Showing papers in "Haemophilia in 2012"

A study of variations in the reported haemophilia B prevalence around the world: A STUDY OF REPORTED HAEMOPHILIA B PREVALENCE

Abstract: Summary. The objectives of this article were to study the reported prevalence of haemophilia B (HB) on a country‐by‐country basis and to analyse whether the prevalence of HB varied by national economy. The prevalence of HB is the proportion of diagnosed, reported cases of HB in a population at a specific point of time. We collected data on the HB prevalence for 105 countries from the World Federation of Hemophilia annual global surveys. Our results showed that the HB prevalence varied considerably among countries, even among the wealthiest of countries. The HB prevalence (per 100 000 males) for the highest income countries was 2.69 ± 1.61 (mean ± SD), whereas the prevalence for the rest of the world was 1.20 ± 1.33 (mean ± SD). Ireland had the highest reported HB prevalence of 8.07 per 100 000 males. There was a strong trend of increasing HB prevalence (per 100 000 males) over time. Prevalence data reported from the WFH compared well with prevalence data from the literature. The WFH annual global surveys have some limitations, but they are the best available source of worldwide haemophilia data. Prevalence data are extremely valuable information for the planning efforts of national healthcare agencies in setting priorities and allocating resources for the treatment of HB.

Inherited platelet disorders.

Abstract: Summary. Inherited diseases of the megakaryocyte lineage give rise to bleeding when platelets fail to fulfill their hemostatic function upon vessel injury. Platelet defects extend from the absence or malfunctioning of adhesion (GPIb-IX-V, Bernard–Soulier syndrome) or aggregation receptors (integrin αIIbβ3, Glanzmann thrombasthenia) to defects of primary receptors for soluble agonists, secretion from storage organelles, activation pathways and the generation of procoagulant activity. In disorders such as the Chediak–Higashi, Hermansky–Pudlak, Wiskott–Aldrich and Scott syndromes the molecular lesion extends to other cells. In familial thrombocytopenia (FT), platelets are produced in insufficient numbers to assure hemostasis. Some FT affect platelet morphology and give rise to the ‘giant platelet’ syndromes (e.g. MYH9-related diseases) with changes in megakaryocyte maturation within the bone marrow and premature release of platelets. Diseases of platelet production may also affect other cells and in some cases interfere with development and/or functioning of major organs. Diagnosis of platelet disorders requires platelet function testing, studies often aided by the quantitative analysis of receptors by flow cytometry and fluorescence and electron microscopy. New generation DNA-based procedures including whole exome sequencing offer an exciting new perspective. Transfusion of platelets remains the most common treatment of severe bleeding, management with desmopressin is often used for mild disorders. Substitute therapies are available including rFVIIa and the potential use of thrombopoietin analogues for FT. Stem cell or bone marrow transplanation has been successful for several diseases while gene therapy shows promise in the Wiskott–Aldrich syndrome.

F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity.

Abstract: Both genetic and treatment-related risk factors contribute to the development of inhibitors in haemophilia An inhibitor surveillance system piloted at 12 US sites has the goal of assessing risk factors through prospective data collection This report examines the relationship of genotype and race/ethnicity to history of inhibitor in a large cohort of US haemophilia patients Mutation analysis was performed on 676 haemophilia A (HA) and 153 haemophilia B (HB) patients by sequencing, Multiplex Ligation-dependent Probe Amplification, and PCR for inversions in F8 introns 22 (inv22) and 1 (inv1) Two HB patients with deletions had history of inhibitor In severe HA, frequency of history of inhibitor was: large deletion 571%, splice site 357%, inv22 268%, nonsense 245%, frameshift 129%, inv1 111% and missense 95% In HA, 196% of 321 White non-Hispanics (Whites), 371% of 35 Black non-Hispanics (Blacks) and 469% of 32 Hispanics had history of inhibitor (P = 00003) Mutation types and novel mutation rates were similar across ethnicities When F8 haplotypes were constructed, Whites and Hispanics showed only H1 and H2 Within H1, history of inhibitor was 124% in Whites, 400% in Blacks (P = 0009) and 324% in Hispanics (P = 0002) Inhibitor frequency is confirmed to vary by mutation type and race in a large US population White patients with history of inhibitor did not exhibit rare F8 haplotypes F8 gene analysis did not reveal a cause for the higher inhibitor frequencies in Black and Hispanic patients

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

Abstract: 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 0.05) 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.

Aspects of current management: orthopaedic surgery in haemophilia.

Abstract: If continuous prophylaxis is not feasible due to expense or lack of venous access, we must aggressively treat major haemarthroses (including arthrocentesis) to prevent progression to synovitis, recurrent joint bleeds, and ultimately end-stage osteoarthritis (haemophilic arthropathy). For the treatment of chronic haemophilic synovitis, radiosynovectomy should always be indicated as the first procedure. If, after three procedures with 6-month interval, radiosynovectomy fails, an arthroscopic synovectomy must be indicated. Between the second and fourth decades, many haemophilic patients develop joint destruction (arthropathy). At this stage possible treatments include alignment osteotomy, arthroscopic joint debridement, arthrodesis (joint fusion) and total joint arthroplasty. For the hip press-fit uncemented components (hemispherical acetabulum, flanged femoral stem, metal-to-polyethylene) are recommended whilst for the knee a posterior-stabilized (PS) cemented design is advised. Muscular problems must not be underestimated in haemophilia due to their risk of developing compartment syndromes (which will require surgical decompression) and pseudotumours (which will require surgical removal or percutaneous treatment). Regarding patients with inhibitors, the advent of APCCs and rFVIIa has made major orthopaedic surgery possible, leading to an improved quality of life for haemophilia patients. Concerning local fibrin seal, it is not always necessary to achieve haemostasis in all surgical procedures performed in persons with haemophilia. However, it could be a good adjunct therapy, mainly when a surgical field potentially will bleed more than expected (i.e. patients with inhibitors), and also in some orthopaedic procedures (mainly the surgical removal of pseudotumours).

Psychosocial aspects of haemophilia: a systematic review of methodologies and findings.

Abstract: Psychosocial factors have a significant impact on quality of life for patients with chronic diseases such as haemophilia Interventions to support the psychosocial needs of patients and their families, such as offering information and assistance, clarifying doubts, and teaching coping strategies to minimize the impact of disabilities, may help to maximize patient outcomes and improve quality of life for their families The aim of this study was to evaluate the current literature on psychosocial aspects of haemophilia Literature searches were performed using the PubMed database to identify studies evaluating psychosocial stressors in persons with haemophilia Articles pertaining to the HIV epidemic were excluded from the analysis, as were those published before 1997 The literature reviews identified 24 studies, covering a range of different populations, generally with small cohorts (n < 100) Most studies were questionnaire based, with almost no overlap in terms of the instruments used Only one study combined questionnaire techniques with qualitative methods Except for two European studies, all publications reported data from a single country Overall, studies tended to show that quality of life is reduced in persons with haemophilia, with a potential impact on education and employment, particularly when prophylactic treatment is not available Carrier status in women may have a psychosocial impact and affect reproductive choices Data on psychosocial aspects of the haemophilia life cycle are lacking in the published literature, along with data from developing countries There is a need for more international, multifaceted research to explore and quantify the social and psychological aspects of life with haemophilia

A national study of pain in the bleeding disorders community: a description of haemophilia pain.

Abstract: Summary. The National Pain Study was a prospective, computer-based, descriptive survey of the pain experience of persons with a bleeding disorder conducted in the United States over a 28 month period from 2007 to 2009. The aim of this study was to (i) determine the language used by patients to describe and differentiate acute and persistent pain, (ii) describe pharmacological and non-pharmacological strategies utilized to control pain, (iii) assess the perceived effectiveness of current pain management on quality of life and, (iv) to determine who provides pain management to this population. One thousand, one hundred and four surveys were received. Only the responses of the 764 respondents who reported having hemophilia A or B were evaluated for this paper. Thirty nine percent of participants reported their pain was not well treated. The average acute pain score associated with a bleed reported was 5.97/10 while the average persistent pain score reported was 4.22/10. The most frequently reported word descriptors for acute pain were: throbbing, aching, sharp, tender and miserable. The most frequently reported word descriptors for persistent pain were aching, nagging, tiring, sharp, and tender. The most frequently reported pain strategies for acute and persistent pain included factor, rest, ice, elevation, and compression. Alcohol and illicit drugs were reportedly used to manage both acute pain as well as persistent pain. Primarily, short-acting opioids and acetaminophen were reported to treat both acute and persistent pain. Hematologists and primary care providers provide the majority of pain management for persons with hemophilia (PWH). Quality of life (QOL) scores were lowest in the domains of pain, energy/fatigue and physical problems indicating disruption of QOL. This substantiates under-recognition and under-treatment of pain in the hemophilia population when combined with the 39% of respondents who felt their pain was not well treated and literature in the general pain population of wide spread under-treatment of pain. Recommendations: The NPS is an initial step in recognizing the prevalence and description of pain in PWH. HTC providers should educate themselves in pain management techniques to better serve this population. Further research is necessary to develop specific pain management guidelines for the bleeding disorders population that include multimodal holistic treatment plans.

WFH: closing the global gap--achieving optimal care.

Abstract: For 50 years, the World Federation of Hemophilia (WFH) has been working globally to close the gap in care and to achieve Treatment for All patients, men and women, with haemophilia and other inherited bleeding disorders, regardless of where they might live. The WFH estimates that more than one in 1000 men and women has a bleeding disorder equating to 6,900,000 worldwide. To close the gap in care between developed and developing nations a continued focus on the successful strategies deployed heretofore will be required. However, in response to the rapid advances in treatment and emerging therapeutic advances on the horizon it will also require fresh approaches and renewed strategic thinking. It is difficult to predict what each therapeutic advance on the horizon will mean for the future, but there is no doubt that we are in a golden age of research and development, which has the prospect of revolutionizing treatment once again. An improved understanding of "optimal" treatment is fundamental to the continued evolution of global care. The challenges of answering government and payer demands for evidence-based medicine, and cost justification for the introduction and enhancement of treatment, are ever-present and growing. To sustain and improve care it is critical to build the body of outcome data for individual patients, within haemophilia treatment centers (HTCs), nationally, regionally and globally. Emerging therapeutic advances (longer half-life therapies and gene transfer) should not be justified or brought to market based only on the notion that they will be economically more affordable, although that may be the case, but rather more importantly that they will be therapeutically more advantageous. Improvements in treatment adherence, reductions in bleeding frequency (including microhemorrhages), better management of trough levels, and improved health outcomes (including quality of life) should be the foremost considerations. As part of a new WFH strategic plan (2012-2014) the WFH has identified several key initiatives for particular emphasis - continuation of the Global Alliance for Progress (GAP) program, a new initiative to address underserved countries and regions (The Cornerstone Initiative), enhancing health outcomes research and analysis, and a new research mentorship program. Despite our progress to date in closing the global gap in care, our work is not complete. Too many patients remain undiagnosed and too few receive adequate treatment. This paper will also discuss historical, present and future challenges and opportunities to close the gap in care and achieve Treatment for All.

Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies.

Abstract: Thrombotic adverse events (AEs) after clotting factor concentrate administration are rare but the actual rate is unknown. A systematic review of prospective studies (1990-2011) reporting safety data of factor concentrates in patients with haemophilia A (HA), haemophilia B (HB) and von Willebrand disease (VWD) was conducted to identify the incidence and type of thrombotic AEs. In 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients treated with 27 different concentrates (20 plasma-derived, 7 recombinant), 20 thrombotic AEs (2 HA, 11 HB, 7 VWD) were reported, including two major venous thromboembolic episodes (both in VWD patients on prolonged replacement for surgery). The remaining thrombotic AEs were superficial thrombophlebitis, mostly occurring at infusion sites in surgical patients and/or during concentrate continuous infusion. The overall prevalence was 3.6 per 10(3) patients (3.6 per 10(4) for severe AEs) and 1.13 per 10(5) infusions, with higher figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non-inhibitor-related AEs. Thrombosis-related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use. Data from prospective studies over the last 20 years suggest that the risk of thrombotic AEs from factor concentrate administration is small and mainly represented by superficial thrombophlebitis. These findings support the high degree of safety of products currently used for replacement treatment.

Pain management in patients with haemophilia: a European survey

Abstract: There are no evidence-based guidelines on pain management in people with haemophilia (PWH), who may suffer acute, disabling pain from haemarthroses and chronic arthropathic pain. To review evidence and to investigate current clinical practice in pain assessment and management in PWH the European Haemophilia Therapy Standardisation Board undertook a literature review and a survey in 22 Haemophilia Treatment Centres (HTC), using a questionnaire and seven clinical scenarios. Consensus was sought on pain assessment and management in PWH. Few clinical studies on pain management in PWH were identified. The HTCs care for 1678 children (47% severe haemophilia, 84% on prophylaxis, 17% with arthropathy and 8% with chronic pain) and 5103 adults (44% severe haemophilia, 40% on prophylaxis, 67% with arthropathy and 35% with chronic pain). Analgesics are prescribed by HTCs in 80% of cases (median; range 0-100%) and in 10% (median; range 0-80%) are bought over the counter. Pain and analgesic use are assessed when reported by patients and at check-ups. Only eight centres use a specific pain scale and/or have specific pain guidelines. Two HTCs arrange regular consultations with pain specialists. For acute pain, the preferred first-line drug is paracetamol for children, and paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for adults. Children with chronic pain are treated with paracetamol or NSAIDs, whereas adults usually receive Cox-2 inhibitors. Second-line therapy is heterogeneous. There is little published evidence to guide pain assessment and management in PWH, and clinical practice varies considerably across Europe. General and specific recommendations are needed.

A systematic review: The use of desmopressin for treatment and prophylaxis of bleeding disorders in pregnancy.

Abstract: Desmopressin (DDAVP) is commonly used for treatment and prevention of bleeding complications in patients with bleeding disorders including haemophilia A, von Willebrand's disease (VWD) and other less common disorders. This article reviews the current evidence for the use of DDAVP in pregnancy to clarify its efficacy and safety with regard to maternal and foetal outcome. A search of the literature found 30 studies that reported DDAVP use in pregnancy for prophylaxis or treatment of bleeding complications with 216 pregnancies reported in total. The most common indication was prophylaxis for prevention of bleeding during pregnancy and postpartum haemorrhage. DDAVP was used successfully in the first and early second trimester for bleeding prophylaxis in 50 pregnancies. No postpartum bleeding complications were reported in 167 out of 172 pregnancies when DDAVP was used for peripartum haemostatic cover. Twenty-nine studies reported no significant adverse events as a result of treatment with DDAVP. One case of water intoxication seizure and one case of premature labour following the use of DDAVP was reported in a single study. Other maternal side effects included facial flushing and headache and were reported by one study. These side effects were generally well tolerated by patients. There were no other significant adverse events reported in any of the studies as a result of DDAVP use. Foetal outcome was recorded in ten studies with no adverse foetal outcomes. In conclusion, this review shows that DDAVP in selected cases is effective in reducing bleeding complications associated with pregnancy and childbirth with a good safety record. Further research is needed to confirm these findings as they are based on the currently available evidence from small studies and case series only.

Personalized prophylaxis: PERSONALIZED PROPHYLAXIS

Abstract: Summary. Prophylaxis is the recommended treatment for people with severe haemophilia. It is unlikely that a single prophylactic regimen, for example based on weight, would be optimal for all patients and therefore each individual should have a personalized regimen, agreed between themselves and their haemophilia centre. This regimen should take into account the individual’s bleeding pattern, the condition of their musculoskeletal system, level and timing of physical activity and measurement of coagulation factor in their blood. It is important to recognize that prophylactic regimens are likely to need to change with time as the circumstances of an individual change. For example, activity may change with age or with the season and an individual’s factor VIII pharmacokinetics vary with age. Knowledge of a patient’s pharmacokinetics is likely to help personalize prophylaxis when combined with other information. Factor VIII pharmacokinetics are simple to measure in routine clinical practice and can be adequately calculated from 2 to 3 blood samples combined with a simple to use computer program. Prophylaxis is expensive and, in countries with a limited health care budget, ways to improve its cost effectiveness need to be considered to allow increased access to this treatment. For example, increasing the frequency of prophylaxis can dramatically reduce the amount of treatment required to sustain measureable factor levels and hence reduce cost. The introduction of longer‐acting coagulation factors may necessitate a change in concepts about prophylaxis because whilst these agents may sustain an apparently adequate trough level with fewer infusions, the length of time a person spends at a low level will be increased and this could increase the risk of bleeding, especially at the time of increased physical activity. There is convincing evidence that prophylaxis is the optimal therapy for severe haemophilia, optimizing treatment for each individual and increasing access to this treatment modality are important goals for the future.

The role of ultrasonography in the diagnosis of the musculo-skeletal problems of haemophilia.

Abstract: Recurrent haemarthrosis is the final cause of haemophilic arthrosic disease in haemophilia patients. Therefore, it is essential to diagnose it early, both clinically and by imaging. In addition, haemophilia patients experience chronic synovitis, joint degeneration, muscle haematoma and pseudotumours. The objective of this article is to highlight the value of ultrasounds in the diagnosis and control of the evolution of musculo-skeletal problems in haemophilia patients. To this end, we have performed a literature search in the PubMed, Web of Science(®) (WOS) and SciVerse bases, using the following keywords: hemophilia or haemophilia and ultrasonography (US), ultrasound, echography and sonography. The search was limited to studies published in English between the years 1991 and 2011, finding a total of 221 references. After reviewing the title or abstract for evidence of the use of US for the diagnosis of musculo-skeletal lesions in haemophilia, we selected 24 of these references. We added data collected from our experience to the most important data found in the references. Our main conclusion is that US is highly valuable for the diagnosis of musculo-skeletal diseases in haemophilia. It is a fast, effective, safe, available, comparative, real-time technique that can help us confirm the clinical examination. It is particularly important in acute haemarthrosis, as it can be used to objectively identify the presence of blood in the joints, measure its size, pinpoint its location, assess its evolution and confirm its complete disappearance.

Healthcare expenditures for males with haemophilia and employer-sponsored insurance in the United States, 2008.

Abstract: Although hemophilia has a potentially high economic impact, published estimates of health care costs for Americans with hemophilia are sparse and non-specific as to the non-bleeding complications of the disease. The objective of this study is to estimate average annual health care expenditures for people with hemophilia covered by employer-sponsored insurance, stratified according to the influence of age, type of hemophilia [A (factor VIII deficiency) versus B (factor IX)], presence of neutralizing alloantibody inhibitors and exposure to blood-borne viral infections. Data from the MarketScan Commercial and Medicare Research Databases were used for the period 2002-2008 to identify cases of hemophilia and to estimate mean and median medical expenditures during 2008. A total of 1,164 males with hemophilia were identified with continuous enrollment during 2008, 933 with hemophilia A and 231 with hemophilia B. Mean health care expenditures were $155,136 [median $73,548]. Mean costs for 30 (3%) males with an inhibitor were 5 times higher than for males without an inhibitor, approximately $697,000 [median $330,835] and $144,000 [median $73,321], respectively. Clotting factor concentrate accounted for 70%-82% of total costs. Average costs for 207 adults with HCV or HIV infection were 1.5 times higher than those for adults without infection. Hemophilia treatment is costly, particularly for individuals with neutralizing alloantibody inhibitors who require bypassing agents. Efforts to understand the cause of inhibitors are needed so that prevention strategies can be implemented and the excess costs resulting from this serious complication of hemophilia care can be avoided.

Treatment patterns, health‐related quality of life and adherence to prophylaxis among haemophilia A patients in the United States

Abstract: Prophylaxis and adherence to prophylaxis are increasingly recognized as important factors for the health-related quality of life (HRQOL) of haemophilia patients. This study aims to assess treatment practices over time, HRQOL and adherence among severe haemophilia A patients in the US. Severe haemophilia A patients or their caregivers participated in a 2009 cross-sectional survey. HRQOL was measured using either PEDS-QL or SF-12; adherence was measured using the VERITAS-Pro. Student t-tests evaluated differences between children vs. adults and self-infusion status. A total of 117 respondents participated in the survey, capturing data for 64 adults (mean age = 37.9 years) and 53 children (mean age = 10.5 years). Although 96% of paediatric patients were currently receiving prophylaxis, only 32 (50%) adults reported receiving prophylaxis at some point in their life. Adults who have always been on prophylaxis reported better physical functioning and physical HRQOL (both P < 0.05) than adults who had not. The paediatric group reported better adherence compared to the adult group on the total scale (38 vs. 45.8, P < 0.05). Children <12 years had higher adherence than adolescents 12-18 years old (35.5 vs. 40.8; P < 0.05). Paediatric patients infused by family members showed better adherence than paediatric self-infusers (P < 0.05). This study showed different treatment patterns between paediatric and adult patients and how the patterns impacted HRQOL. It also provided the first standardized evaluation of adherence using the VERITAS-Pro in a US national sample. This study enhances understanding of treatment practices and adherence for the US haemophilia population and may offer insight into where adherence can be improved.

Exploring the biological basis of haemophilic joint disease: experimental studies.

Abstract: Haemophilia has been recognized as the most severe among the inherited disorders of blood coagulation since the beginning of the first millennium. Joint damage is the hallmark of the disease. Despite its frequency and severity, the pathobiology of blood-induced joint disease remains obscure. Although bleeding into the joint is the ultimate provocation, the stimulus within the blood inciting the process and the mechanisms by which bleeding into a joint results in synovial inflammation (synovitis) and cartilage and bone destruction (arthropathy) is unknown. Clues from careful observation of patient material, supplemented with data from animal models of joint disease provide some clues as to the pathogenesis of the process. Among the questions that remain to be answered are the following: (i) What underlies the phenotypic variability in bleeding patterns of patients with severe disease and the development of arthropathy in some but not all patients with joint bleeding? (ii) What is the molecular basis underlying the variability? (iii) Are there strategies that can be developed to counter the deleterious effects of joint bleeding and prevent blood-induced joint disease? Understanding the key elements, genetic and/or environmental, that are necessary for the development of synovitis and arthropathy may lead to rational design of therapy for the targeted prevention and treatment of blood-induced joint disease.

Clinical outcomes and patient satisfaction following total joint replacement in haemophilia – 23-year experience in knees, hips and elbows

Abstract: Joint replacement surgery is an available option for end-stage haemophilic arthropathy. However, reports with long-term follow-up are limited. Moreover, patient satisfaction in this setting has never been measured. We share our institution's experience with joint arthroplasty in haemophilic arthropathy and report on clinical outcomes and patient satisfaction. Between 1985 and 2007, 65 consecutive joints in 45 patients (mean age: 48.6; range: 22-83) underwent joint replacement surgery. Of these, 40 total knee replacements in 31 patients, 18 total hip replacements in 16 patients and 6 total elbow replacements in 3 patients were included. Average follow-up was 10.7 years (2.4-24.3). Charts were reviewed retrospectively and patients were asked to return for clinical assessment and completion of questionnaires. According to the Knee Society clinical score, postoperative results were good to excellent in 83% of knees. According to the Harris Hip Score, results were good to excellent in 31% of hips. According to the Mayo Elbow Performance Score, results were good to excellent in 83% of elbows. Complication rates are higher than in the non-haemophilic population, while prosthesis survival rates are lower. Patient satisfaction with pain relief is higher than satisfaction with functional improvement. For 88% of joints, patients are willing to have the same operation again. This study confirms previous knowledge on the role of total joint arthroplasty in haemophilic arthropathy. Despite high complication rates and modest functional outcomes, the operations are valuable for achieving pain relief. In general, patients find that risks are outweighed by the benefits.

Health care expenditures for Medicaid-covered males with haemophilia in the United States, 2008.

Abstract: Although haemophilia is an expensive disorder, no studies have estimated health care costs for Americans with haemophilia enrolled in Medicaid as distinct from those with employer-sponsored insurance (ESI). The objective of this study is to provide information on health care utilization and expenditures for publicly insured people with haemophilia in the United States in comparison with people with haemophilia who have ESI. Data from the MarketScan Medicaid Multi-State, Commercial and Medicare Supplemental databases were used for the period 2004-2008 to identify cases of haemophilia and to estimate medical expenditures during 2008. A total of 511 Medicaid-enrolled males with haemophilia were identified, 435 of whom were enrolled in Medicaid for at least 11 months during 2008. Most people with haemophilia qualified for Medicaid based on 'disability'. Average Medicaid expenditures in 2008 were $142,987 [median, $46,737], similar to findings for people with ESI. Average costs for males with haemophilia A and an inhibitor were 3.6 times higher than those for individuals without an inhibitor. Average costs for 56 adult Medicaid enrollees with HCV or HIV infection were not statistically different from those for adults without the infection, but median costs were 1.6 times higher for those treated for blood-borne infections. Haemophilia treatment can lead to high costs for payers. Further research is needed to understand the effects of public health insurance on haemophilia care and expenditures, to evaluate treatment strategies and to implement strategies that may improve outcomes and reduce costs of care.

Identification and long-term observation of early joint damage by magnetic resonance imaging in clinically asymptomatic joints in patients with haemophilia A or B despite prophylaxis.

Abstract: Severe haemophilia is associated with recurrent joint bleeds, which can lead to haemophilic arthropathy. Subclinical joint bleeds have also been associated with joint damage detected using magnetic resonance imaging (MRI). We investigated the development of early changes in clinically asymptomatic joints using MRI in haemophilia A or B patients receiving prophylactic therapy. In this single-centre retrospective cohort study, patients with clinical evidence of joint damage in one ankle and one clinically asymptomatic ankle, in which we performed an MRI scan of both ankles in one session, were enrolled. MRI findings were graded using a 4-point scoring system (0 = normal findings and III = severe joint damage). Since 2000, 38 MRIs in 26 patients have been performed. Starting at a median age of 4 years, 23 patients received prophylaxis 2-3 times weekly. On-demand treatment was performed in three patients. Eight patients (31%) presented with an MRI score of 0, 12 (46%) had a score of I, four (15%) had a score of II, and two (8%) had a score of III in the clinically unaffected ankle. The six patients with MRI scores of II and III had started regular prophylaxis between the ages of 2 years and 15 years; none had developed an inhibitor or experienced a clinically evident bleed in the asymptomatic ankle. During our study, five of 26 patients had a worsening of MRI findings without experiencing a joint bleed. Early morphological changes in clinically asymptomatic ankles can be detected using MRI, despite adequate prophylaxis.

Combined treatment with APCC (FEIBA®) and tranexamic acid in patients with haemophilia A with inhibitors and in patients with acquired haemophilia A--a two-centre experience.

Abstract: Summary. The management of bleeding in haemophilia patients with inhibitors can be challenging when using monotherapy with either activated prothrombin complex concentrate (APCC) or recombinant activated FVII (rFVIIa) fail. The antifibrinolytic agent tranexamic acid (TXA) increases clot stability and is used concomitantly with coagulation factor replacement to improve haemostasis in haemophilia patients without inhibitors in many countries in Europe. Combined treatment with TXA and rFVIIa is not contraindicated in haemophlia patients with inhibitors. However, the combined approach of TXA and APCC has not been investigated due to safety concerns of increased risk of thrombosis or disseminated intravasal coagulation (DIC). The aim of this study is to report our experience of concomitant use of APCC and TXA in haemophilia A patients with inhibitor and in patients with acquired haemophilia A with respect to safety and efficacy. Seven (n = 6) haemophilia A patients with inhibitors and one (n = 1) with acquired haemophilia A from Oslo (Norway) and Stockholm (Sweden) were included in the study. The APCC was given at doses consistent to the manufacturers’ recommendation. TXA was administered concomitantly either 10 mg kg−1 every 6–8 h intravenously or 20 mg kg−1 every 6–8 h orally. Haemostatic response was assessed by thromboelastography (TEG) and thrombin generation assay (TGA) in three of the patients. A total number of three bleeding episodes and two minor and six major surgical procedures were performed under the coverage with APCC and TXA. Haemostatic outcome was rated excellent or good in 10 of 11 (91%) treatment episodes. One episode was rated with poor effect. No episodes of arterial, venous thrombosis or DIC occurred during or after the treatment. Data from TEG and TGA analysis showed no signs of hypercoagulability following the combined treatment. This report demonstrates that, in a limited number of patients, combined treatment with APCC and TXA seemed to be safe, tolerated and relatively effective in management of bleeding episodes and in preventing haemorrhage during surgery in haemophilia patients with inhibitors and in a patient with acquired haemophilia A. Further studies should be performed to confirm these data.

Treatment of inherited platelet disorders

Abstract: Summary. For patients affected by severe inherited platelet dysfunctions, e.g. Glanzmann thrombasthenia (GT) or Bernard-Soulier syndrome (BSS), platelet transfusion is frequently needed for controlling spontaneous bleeding, and is always needed when trauma occurs or surgery is performed. For the mild-to-moderate bleeding entities, e.g. storage pool disease, thrombaxane A2 receptor defect, platelet transfusion is usually unnecessary. Transfusion of platelets should be used selectively and sparingly because of the substantial risk of alloimmunization against HLA antigens and/or platelet glycoproteins (GP) αIIb, β3, or αIIbβ3 in GT, and GPI-IX-V in BSS, which may lead to refractoriness to therapy. To reduce the risk, HLA-matched single donors of platelets should be used. If such donors are unavailable, leucocyte-depleted blood components should be used. Therapy other than platelet transfusion includes: (i) Prevention (vaccination against hepatitis B, avoidance of non-steroidal anti-inflammatory drugs, preservation of dental hygiene, correction of iron deficiency and prenatal diagnosis). (ii) Topical measures (compression with gauze soaked with tranexamic acid, fibrin sealants, splints for dental extractions and packing for nose bleeds). (iii) Antifibrinolytic agents that are useful for minor surgery and as adjuncts for other treatment modalities. (iv) Desmopressin that increases plasma levels of von Willebrand factor and factor VIII giving rise to increased platelet adhesiveness and aggregation associated with shortened bleeding time. (v) Recombinant factor VIIa (rFVIIa). GT patients have been treated for bleeding episodes by rFVIIa with partial success. The mechanism by which rFVIIa arrests bleeding is probably related to increased thrombin generation by a tissue factor-independent process, enhanced platelet adhesion and restoration of platelet aggregation. (vi) Female hormones. Excessive bleeding during menarche in patients with GT or BSS can be controlled by high doses of oestrogen followed by high doses of oral oestrogen–progestin. Menorrhagia later in life can be managed by continuous oral contraceptives. Depo-medroxyprogesterone acetate administered every 3 months is an alternative when combined oral contraceptives are contraindicated.

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

Abstract: 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.

Recommendations for assessment, monitoring and follow-up of patients with haemophilia

Abstract: Over the last few decades, clinical follow-up of patients with haemophilia has become more complex as a result of the introduction of new treatment strategies, the presence of comorbidities related to haemophilia or ageing, as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia. This publication describes the parameters and information that should be documented and the tests, examinations and interventions required for optimal follow-up of a patient with haemophilia. In the absence of formal studies, the present recommendations have been established as result of a series of consensus meetings in the frame of the European Haemophilia Therapy Standardization Board (EHTSB). The following 11 domains were identified: Baseline information, Current status, Treatment, Inhibitor status, Bleeding, Joint status and pain, Comorbidities, Dental care, Physical activities, Social participation and Quality of life. For each domain, details are proposed for the relevant parameters to be captured and monitored as well as the relevant tools that facilitate data collection. Adopting these recommendations should help the individual care of patients and, even though this is not the primary objective of this article, it should also help at national and international level to shape a new approach to haemophilia by working towards a more standardized outcome assessment. Greater standardization should have implications for data collection, improvements in treatment evaluation and optimizing resources.

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A

Abstract: OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Prevalence of depression in adults with haemophilia.

Abstract: Multiple factors place adults with haemophilia at risk for depression. Health outcomes can be compromised in depressed patients secondary to increased risk taking behaviour and poor compliance with treatment recommendations. To assess the prevalence and risk factors associated with depression in adult patients with haemophilia treated at a haemophilia treatment centre. Adults with haemophilia were screened for depression during their annual clinic visit using the Patient Health Questionnaire 9 (PHQ-9), a validated tool for depression screening in adults. Depression was defined as a PHQ-9 score ≥ 5. Risk factors associated with depression were collected by chart review and correlated with depression scores. A total of 41 adult patients consented to the study and 37% met criteria for depression. Fifty-three per cent of patients with depression reported moderate to severe symptoms of depression (PHQ-9 score >10). Seventy-six per cent of patients with depression reported suffering functional impairment due to their depressive symptoms. Lack of social support and unemployment were significantly associated with higher PHQ-9 scores (P = 0.04 and P = 0.01 respectively). Adult patients with haemophilia have a high prevalence of depression. The addition of depression screening to the comprehensive care of adults with haemophilia may result in improved overall health outcomes and treatment adherence.

Immunoprotective effect of von Willebrand factor towards therapeutic factor VIII in experimental haemophilia A

Abstract: The development of inhibitory anti-factor VIII (FVIII) antibodies in patients with haemophilia A following replacement therapy is associated with several types of risk factors. Among these, the purity of FVIII concentrates, and in particular the presence of von Willebrand factor (VWF), was controversially proposed to influence the immunogenicity of exogenous FVIII. We re-assessed in vivo and in vitro the immuno-protective effect of VWF towards FVIII. The immuno-protective effect of VWF towards FVIII was investigated in vivo, in a model of haemophilia A. We studied the endocytosis of FVIII by murine bone marrow-derived dendritic cells and evaluated the capacity of VWF to block the internalization of FVIII. We characterized the relevance of VWF for the accumulation of FVIII in the marginal zone of the spleen, a secondary lymphoid organ where the immune response to therapeutically administered FVIII initiates. Our results confirm that VWF reduces the immunogenicity of FVIII in FVIII-deficient mice. Paradoxically, VWF is important for the accumulation of FVIII in the marginal zone of the spleen. We propose that VWF exerts at least two non-mutually exclusive immunoprotective roles towards FVIII in haemophilic mice: VWF prevents the endocytosis of FVIII by professional antigen-presenting cells by blocking the interaction of FVIII with as yet unidentified endocytic receptor(s). Hypothetically, VWF, by virtue of increasing the half-life of FVIII in the circulation, may allow an increased contact time with tolerogenic marginal zone B cells in the spleen.

Rare bleeding disorders: RARE BLEEDING DISORDERS

Abstract: Summary. Rare bleeding disorders (RBDs) include the inherited deficiencies of fibrinogen, factor (F)II, FV, FV+FVIII, FVII, FX, FXI and FXIII. There have been remarkable advances in understanding the molecular profiles that lead to each type of coagulation factor deficiency. However, as a consequence of their rarity, clinical data regarding the characteristics of bleeding symptoms and their management remain limited. The clinical manifestations in different RBDs are heterogeneous, and the residual plasma coagulant factor level does not always predict bleeding tendency. In this review, we describe the general features and recent advances in understanding three such deficiencies: FXI, FVII and fibrinogen deficiencies.

Intracranial haemorrhage in the Italian population of haemophilia patients with and without inhibitors.

Abstract: Intracranial haemorrhage (ICH) is the most serious bleeding symptom in haemophiliacs, resulting in high rates of mortality and disabling sequelae. The Association of Italian Haemophilia Centres carried out a retrospective survey (1987-2008) of ICH occurring in haemophiliacs with the goals to establish: (i) incidence, location of bleeding, death rate and disabling sequels; (ii) risk factors for ICH; and (iii) treatment used during the acute phase of ICH and for recurrence prevention. A total of 112 ICH episodes had occurred in 88 patients (78 haemophilia A, 10 haemophilia B), 24 of whom experienced recurrences. The cumulative hazard of ICH for the whole cohort over the entire follow-up period was 26.7 per 1000 patients, and the annualized rate of ICH was 2.50 events per 1000 patients (95% CI 1.90-3.31). The risk of ICH was higher in the youngest children (24.4 per 1000, 95% CI 12.7-47.0 in the first year of age and 14.9, 95% CI 7.1-31.4 in the second year of age) and then progressively rose again after the age of 40. Univariate, bivariate (age-adjusted) and multivariate analysis investigating the effects of patient characteristics on ICH occurrence showed that haemophilia severity and inhibitor status were strongly associated with ICH [severe vs. mild, HR 3.96 (2.39-6.57); inhibitor vs. non-inhibitor 2.52 (1.46-4.35)]. HCV infection was also associated with the risk of ICH [HR 1.83 (1.25-2.69)]. Therapeutic suggestions based upon our experience to control ICH recurrence are provided.

A retrospective cohort study of cancer incidence among patients treated with radiosynoviorthesis.

Abstract: Radiosynoviorthesis (RS) is an intra-articular injection of a radioactive colloid for the treatment of synovitis administered most often to patients with rheumatoid arthritis or haemophilia. Although highly cost-effective in comparison with surgical or arthroscopic synovectomy, the risk of cancer associated with this treatment is not well known. We evaluated the incidence of cancer in a group of patients treated with RS. A cohort of 2412 adult patients with a variety of underlying conditions (mainly rheumatoid arthritis) and treated with at least one RS between January 1976 and December 2001, was recruited from two centres in Montreal. Cancer incidence and mortality data for cohort members over that time period were obtained from regulatory agencies using linkage. Background rates for all and specific types of cancer were obtained for the provincial (Quebec) and national (Canada) population according to age, gender and calendar period categories. Category-specific rates in the cohort were compared with rates in similar categories from the general population generating standardized incidence ratios (SIR). The effects of specific isotope doses and of number of RS treatments were analysed using a Cox-regression model. No increase in the risk of cancer was observed (SIR 0.96; 95% confidence interval 0.82-1.12). There was no dose-response relationship with the amount of radioisotope administered or number of RS treatments. The study provides some indication for the safety of the procedure but homogenous diagnostic groups of younger patients (such as haemophilic patients) receiving RS will need more evaluation.

Treatment trends for haemophilia A and haemophilia B in the United States: results from the 2010 practice patterns survey.

Abstract: Frequent evaluation of haemophilia treatment is necessary to improve patient care. The 2010 Practice Patterns Survey (PPS) investigated current trends in haemophilia treatment in the United States, as reported by nurses. The aim was to document practice patterns for haemophilia A and haemophilia B Survey questionnaires were sent to nurses at haemophilia treatment centres (HTCs) across the United States. Seventy-one of 126 HTCs (56%) responded to the survey. Factor dosage across treatment modalities ranged from 20 to 50 IU kg(-1) for severe haemophilia A. Dosage for severe haemophilia B was more variable ( 100 IU kg(-1)). On-demand dosing regimens were inconsistent for haemophilia A and more so for haemophilia B. Rates of adherence to prescribed treatment were similar for both haemophilia types (∼80%). The main barrier to adherence was identified as inconvenience. More bleeding episodes occurred in adults (16.6 bleeding episodes per year) with severe haemophilia A than in younger patients (11.3 bleeding episodes per year) before switching patients to prophylaxis. For both haemophilia types, most patients who switched from prophylaxis to on-demand treatment were aged 13-24 years; these patients also had the lowest adherence (60-71%). More paediatric patients with severe haemophilia A and inhibitors (53%) received prophylactic bypassing therapy than their haemophilia B counterparts (38%). Adults with severe haemophilia A faced challenges in relation to co-morbidities and long-term care. This PPS provides insights into previously unexplored aspects of haemophilia care that will serve to increase awareness and promote discussion of current issues affecting haemophilia patient care.