Real-world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A.

INTRODUCTION: Prophylaxis with extended half-life factor VIII (FVIII) is approved for haemophilia A, but data regarding routine clinical use are limited. AIM: To assess real-world experience of ADYNOVATE® (Antihemophilic Factor (Recombinant), PEGylated prophylaxis in children and adults with haemophilia A. METHODS: A retrospective chart review was conducted in three US haemophilia treatment centres. Records of all patients who began Adynovate prophylaxis in routine clinical practice were identified. Demographic, clinical and patient-reported information beginning 6 months before initiation of Adynovate until the record review was analysed. RESULTS: Fifteen patients (aged 9 months to 28 years), with median 9 months' use of Adynovate (range 1-15 months), were identified. All had switched from another prophylactic regimen, 13 (87%) from standard half-life recombinant FVIII. Nine (60%) patients had ≥1 bleed within 6 months preswitch. The most frequent reason for switching was to reduce infusion frequency (14 patients). After switching, infusion frequency reduced for 13 patients, and overall weekly factor consumption decreased by 19%. Eight (53%) patients had no bleeds postswitch, three (20%) had spontaneous joint bleeds (vs four pre-switch), and three (20%) had only mild traumatic bleeds. Patient/parental satisfaction with Adynovate was documented as positive in 13 of 15 (87%) cases; 2 patients were not satisfied and discontinued Adynovate. No adverse events were considered related to Adynovate. CONCLUSION: In patients who switched from a standard half-life FVIII to Adynovate prophylaxis in routine clinical practice, bleeding control was generally improved or maintained, with a lower infusion frequency and factor consumption in most patients.

Radionuclide synovectomy/synoviorthesis (RS) in patients with bleeding disorders: A review of patient and procedure demographics and functional outcomes in the ATHNdataset.

INTRODUCTION: Radionuclide synovectomy/synoviorthesis (RS) to manage proliferative synovitis in persons with bleeding disorders has been utilized for decades; however, aggregate US results are limited. AIM: To determine the prevalence of RS utilization, patient and procedure related demographics and functional outcomes in United States haemophilia treatment centres (HTCs). The ATHNdataset includes US patients with bleeding disorders who have authorized the sharing of their demographic and clinical information for research. METHODS: We performed a multi-institutional, observational cohort study utilizing this dataset through 2010. Cases treated with RS procedure were compared to controls within the dataset. Standard template for data collection included patient and procedure related demographics as well as functional outcomes including range of motion (ROM) of the affected joint. Normative age- and sex-matched control ROM was obtained from published data. RESULTS: In the ATHNdataset there were 19 539 control-patients and 196 case-patients treated with RS. Patients with severe haemophilia were more likely to have had RS compared to those with mild/moderate haemophilia, although the proportion of RS performed was similar between severe HA and HB. Inhibitory antibodies, HIV and hepatitis C infection were significantly more common in cases. There were 362 RS procedures captured with 94 cases having >1 RS procedures. CONCLUSIONS: Right-sided joint procedures were more prevalent than left-sided procedures. Overall, case-patients had worse joint ROM compared to control-patients and published normative values. Geographically, there was regional variation in RS utilization, as the Southeast region had the largest percent of case-patients.

Choosing outcome assessment tools in haemophilia care and research: a multidisciplinary perspective.

INTRODUCTION: The implementation of early long-term, regular clotting factor concentrate (CFC) replacement therapy ('prophylaxis') has made it possible to offer boys with haemophilia a near normal life. Many different regimens have reported favourable results, but the optimum treatment regimens have not been established and the cost of prophylaxis is very high. Both for optimizing treatment and reimbursement issues, there is a need to provide objective evidence of both short- and long-term results and benefits of prophylactic regimens. AIMS: This report presents a critical review of outcome measures for use in the assessment of musculoskeletal health in persons with haemophilia according to the International Classification of Functioning, Disability and Health (ICF). This framework considers structural and functional changes, activities and participation in a context of both personal and environmental factors. METHODS: Results were generated by a combination of a critical review of available literature plus expert opinion derived from a two day consensus conference between 48 health care experts from different disciplines involved in haemophilia assessment and care. Outcome tools used in haemophilia were reviewed for reliability and validity in different patient groups and for resources required. RESULTS AND CONCLUSION: Recommendations for choice of outcome tools were made according to the ICF domains, economic setting, and reason for use (clinical or research). The next step will be to identify a 'core' set of outcome measures for use in clinical care or studies evaluating treatment.

Ozonated water is inferior to propanol-based hand rubs for disinfecting hands.

Ozone is a strong oxidizing biocide that has broad-spectrum antimicrobial properties. The aim of the study was to compare the efficacy of ozone to a propanol-based hand rub for hand disinfection. Twenty subjects were enrolled in an in-vivo cross-over trial (prEN 12791). Subjects treated their hands with the reference procedure (propan-1-ol 60%) or with ozone (4 ppm). Post-wash bacterial counts were determined from one hand (immediate effect), and from the other hand that had been gloved for 3h (delayed effect). The investigation indicated that ozone is inferior to propan-1-ol 60% hand rub for hand asepsis.

Moderators of response in exercise treatment for depression: A systematic review.

INTRODUCTION: Exercise have antidepressant effects in people with Major Depressive Disorder (MDD). However, about to half of patients do not respond to exercise. The identification of factors that moderates the antidepressant effects of exercise in people with MDD may help researchers and health professionals to identify sub-groups of patients that would benefit more from exercise. METHODS: A systematic review was carried out using Medline(PubMed), EMBASE and psycINFO up to April 2015. Individual and composite moderators were summarized and the strength of the evidence was assessed. RESULTS: Eleven studies were included for review resulting in the identification of potential individual (two biological, three clinical, two psychological and two social individual) and two potential composite moderators (the interaction between BDNF and Body Mass Index (BMI) and between family history of mental illness and gender). Only the two biological features and the BDNF x BMI interaction provided confirmatory evidence. LIMITATIONS: Due the different statistical approaches used in the studies, it was not possible to perform meta-analyses. The small number of studies and the exploratory nature of the evidence limits a wider generalization of the findings. CONCLUSION: Potential clinical, psychological, social or biological moderators were identified. However, the small number of studies and the limited strength of the evidence requires further studies before drawn definitive results. Further trials should consider the inclusion of moderators analysis using an a-priori, theoretical/evidence based hypothesis in order to provide high quality evidence for the use of personalized medicine in exercise for depression.

Characterization of the anti-factor VIII immunoglobulin profile in patients with hemophilia A by use of a fluorescence-based immunoassay.

BACKGROUND: The development of neutralizing antibodies, referred to as inhibitors, against factor VIII is a major complication associated with FVIII infusion therapy for the treatment of hemophilia A (HA). Previous studies have shown that a subset of HA patients and a low percentage of healthy individuals harbor non-neutralizing anti-FVIII antibodies that do not elicit the clinical manifestations associated with inhibitor development. OBJECTIVE: To assess HA patients' anti-FVIII antibody profiles as potential predictors of clinical outcomes. METHODS: A fluorescence immunoassay (FLI) was used to detect anti-FVIII antibodies in 491 samples from 371 HA patients. RESULTS: Assessments of antibody profiles showed that the presence of anti-FVIII IgG1 , IgG2 or IgG4 correlated qualitatively and quantitatively with the presence of an FVIII inhibitor as determined with the Nijmegen-Bethesda assay (NBA). Forty-eight patients with a negative inhibitor history contributed serial samples to the study, including seven patients who had negative NBA titers initially and later converted to being NBA-positive. The FLI detected anti-FVIII IgG1 in five of those seven patients prior to their conversion to NBA-positive. Five of 15 serial-sample patients who had a negative inhibitor history and had anti-FVIII IgG1 later developed an inhibitor, as compared with two of 33 patients with a negative inhibitor history without anti-FVIII IgG1 . CONCLUSIONS: These data provide a rationale for future studies designed both to monitor the dynamics of anti-FVIII antibody profiles in HA patients as a potential predictor of future inhibitor development and to assess the value of the anti-FVIII FLI as a supplement to traditional inhibitor testing.

Metaphyseal osteopathy in three Australian Kelpie siblings.

CASE REPORT: Metaphyseal osteopathy (MO) was diagnosed in three Australian Kelpie puppies that were presented for veterinary assessment of lameness. The three puppies were siblings. Each was from a different litter by the same breeding pair. The puppy in case one was seen by the authors, and the puppies in cases two and three were patients at other veterinary hospitals. However, the medical records and radiographs were examined and reviewed for this report. Radiographic investigation of the lameness revealed pathognomonic appearance of MO affecting the metaphyseal region of the long bones in all three puppies. The diagnosis was confirmed on histopathology in one patient. CONCLUSION: MO is considered a disease of large and giant-breed dogs, being rarely reported in non-large-breed dogs, and has not been reported in the Australian Kelpie, which is considered a medium-breed dog. This case series suggests a previously unreported breed predisposition to MO in the Australian Kelpie.

Late immune tolerance induction in haemophilia A patients.

The incidence of inhibitor development in patients with severe haemophilia A is approximately 30%. Immune tolerance induction (ITI) is commonly utilized to eradicate these antibodies and is successful in 63-100% of cases. Potential predictors of a poor outcome in ITI include a high preinduction titre, high historical peak titre, older age at start of ITI and prolonged interval from diagnosis to start of ITI. The goal of this study was to characterize the outcomes of patients from our centre who have undergone late ITI, many of whom had poor prognostic features. Medical records of patients in our centre with severe/moderately severe haemophilia A (<2% FVIII activity) and history of inhibitor were reviewed. Data were abstracted from all patients who attempted late ITI. Nine patients underwent late ITI between January 1999 and December 2011. Within this cohort, 7 (78%) patients were black, 6 (67%) were <21 years old and 4 (44%) had a family history of inhibitor. Three patients had previously received ITI unsuccessfully. To date, 4 (44%) patients are tolerized (persistently negative inhibitor titre, FVIII recovery >66% and successfully treated with FVIII products ± FVIII t(½) of >6 h). Three patients are partially tolerized (have low responding inhibitor, variable FVIII recovery and successfully treated with FVIII products). Two patients are not tolerized. Some patients with haemophilia A and long-standing inhibitors may benefit from ITI.

Inter- and intra-operator variability associated with extracapsular suture tensioning: an ex vivo study.

OBJECTIVES: To determine inter- and intra- operator variability associated with extracapsular suture tensioning as performed during lateral fabello-tibial suture placement. STUDY DESIGN: Ex vivo study. METHODS: Fifteen Greyhound cadaveric pelvic limbs were prepared by cutting the cranial cruciate ligament and placing an extracapsular fabello-tibial suture. On two occasions, three surgeons tensioned the extracapsular suture of each stifle. Stifles were returned to 135 degrees of flexion and the suture tension was measured using a commercially available suture tensioner with inbuilt tensiometer. STATISTICAL ANALYSIS: Intra-operator and inter-operator agreement were assessed using the limits of agreement method. A linear mixed effects model was specified to assess the effect of operator, repeated estimates and stifle order on tension applied. RESULTS: The mean difference within the three operators ranged from 0 to 14.7N. With 95% limits of agreement, on most occasions for all three operators, the difference was between -31.7 and 41.0 N. The mean difference between the three operators ranged from 6.0 to 30.7 N. With 95% limits of agreement, on most occasions the difference between operators was between -25.6 and 62.5 N. CLINICAL SIGNIFICANCE: Marked variation exists in the tension applied during fabello-tibial suture application, both within and between surgeons. This variation may lead to inconsistent clinical outcomes. Further studies are required to determine the clinical consequences of this marked variation in extracapsular suture tensioning.

An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group.

Evaluation of prophylactic treatment of haemophilia requires sensitive methods. To design and test a new magnetic resonance imaging (MRI) scale for haemophilic arthropathy, two scales of a combined MRI scoring scheme were merged into a single scale which includes soft tissue and osteochondral subscores. Sixty-one joint MRI's of 46 patients with haemophilia were evaluated by four radiologists using the new and older scales. Forty-six of the joints were evaluated using two X-ray scales. For all MRI scores, interreader agreement and correlations with X-ray scores and lifetime number of haemarthroses were analysed. The interreader agreement intraclass correlation coefficient was 0.82, 0.89 and 0.88 for the soft tissue and osteochondral subscores and the total score, as evaluated according to the new MRI scale, compared to 0.80 and 0.89 as for the older scales. The total score and osteochondral subscore according to the new scale, as well as scores according to the older scales were correlated (P < 0.01) with number of haemarthroses (Spearman correlation 0.35-0.68) and with the X-ray scores (Spearman correlation 0.40-0.76), but no correlation (P > 0.05) was found between the soft tissue subscore of the new MRI scale and the X-ray scores. The new MRI scale is simpler to apply than the older and has similar reader reliability and correlation with lifetime number of haemarthroses, and by separating soft tissue and osteochondral changes it gives additional information. The new scale is useful for analyses of early and moderate stages of arthropathy, and may help to evaluate prophylactic haemophilia treatment.

Evaluation of a novel flow chamber system to assess clot formation in factor VIII-deficient mouse and anti-factor IXa-treated human blood.

Blood flow properties play important roles in the regulation and formation of thrombus. To evaluate the influence of blood flow on thrombus formation in haemophilia, whole blood samples were obtained from FVIII-deficient (FVIII(-/-) ) and wild-type (FVIII(+/+) ) mice (n = 6 respectively), and from six human volunteers. Anti-FIXa aptamer was added to human blood to model acquired haemophilia B. Recalcified whole blood samples containing corn trypsin inhibitor and danaproid were perfused over the microchip coated with collagen and tissue thromboplastin at shear rates of 1100 and 110 s(-1) . Thrombus formation in the capillary was quantified by monitoring flow pressure changes. The intervals to 5 kPa (T(5) ) and 40 k Pa (T(40) ) reflect the onset and growth of thrombus formation respectively. Furthermore, fibrin and platelets in thrombi were quantified by immunostaining. T(5) at both shear rates were similar in FVIII(-/-) and FVIII(+/+) mice. T(40) of FVIII(-/-) mice (1569 ± 565 s) was significantly delayed compared with FVIII(+/+) mice (339 ± 78 s) at 110 s(-1) (P < 0.05), but not at 1100 s(-1) . The delay was normalized by adding human FVIII (2 IU mL(-1) ). Similarly, adding anti-FIXa aptamer to human blood prolonged T(40) at 110 s(-1) (P < 0.01), but not at 1100 s(-1) . Impaired production of fibrin due to anti-FIXa aptamer at 110 s(-1) was shown in the immunostained thrombus. Our perfusion experiments demonstrated that shear rates influence thrombus formation patterns in haemophilia, and that reduced activity of intrinsic tenase (FIXa-FVIIIa) becomes evident under venous shear rates.

Medical radiation exposure in children with bleeding disorders: an institutional experience.

Patients with bleeding disorders may be exposed to ionizing radiation during medical care. We hypothesized that children with severe haemophilia may have higher radiation exposure than those with mild bleeding disorders (MBDs). To compare medical radiation exposure rates between children with severe haemophilia and MBDs. Charts of 35 pediatric patients with severe haemophilia were randomly selected from a database of active male patients followed in our bleeding disorders clinic from 2000 to 2010. Case patients were age and sex matched with two control patients with MBDs [Type 1 von Willebrand disease (VWD) or mild platelet function defect (PFD)]. By retrospective review, data on radiation exposure in millisieverts (mSv) was collected from radiological studies performed within Emory/CHOA. The rates of exposure between cohorts were compared using the Mann-Whitney Test. Case patients had a mean of 11.3 (median 8, IQR = 29) radiographic studies compared with 1.8 (median 1, IQR = 11) for controls (P < 0.001). The mean effective dose of radiation per patient per year of study was two mSv for case patients (median 0.4, IQR = 3) and 0.4 mSv for control patients (median 0.01, IQR = 0.3) (P < 0.001). Overall, 1.4% of controls and 31.4% of cases accumulated high to very high levels of exposure ( > 20 mSv). Case patients with severe hemophilia accumulated significantly more medical radiation exposure than controls. While the use of ionizing radiation is often necessary for management of these patients, avoidance of unnecessary exposure along with exploration of alternative imaging techniques and low dose protocols should be considered whenever possible.

Osteosarcoma at the site of titanium orthopaedic implants in a dog.

An Alaskan Malamute underwent unilateral tibial tuberosity advancement (TTA) surgery to stabilise a stifle joint with a deficient cranial cruciate ligament. The dog made an excellent recovery with no postoperative complications, until 20 months post-surgery when he presented with acute onset ipsilateral pelvic limb lameness. Osteosarcoma (OSA) was diagnosed adjacent to the titanium implants. Currently, there is a paucity of information on the epidemiology of OSA adjacent to orthopaedic implants in canine patients. The clinical, radiological and pathological findings of this case of periprosthetic OSA, and a potential causal relationship between titanium implants and bone neoplasia, are discussed.

Prevalence of malignancies among U.S. male patients with haemophilia: a review of the Haemophilia Surveillance System.

The prevalence of malignancies in US male patients with haemophilia, with or without concomitant viral infections, remains unknown. To estimate the prevalence of malignancy in US male patients with haemophilia. We investigated the prevalence of malignancies among male patients with haemophilia using data from a six-state haemophilia surveillance project. Case patients with malignancies were identified using International Classification of Diseases, 9th Revision, Clinical Modification codes abstracted from hospital records and death certificates during the surveillance period. Cancer prevalence rates were calculated for each year during the surveillance and compared with age- and race-specific prevalence rates among the U.S. male population obtained from the Surveillance, Epidemiology and End Results (SEER) Program. A total of 7 cases of leukaemia, 23 cases of lymphoma and 56 classifiable solid malignancies were identified among 3510 case patients during a total of 15,330 annual data abstraction collections. The rates of leukaemia, lymphoma and liver cancer among case patients were significantly higher than the rates among U.S. males as judged by prevalence ratios of 3.1 [95% confidence interval (CI) = 1.4-7.0] and 2.9 (95% CI =1.8-4.6), respectively. In contrast, the prevalence ratio of prostate cancer was lower than expected at 0.49 (95% CI = 0.31-0.77). Overall the prevalence of most cancers among case patients was similar to that of the U.S. male population. However, patients with haemophilia who have unexplained symptoms should be evaluated for malignancy.

Pathophysiology, diagnosis and prevention of arthropathy in patients with haemophilia.

Recurrent haemarthroses in patients with severe and moderate haemophilia can result in the development of one or more target joints and subsequent degenerative joint disease. This debilitating process is characterized by physical and physiological changes in articular cartilage, synovium and bone. Models of degenerative joint disease have been examined after the addition of whole blood or blood components to cell cultures or animal joints, or by monitoring biomarkers in individuals with and without haemophilia. Inhibition of cartilage-based proteoglycan synthesis and induction of proliferative synovitis are commonly observed in these models of degenerative joint disease. Clinical evaluation of joint disease includes use of specially designed physical examination and radiographic tools. Efforts to prevent or limit arthropathy include the use of prophylactic factor infusion regimens, surgical joint intervention or both.

Adenotonsillectomy in patients with desmopressin responsive mild bleeding disorders: a review of the literature.

SUMMARY: Many patients with mild inherited bleeding disorders such as von Willebrand disease (VWD), mild haemophilia A (HA) and platelet function defects (PFD) undergo adenoidectomy and/or tonsillectomy (AT) procedures each year. Management of bleeding in these patients can be challenging, as little published data exist to guide haemostatic management during these relatively common procedures. Therefore, the literature was reviewed to identify AT procedures in patients with 1-deamino-8-D-argine vasopressin responsive mild bleeding disorders. The review revealed no randomized prospective trials of haemostatic management in this patient population. Case reports and small case series identified 144 patients who had AT procedures. Frequency of desmopressin and antifibrinolytic dosing varied widely. Fifteen percentage of patients experienced postoperative bleeding with nearly half being early (<24 h) bleeding and half being late (>24 h) bleeding. Hyponatraemia complicated the procedures in 47% of cases and six hyponatremic seizures were reported. Issues identified by this review that need to be addressed in future clinical trials include type and amount of fluid restriction when utilizing desmopressin, duration of antifibrinolytic therapy and duration and frequency of desmopressin dosing.

Malignancy in patients with haemophilia: a review of the literature.

Haemophilia A and B are rare X-linked conditions. Elevated rates of HIV and hepatitis C related malignancies in these patients are well reported, however rates of other types of cancers are not. Therefore, a retrospective literature review of cancer in patients with haemophilia was conducted. A Medline search of articles from January 1966 to July 2009 utilizing the keywords haemophilia, leukaemia, malignancy, mortality, neoplasm and cancer was performed. The articles were reviewed and additional relevant publications were located from the references. Data on age, type and severity of haemophilia, HIV status, type of malignancy and outcomes were recorded as available. Thirty-two cases of leukaemia were identified as well as 159 malignant solid tumours. Specific incidence and prevalence rates could not be calculated due to the limited nature of the information available in the reports. Many types of malignancy have been reported in persons with haemophilia irrespective of infection with HIV and hepatitis C yet prevalence and incidence rates compared to the general population remain unknown. Patients with haemophilia can manifest non infectious related malignancies and symptomatic patients should be evaluated accordingly.

Changes in net ecosystem productivity of boreal black spruce stands in response to changes in temperature at diurnal and seasonal time scales.

Net ecosystem productivity (NEP) of boreal coniferous forests is believed to rise with climate warming, thereby offsetting some of the rise in atmospheric CO(2) concentration (C(a)) by which warming is caused. However, the response of conifer NEP to warming may vary seasonally, with rises in spring and declines in summer. To gain more insight into this response, we compared changes in CO(2) exchange measured by eddy covariance and simulated by the ecosystem process model ecosys under rising mean annual air temperatures (T(a)) during 2004-2006 at black spruce stands in Saskatchewan, Manitoba and Quebec. Hourly net CO(2) uptake was found to rise with warming at T(a) < 15 degrees C and to decline with warming at T(a) > 20 degrees C. As mean annual T(a) rose from 2004 to 2006, increases in net CO(2) uptake with warming at lower T(a) were greater than declines with warming at higher T(a) so that annual gross primary productivity and hence NEP increased. Increases in net CO(2) uptake measured at lower T(a) were explained in the model by earlier recovery of photosynthetic capacity in spring, and by increases in carboxylation activity, using parameters for the Arrhenius temperature functions of key carboxylation processes derived from independent experiments. Declines in net CO(2) uptake measured at higher T(a) were explained in the model by sharp declines in mid-afternoon canopy stomatal conductance (g(c)) under higher vapor pressure deficits (D). These declines were modeled from a hydraulic constraint to water uptake imposed by low axial conductivity of conifer roots and boles that forced declines in canopy water potential (psi(c)), and hence in g(c) under higher D when equilibrating water uptake with transpiration. In a model sensitivity study, the contrasting responses of net CO(2) uptake to specified rises in T(a) caused annual NEP of black spruce in the model to rise with increases in T(a) of up to 6 degrees C, but to decline with further increases at mid-continental sites with lower precipitation. However, these contrasting responses to warming also indicate that rises in NEP with climate warming would depend on the seasonality (spring versus summer) as well as the magnitude of rises in T(a).