Scientific Advisory Council of the National Hemophilia Foundation was held in New Orleans, LA, on November 11, 2010, to discuss the impediments to conducting clinical research in persons with haemophilia, von Willebrand's disease and rare bleeding disorders. The conference combined presentations providing academic, non-profit and industry perspectives with periods of open discussion. The objective of this conference was to identify the many challenges involved in facilitating U.S. Food and Drug Administration approval of innovative products for these patient populations.

Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS-Va).

This study describes health-related quality of life (HRQoL) of persons with haemophilia A in the United States (US) and determines associations between self-reported joint pain, motion limitation and clinically evaluated joint range of motion (ROM), and between HRQoL and ROM. As part of a 2-year cohort study, we collected baseline HRQoL using the SF-12 (adults) and PedsQL (children), along with self-ratings of joint pain and motion limitation, in persons with factor VIII deficiency recruited from six Haemophilia Treatment Centres (HTCs) in geographically diverse regions of the US. Clinically measured joint ROM measurements were collected from medical charts of a subset of participants. Adults (N = 156, mean age: 33.5 ± 12.6 years) had mean physical and mental component scores of 43.4 ± 10.7 and 50.9 ± 10.1, respectively. Children (N = 164, mean age: 9.7 ± 4.5 years) had mean total PedsQL, physical functioning, and psychosocial health scores of 85.9 ± 13.8, 89.5 ± 15.2, and 84.1 ± 15.3, respectively. Persons with more severe haemophilia and higher self-reported joint pain and motion limitation had poorer scores, particularly in the physical aspects of HRQoL. In adults, significant correlations (P < 0.01) were found between ROM measures and both self-reported measures. Except among those with severe disease, children and adults with haemophilia have HRQoL scores comparable with those of the healthy US population. The physical aspects of HRQoL in both adults and children with haemophilia A in the US decrease with increasing severity of illness. However, scores for mental aspects of HRQoL do not differ between severity groups. These findings are comparable with those from studies in European and Canadian haemophilia populations.

Haemophilia utilization group study - Part Va (HUGS Va): design, methods and baseline data.

To describe the study design, procedures and baseline characteristics of the Haemophilia Utilization Group Study - Part Va (HUGS Va), a US multi-center observational study evaluating the cost of care and burden of illness in persons with factor VIII deficiency. Patients with factor VIII level ≤ 30%, age 2-64 years, receiving treatment at one of six federally supported haemophilia treatment centres (HTCs) were enrolled in the study. Participants completed an initial interview including questions on socio-demographical characteristics, health insurance status, co-morbidities, access to care, haemophilia treatment regimen, factor utilization, self-reported joint pain and motion limitation and health-related quality of life. A periodic follow-up survey collected data regarding time lost from usual activities, disability days, health care utilization and outcomes of care. HTC clinicians documented participants' baseline clinical characteristics and pharmacy dispensing records for 2 years. Between July 2005 and July 2007, 329 participants were enrolled. Average age was 9.7 years for children and 33.5 years for adults; two-thirds had severe haemophilia. The distributions of age, marital status, education level and barriers to haemophilia care were relatively consistent across haemophilic severity categories. Differences were found in participants' employment status, insurance status and income. Overall, children with haemophilia had quality of life scores comparable to healthy counterparts. Adults had significantly lower physical functioning than the general US population. As one of the largest economic studies of haemophilia care, HUGS Va will provide detailed information regarding the burden of illness and health care utilization in the US haemophilia A population.

Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention's (CDC) Universal Data Collection (UDC) project.

Lack of detailed natural history and outcomes data for neonates and toddlers with haemophilia hampers the provision of optimal management of the disorder. We report an analysis of prospective data collected from 580 neonates and toddlers aged 0-2 years with haemophilia enrolled in the Universal Data Collection (UDC) surveillance project of the Centers for Disease Control and Prevention (CDC). This study focuses on a cohort of babies with haemophilia whose diagnosis was established before the age of two. The mode of delivery, type and severity of haemophilia, onset and timing of haemorrhages, site(s) of bleeding, provision of prophylaxis with coagulation factor replacement therapy, and the role played by the federally funded Haemophilia Treatment Centers (HTC) in the management of these infants with haemophilia were evaluated. Seventy-five per cent of haemophilic infants were diagnosed early, in the first month of life, especially those with a family history or whose mothers were known carriers; infants of maternal carriers were more likely to be delivered by C-section. Involvement of an HTC prior to delivery resulted in avoidance of the use of assisted deliveries with vacuum and forceps. Bleeding from the circumcision site was the most common haemorrhagic complication, followed by intra- and extra-cranial haemorrhages and bleeding from heel stick blood sampling. Eight per cent of the infants were administered factor concentrate within 24 h of birth; more than half were treated to prevent bleeding. This study highlights the significant rate and the sites of initial bleeding unique to very young children with haemophilia and underscores the need for research to identify optimal evidence-based recommendations for their management.

Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders.

We performed quantitative PCR-based serial chimerism testing of whole blood (WB) and CD3+ cells and retrospectively correlated the results of chimerism tests and the risk of graft loss in children undergoing transplant for non-malignant disorders. Twenty-four children were included in this study. All patients initially engrafted; subsequently, 12% lost the graft, 21% achieved complete donor chimerism and 67% had mixed chimerism (MC). Patients underwent delayed taper of cyclosporine (CsA) if they had MC. Overall survival was 87+/-7% (s.d.) at 5-years post transplant, and it was not affected by chimerism status. Both WB and CD3+ chimerism showed significant fluctuations with a peak in autologous cell signal occurring at a median of 7 months for WB and 2 months for CD3+ cells. Initial post transplant chimerism percentage in either WB or CD3+ lineage was not related to graft loss. Increasing MC to >30% host cells was seen in 33% of patients, and it was related to increased risk of graft loss, as previously published. However, 63% of children with increasing MC did not lose their graft. Additional studies of post transplant chimerism are required to improve our ability to accurately identify children at risk of graft loss following transplant for non-malignant disorders.

Factor V deficiency: a concise review.

Factor V (FV; proaccelerin or labile factor) is the plasma cofactor for the prothrombinase complex that activates prothrombin to thrombin. FV deficiency can be caused by mutations in the FV gene or in genes encoding components of a putative cargo receptor that transports FV (and factor VIII) from the endoplasmic reticulum to the Golgi. Because FV is present in platelet alpha-granules as well as in plasma, low FV levels are also seen in disorders of platelet granules. Additionally, acquired FV deficiencies can occur in the setting of rheumatologic disorders, malignancies, and antibiotic use and, most frequently, with the use of topical bovine thrombin. FV levels have limited correlation with the risk of bleeding, but overall, FV-deficient patients appear to have a less severe phenotype than patients with haemophilia A or B. The most commonly reported symptoms are bleeding from mucosal surfaces and postoperative haemorrhage. However, haemarthroses and intramuscular and intracranial haemorrhages can also occur. Because no FV-specific concentrate is available, fresh frozen plasma remains the mainstay of treatment. Antifibrinolytics can also provide benefit, especially for mucosal bleeding. In refractory cases, or for patients with inhibitors, prothrombin complex concentrates, recombinant activated FVIIa, and platelet transfusions have been successfully used. Some patients with inhibitors may also require immunosuppression.

Unresolved issues in diagnosis and management of inherited bleeding disorders in the perinatal period: a White Paper of the Perinatal Task Force of the Medical and Scientific Advisory Council of the National Hemophilia Foundation, USA.

Haemophilia and inherited bleeding disorders in newborns and their carrier mothers pose unique challenges. The pattern of bleeding and the causes and risk factors for bleeding are decidedly different than an older child or an adult with haemophilia/inherited bleeding disorder. This document outlines the needs for further research and education, summarizes the state of the art background information and provides guidance regarding research, education and access to care issues in this population.

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.

Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with haemophilia.

Individuals with Haemophilia are at risk from hepatitis A virus (HAV) infection through exposure to blood products. Havrix(R), an intramuscular hepatitis A vaccine, is currently recommended for the prevention of disease caused by hepatitis A virus. Because bleeding may complicate intramuscular injections in those with bleeding disorders, we conducted a randomized, Phase IV clinical trial to compare the safety and immunogenicity of Havrix(R) given by the subcutaneous (s.c) vs. intramuscular (i.m.) route. A total of 45 children with Haemophilia were vaccinated subcutaneously, while their 41 nonhaemophlic siblings were vaccinated intramuscularly, at a dose of 720 Elisa units (EL.U.) at time 0 and 6 months. All children were anti-HAV and anti-HIV negative at baseline, and the haemophilic group did not differ from their siblings in alanine aminotransferase (ALT; 25 IU L-1 vs. 22 IU L-1), or in age; 8.5 years vs. 8.7 years. The vaccine was well tolerated, with minor adverse events being similar between groups; 21 (47%) vs. 24 (58%), P > 0.05. Local symptoms included soreness in 39 (45%), erythema in 25 (29%), swelling in 21 (24%), and bruising in six (7%), with no differences between groups. The proportion seroconverting to anti-HAV IgG positive did not differ between groups; 98% vs. 97% at month 1; 82% vs. 93% at month 6; and 100% vs. 100% at month 8, respectively. The HAV geometric mean titre was lower in those with Haemophilia, 185 vs. 233 mIU mL-1 at month 1; 68 vs. 94 mIU mL-1 at month 6; and 584 vs. 1082 mIU mL-1 at month 8, respectively. We conclude that Havrix(R) is safe and immunogenic when administered s. c. in children with Haemophilia.

Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk.

Haemophilia B is an X-linked recessive coagulopathy due to mutations in the factor IX gene. Occasionally, patients receiving factor IX replacement therapy develop inhibiting antibodies to the factor IX protein, and it has been recently documented that a subset of these patients have had anaphylactic responses to factor IX replacement therapy in association with the development of inhibiting antibodies. To determine the relationship between mutation type and the risk of anaphylaxis, eight unrelated patients from families in whom anaphylaxis had occurred were genotyped. The mutations were compared to those in 550 haemophilia B patients and to those in 276 patients with clinically severe disease. Individuals with complete gene deletions were found to be at greatest risk for anaphylaxis, with an estimated risk of 26% or greater. Anaphylaxis was less likely to occur in patients with protein truncation mutations or partial gene deletions and least likely to occur with missense mutations. Genotypes can help physicians and patients anticipate the likelihood of anaphylaxis, a potentially life-threatening complication of factor IX replacement therapy. The very high risk of anaphylaxis associated with a complete gene deletion suggests that the lack of expression of a partial protein product may predispose to anaphylaxis and/or that the absence of a closely linked, codeleted gene enhances the anaphylactic immune response.

Germline origins in the human F9 gene: frequent G:C-->A:T mosaicism and increased mutations with advanced maternal age.

The factor IX gene (F9) is an advantageous system for analyzing recent spontaneous germline mutation in humans. Herein, the male:female ratio of mutation ("r") in F9 have been estimated by Bayesian analysis from 59 germline origin families. The overall "r" in F9 was estimated at 3.75. The "r"s varied with the type of mutation. The "r"s ranged from 6.65 and 6.10 for transitions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, to 0.57 and 0.42 for microdeletions/microinsertions and large deletions (>1 kb), respectively. The "r" for the two subtypes of non-CpG transitions differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism was detected in 11% of the 45 origin individuals for whom the causative mutation was visualized directly by genomic sequencing of leukocyte DNA (estimated sensitivity of approximately one part in 20). Four of the five defined somatic mosaics had G:C to A:T transitions at non-CpG dinucleotides, hinting that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 US Caucasian families in which the age of the origin parent and the year of conception for the first carrier/hemophiliac were available. No evidence for a paternal age effect was seen. However, an advanced maternal age effect was observed (P=0.03) and was particularly prominent for transversions (average of the 79th percentile when maternal age was normalized for the year of conception). This suggests that an increased maternal age results in a higher rate of transmitted mutation, whereas the increased number of mitotic replications associated with advanced paternal age has little, if any, effect on the rate of transmitted mutation.

Perioperative management of von Willebrand's disease in otolaryngologic surgery.

von Willebrand's disease (VWD) is the most common hereditary bleeding disorder. Unchecked or improperly managed, VWD-associated hemorrhage can lead to catastrophic surgical outcome. Based on the authors' recent experience with 21 procedures in 12 patients, a contemporary protocol for successful perioperative management of VWD in otolaryngologic surgery is presented. In patients with VWD type 1 or 2a, desmopressin, a synthetic vasopressin analog, is administered both pre- and postoperatively to release von Willebrand factor (VWF) from storage sites. In type 2b or 3, a factor VIII concentrate rich in VWF is administered. In addition, a 10- to 14-day course of intravenous and/or oral Amicar (Immunex Corp., Seattle, WA) may be prescribed postoperatively. Intraoperatively, the surgical laser is used to further decrease blood loss and augment hemostasis. This medical and surgical protocol minimizes the risk of hemorrhage and of transfusion-related complications through the judicious use of preoperative and postoperative coagulation replacement products. Using these guidelines in a variety of otolaryngologic cases, the authors have had no bleeding complications at their institution.

One course versus two courses of antithymocyte globulin for the treatment of severe aplastic anemia in children.

PURPOSE: The aim of the therapeutic trials was to optimize the treatment of severe aplastic anemia (SAA) and moderate aplastic anemia in children who lack a suitable bone marrow donor, using immunosuppressive therapy in the most effective combination and dose. PATIENTS AND METHODS: Two sequential therapeutic trials for the treatment of severe and moderate aplastic anemia in children were conducted by 10 institutions. The treatment protocols included antithymocyte globulin (ATG), prednisone, and cyclosporine A (CSA); patients entered on the first protocol, 0190 (ATG X 2), were given two courses of ATG, and those enrolled on the second protocol, 0190B (ATG X 1), were given only one course of ATG. Ten patients were evaluable on ATG X 2. All patients had SAA; three had hepatitis-induced severe aplastic anemia (HI-SAA). Twelve patients were evaluable on ATG X 1; all had SAA, one of whom had HI-SAA. RESULTS: Seven of 10 patients on ATG X 2 responded, and eight of 12 patients treated on ATG X 1 responded. CONCLUSION: Treatment with immunosuppressive therapy using ATG, CSA, and prednisone was very well tolerated. The response rates in both protocols were similar, and results compare favorably with those of previous therapeutic trials, suggesting that a second course of ATG is not necessary.

Factor IX inhibitors and anaphylaxis in hemophilia B.

PURPOSE: We present clinical and laboratory data on 18 children from 12 hemophilia treatment centers in the United States, Canada, and Europe with the purpose of disseminating information regarding a recently recognized, potentially life-threatening complication of treatment in very young children with hemophilia B. PATIENTS AND METHODS: Twelve hemophilia centers from the United States, Canada, and Europe provided clinical information and laboratory data concerning 18 children who had severe allergic reactions to infused factor (F) IX in close association with the development of an inhibitor to FIX. Laboratory testing for establishment of the diagnosis of hemophilia B and inhibitor to FIX was done locally at the centers treating these patients. FIX gene analysis was performed at one of six molecular genetics institutes. RESULTS: All 18 children had severe hemophilia B, and in each an inhibitor antibody to FIX developed. The median age at the time of anaphylaxis (or anaphylactoid reaction) was 16 months, and the median number of exposure days to FIX was 11. The FIX inhibitor was detected almost simultaneously with the first occurrence of anaphylaxis in 12 of 18 patients. Maximum inhibitor titers were 4.5-600 Bethesda units (BU), with a median titer of 48 BU. FIX gene analysis, performed in 17 of 18 patients, demonstrated complete deletion of the FIX gene in 10 and major derangements in seven. Immune tolerance induction (ITI) regimens have been attempted in 12 patients, with generally poor responses. Two of the 12 experienced nephrotic syndrome while on ITI. Recombinant FVIIa has been successfully used to treat bleeding episodes in 11 of these children. CONCLUSION: Physicians treating young children with hemophilia B should be aware of the potentially life-threatening complication of anaphylaxis. Children with complete gene deletions or major derangements of the FIX gene appear to be at greater risk. Those identified by genotype as being at greater risk may need to receive their first 10-20 treatments in a medical facility equipped for handling such emergencies. Recombinant FVIIa, although not licensed for use in the United States, appears to be the most suitable treatment option for bleeding episodes in such patients.

Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B.

The safety and efficacy of a monoclonal antibody purified factor IX concentrate were evaluated in two continuing trials of 32 previously untreated patients with mild, moderate, or severe hemophilia B. Patients were evaluated every 2 weeks for 24 weeks and every 3 months thereafter for at least 1 year. No patients became positive for human immunodeficiency virus antibody or hepatitis C virus antibody during the trial. Two patients developed a false-positive hepatitis B core antibody, one transiently, but neither had elevated levels of alanine aminotransferase (ALT). None of the 25 patients evaluable for non-A, non-B, non-C hepatitis by strict International Society of Thrombosis and Hemostasis criteria developed elevated levels of ALT indicative of posttransfusion infection. Anaphylaxis occurred in one subject who also developed an inhibitor to factor IX (19.3 Bethesda units). Five of the eight adverse events reported (63%) were mild in severity, and the relationship of three of these to therapy was considered remote. Hemostasis with monoclonal antibody purified factor IX concentrate was excellent in all patients.