Showing papers in "Haemophilia in 2011"

Range of motion measurements: reference values and a database for comparison studies

Abstract: Many diseases and injuries can impair joint mobility Normal reference values are needed to determine extent of impairment to assess and monitor joint motion There is very little published data describing normal joint range of motion (ROM) for healthy men and women across a wide span of ages We enrolled male and female subjects aged between 2 and 69 years who were free from conditions that could potentially limit joint mobility for the study Nine licensed physical therapists used universal goniometers to determine passive joint motion bilaterally of elbow flexion, extension, supination and pronation, shoulder flexion, hip flexion and extension, knee flexion and extension, and ankle dorsiflexion and plantarflexion Descriptive statistics were calculated for male and female subjects in four age groups: 2-8, 9-19, 20-44 and 45-69 years Joint ROM measurements were obtained on a total of 674 (536% female) healthy, normal subjects aged 2-69 years Female subjects had greater joint mobility in all age groups in nearly all joints and the gender difference was most obvious in measures of ankle plantarflexion, elbow pronation and supination Range of motion average values for all joints decreased with advancing age for both men and women and, in most cases, were significantly different than most commonly used normative values Our study of ROM measurements taken by trained physical therapists on a large sample of healthy individuals revealed significant gender- and age-related variation that may be an important consideration in patient assessment

Clinical severity of haemophilia A: does the classification of the 1950s still stand?

Abstract: The classification of haemophilia originates from 1950s and has been adopted unchallengedly by the ISTH in 2001. The aim of this study was: does the current classification compare onset of bleeding and age at first treatment, as well as annual joint bleeding frequency according to baseline FVIII activity? Data on age and reason of diagnosis, onset of treatment, onset of bleeding and bleeding frequency from 411 patients with haemophilia A born after 1970 were collected. Data were analysed according to base-line FVIII activity levels. Age at diagnosis, onset of bleeding and start of treatment according to FVIII activity were compared with the current classification. Overall, the distinction between severe and non-severe haemophilia was clear. The distinction between mild and moderate haemophilia was more difficult, mostly due to the wide variability in the group of patients with moderate haemophilia. Patients with severe haemophilia experienced their milestones like diagnosis, first treatment and joint bleed earliest, mostly as infants aged 0-3 years, whereas patients with moderate haemophilia reached these milestones around toddler age, 2-7 years, and patients with mild haemophilia reached them when they were in elementary school, around the ages of 5-14 years. This study confirms the clinical distinction between severe and non-severe haemophilia A. However, the group of moderate haemophilia patients showed a wide variability, warranting close follow-up and individualized treatment.

Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia

Abstract: The pharmacokinetic (PK) response to factor VIII (FVIII) and factor IX varies between patients and this has important clinical implications for treatment. Although PK is affected by patient characteristics, this relationship is too weak to infer a result for an individual and, if required, PK must be measured. An important determinant of the efficacy of prophylaxis is the length of time an individual spends with a low level of coagulation factor. This time is more dependent on the patient's coagulation factor half-life and the frequency of dosing than in vivo recovery and dose infused. Improved understanding of the effect of PK and dose frequency on factor levels in patients on prophylaxis will help tailor regimens to individuals better and allow more cost effective use of coagulation factor concentrates. Calculations suggest that adults need less FVIII per kg body weight than children. The effect of half-life on trough levels questions the logic of Monday, Wednesday, Friday dosing and suggests a role for innovative regimens including low-dose daily treatment which leads to either higher trough levels or decreased FVIII requirement. This may expand access to prophylaxis in healthcare systems with limited resources and potentially improve patient outcomes. The ideal trough level will vary between individuals and at different times of their lives and may be <1 IU dL(-1). If PK is to be used in routine clinical practice, a simplified method for its measurement is required and this methodology is becoming available.

Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels

Abstract: Many studies in the field of haemophilia and other coagulation deficiencies require analyses of bleeding frequencies. In haemophilia, the association of bleeding frequency with factor VIII (FVIII) activity levels is known from experience, but significant results are lacking. Bleeding frequencies in haemophilia are highly skewed count data, with large proportions of zeros. Both the skewness and the high amount of zeros pose a problem for standard (linear) modelling techniques. This study investigated the optimal analysing strategy for bleeding data by using the association of residual clotting factor level and number of joint bleeds in moderate and mild patients treated on demand as example. In total, 433 patients with moderate (27%) and mild (73%) haemophilia A treated on demand were included in this study. One year of self-reported data on joint bleed frequency and baseline clotting factor activity were analysed using Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial distributions. Multivariate regression analysis using negative binomial distribution provided the optimum data analytical strategy. This model showed 18% reduction [Rate ratio (RR) 0.82; 95%confidence interval (CI) 0.77-0.86] of bleeding frequency with every IU dL(-1) increase in residual FVIII activity. The actual association is expected to be higher because of exclusion (30 out of 463 patients) of patients on prophylaxis (baseline FVIII levels 0.01-0.06 IU mL(-1)). The best way to analyse low frequency bleeding data is using a negative binomial distribution.

Standardization of thromboelastography: a report from the TEG‐ROTEM working group

Abstract: Laboratory evaluation of bleeding disorders has been performed with the standard clotting assays such as the PT and PTT for several decades. Our improved understanding of the process of blood coagulation has now revealed the important role played by the cellular elements such as platelets, monocytes and red blood cells. The need for a test that can assess clotting in a more 'global' manner, beyond the initiation of clot formation, has led to greater interest in assays such as thrombin generation and thromboelastography. Even though there are several publications using thromboelastography it remains a research tool as the methodology is not standardized. In an attempt to show reproducibility and consistency using thromboelastography, a group of investigators from different countries joined hands to form the TEG-ROTEM Working Group. Two studies were performed using PRP and FVIII deficient plasma and an intrinsic pathway activator. This article summarizes the results of the first international effort at standardization of thromboelastography. Both of the instruments using this technology (TEG(®) and ROTEM(®)) were used. Nine laboratories from countries around the globe participated in this effort. The results showed a significant inter-laboratory variance with CV's greater than 10%. Although these results were not satisfactory, this has been the first effort to standardize this methodology and significant work remains to be done to improve reliability and reproducibility. These studies were performed on PRP and the results may be more reliable when preformed on whole blood samples. We believe that it is important to continue this work so that we may investigate the usefulness and potential applications of thromboelastography in the evaluation of bleeding and thrombosis.

Joint protection in haemophilia

Abstract: Haemarthroses (intra-articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on-demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by-passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non-inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.

Ultrasound detects joint damage and bleeding in haemophilic arthropathy: a proposal of a score.

Abstract: Haemarthrosis triggers haemophilic arthropathy (HA) because bleeding starts synovitis immediately, damages cartilage and leads to loss of function and disability. The aim of our study was to investigate the capacity of ultrasonography (US) in detecting bleeding and joint damage in HA. The joints of 62 patients (pts) with haemophilia A or haemophilia B were consecutively evaluated and scored (score ranging from 0 to 21) for effusion (E), bone remodelling (BR), cartilage damage (CD), synovial hypertrophy (SH), haemosiderin (H), osteophytes (O), haemarthrosis (Hae), erosion (Er) and fibrotic septa (FS) with US. X-rays [Pettersson Score (PXS)] were performed in 61 patients and clinical evaluation [World Federation Haemophiliac orthopaedic score (WFHO)] was performed in all patients. A total of 20 healthy subjects and 20 patients affected by Rheumatoid Arthritis (RA) were used as controls. Power Doppler US (PDUS) was performed in all patients on the knee, ankle and elbow joints. A total of 83 joints were studied (50 knees; 12 elbows and 21 ankles). US showed effusion in 57 joint, bone remodelling in 62, cartilage damage in 64, synovial hypertrophy in 45, haemosiderin in 39, osteophytes in 30, haemarthrosis in 24, erosion in 5 and fibrotic septa in 3. The X-rays score showed remodelling in 47 joints, narrowing joint space in 44, displacement/angulation in 39, osteoporosis in 42, subchondral irregularity in 44, subchondral cyst formation in 37, osteophytes in 36 and erosions in 25. The US score in healthy subjects was always ≤ 5 (range 0 to 4). In haemophiliacs, 34 of 83 joints showed US score ≤ 5, and 49 US score > 5. Joints with US score ≤ 5 had a low PXS (SRCC = 0.375, P 5 showed a high PXS (SRCC = 0.440, P < 0.01). A significant correlation between US score and PXS for bone remodelling [Spearman's rho Correlation Coefficient (SRCC) = 0.429, P < 0.01] and for osteophytes (SRCC = 0.308, P < 0.05) was found. The correlation between the US score and number of bleedings in 83 joints was very significant (SRCC = 0.375, P < 0.01). A total of 24 bleeding joints were identified and verified with aspiration of haematic fluid. US may detect bone and cartilage alterations and synovitis. Indeed, PDUS identified bleeding also in asymptomatic joints and was able to show different entity of haemarthrosis. US may be a feasible and reliable tool to evaluate joint modifications in HA.

Management of acute haemarthrosis in haemophilia A without inhibitors: literature review, European survey and recommendations

Abstract: Acute haemarthrosis is a frequent type of bleeding in individuals with haemophilia. Delayed and/or inadequate treatment can trigger a series of pathological changes within the joint, leading to a painful and disabling arthropathy. The early management of intra-articular bleeding has the potential to prevent chronic joint disease and may include a combination of factor replacement, rest, ice, rehabilitation and, in certain cases, joint aspiration. Little data are, however, available regarding the optimal management of acute haemarthrosis, especially with respect to replacement therapy and the use of adjunctive therapies (aspiration, avoidance of weight bearing and immobilization, as well as the use of anti-inflammatory medication and embolization). To provide more insight into the management of acute haemarthrosis in patients with haemophilia, a literature review was conducted. Concomitantly, current management was surveyed in 26 European haemophilia comprehensive care centres representing 15 different countries. The review highlights the need for future robust studies to better define the appropriate replacement therapy and the role of adjunctive therapies such as aspiration. The survey reveals much heterogeneity in the management of acute haemarthrosis across the EU. Within the constraints discussed, treatment recommendations are presented that reflect the literature, current practice and the clinical experience of the European Haemophilia Therapy Standardisation Board (EHTSB).

Low dose secondary prophylaxis reduces joint bleeding in severe and moderate haemophilic children: a pilot study in China

Abstract: Summary. The most common bleeding in haemophilic patients is in joints, and joint disability is the most common complications in these patients receiving inadequate treatment. Limited by economy and inadequate treatment, developing countries face huge challenge to reduce disability and improve quality of life (QoL) of haemophilic children. The aim of this study was to investigate the effect of low dose secondary prophylaxis in China. Children with moderate and severe haemophilia from the Beijing Children Hospital, Beijing, China, and with established joint disease, were followed for a 12-week observation period followed by a 12-week low dose secondary prophylaxis-study period (for haemophilia A, factor VIII concentrate 10 IU kg−1 twice weekly; for haemophilia B, factor IX concentrate 20 IU kg−1 weekly). The reduction of joint bleeding, improvement of joint function and QoL during prophylaxis were analysed. In total 34 children (median age 7.8 years) were analyzable. The number of joint bleeds decreased from a total of 337 (individual range 3–24, mean 9.9) during the observation period to 57 (range 0–6, mean 1.7) during the study period with an overall of reduction 83%. Joint function improved in 66.7% of disease joints, with 23.2% of which were considered good to moderate. School attendance improved in all subjects, sports participation and daily activity improved moderately. Low dose secondary prophylaxis significantly reduces frequency of joint bleeding; with moderate improvement in joint function, school attendance, sport participation and daily activities. Low dose secondary prophylaxis is therefore, cost-effective as applied to developing countries such as China, although there are still unresolved issues.

Assessment and management of pain in haemophilia patients.

Abstract: Haemophilia patients experience acute pain during joint bleeds and chronic pain from haemophilic arthropathy. More than 50% of haemophilia patients have painful joints that cause disability and impair quality of life. Unfortunately, only a few clinical studies have investigated the non-pharmacological or pharmacological treatments for pain or the adverse effects of pain on the health and quality of life of children and adults with haemophilia. There are no detailed algorithms or guidelines for pain management in haemophilia patients, and treatment is largely empirical. Therefore, a standardized approach to the management of pain in haemophilia patients is needed. This approach should include a close relationship between pain specialists and the staffs at haemophilia treatment centres; validated instruments specific to haemophilia for assessing pain, quality of life and disability; and stepwise algorithms/protocols for treatment of chronic vs. acute pain and prophylactic vs early treatment. A pain treatment protocol should include a definition of the problem of pain and best practices for physicians. A call to action is needed to standardize treatment approaches to pain and to develop algorithms/protocols for the management of pain in haemophilia patients. This review will highlight the prevalence and devastating impact of pain in haemophilia patients, currently available treatment options and identify the unmet needs for pain management.

Management of pregnancy, labour and delivery in women with inherited bleeding disorders.

Abstract: Pregnancy, labour and delivery present intrinsic haemostatic challenges to women with and carriers of bleeding disorders and their offspring Deficiency of fibrinogen and factor XIII are associated with miscarriage, placental abruption and foetal loss The risk of antenatal complications including antepartum haemorrhage is unknown in women with other bleeding disorders There is a significant risk of postpartum haemorrhage (primary and secondary) in women with all types of bleeding disorders This can be serious and life threatening in those with severe defects such as Bernard Soulier syndrome and Glanzmann's thrombasthenia Three to four percent of infants with haemophilia experience cranial bleeding that occurs during labour and delivery The safest method of delivery for affected babies remains controversial However, the rate of planned Caesarean section is increasing among known carriers of haemophilia If vaginal delivery is planned, prolonged labour and difficult delivery especially vacuum extraction are associated with the highest risk of cranial bleeding and should be avoided The optimal management of pregnancy in women with inherited bleeding disorders requires a multidisciplinary approach and advanced individualized management plan taking into consideration obstetric and bleeding risk factors Women with mild or moderate bleeding disorders can be managed at their local maternity unit in close collaboration with a tertiary centre However, those with severe or rare disorders or carrying an affected infant should be managed in a tertiary centre with an onsite Haemophilia centre

First 20 years with recombinant FVIIa (NovoSeven).

Abstract: This review describes the background for the development of recombinant FVIIa (rFVIIa; NovoSeven) for use in haemophilic patients with inhibitors. The first proof of principle for using pharmacological doses of FVIIa as a haemostatic agent was obtained by producing small amounts of pure plasma-derived FVIIa, which showed encouraging effect in two patients with haemophilia A and inhibitors. To make pure FVIIa available for use in a larger number of patients, rFVIIa was produced that was approved for use in patients with inhibitors against coagulation factors (congenital haemophilia and acquired haemophilia) in 1996 (EU), 1999 (USA) and 2000 (Japan). The efficacy rate in severe bleedings and in major surgery including major orthopaedic surgery has been found to be around 90% in controlled studies, and no serious safety concerns have been demonstrated. The availability of rFVIIa has facilitated the performance of elective major surgery in haemophilia patients with inhibitors. Further steps along the vision of providing a treatment for inhibitor patients similar to non-inhibitor patients have been the efficacy of rFVIIa in home-treatment and recently the encouraging experience in prophylaxis. The concept of using pharmacological doses of rFVIIa as a haemostatic agent is a new one, which has caused difficulties in finding the correct dose. A step forward has been the demonstration that similar efficacy can be achieved after one single dose of 270 μg kg(-1) instead of three injections of a dose of 90 μg kg(-1). The higher clearance rate in children suggests that higher doses may be beneficial in children. The availability of rFVIIa has made advances in the understanding of coagulation processes possible. In a cell-based in vitro model, it has been shown that rFVIIa binds to preactivated platelets if present in concentrations of 30 nm or higher. By doing so, it activates FX into FXa and enhances the thrombin generation on the activated platelet surface in the absence of FVIII/FIX. Through the increased thrombin generation, a firm, well-structured fibrin haemostatic plug, which is resistant to premature lysis, is formed. By exploiting this mechanism of action, rFVIIa may also be effective in situations other than haemophilia, characterized by an impaired thrombin generation.

International comparative field study of N8 evaluating factor VIII assay performance.

Abstract: Discrepancies between the one-stage clotting assay and the chromogenic method, and also among different variations of each method, have been a significant challenge for one B-domain deleted FVIII product. N8 is a B-domain truncated FVIII product developed by Novo Nordisk. The comparison of N8 and Advate(®) was performed in an international, multicentre, randomized and blinded field study of simulated postinfusion samples. Overall, Advate(®) and N8 performed similarly in the one-stage assay. In the one-stage clotting assay, the measured mean FVIII levels of Advate(®) vs. N8 were 0.046/0.047, 0.24/0.24, 0.58/0.60 and 0.82/0.83 IU mL(-1) for the target values of 0.03, 0.2, 0.6 and 0.9 IU mL(-1) , respectively. In the chromogenic assays, the concentration estimates showed a tendency towards higher N8 values as compared with Advate(®) ; the measured FVIII levels of Advate(®) vs. N8 were 0.030/0.032, 0.22/0.24, 0.65/0.74 and 0.98/1.08 IU mL(-1) for the target values of 0.03, 0.2, 0.6 and 0.9 IU mL(-1) , respectively. In the one-stage assays, the measured values were above 150% of target at the lowest concentration, decreasing to around 90% of target at the highest concentration. In contrast, the chromogenic assays were close to target at the lowest concentration and consistently above target at the three highest concentrations. Therefore, the ratio of chromogenic/one-stage potencies was concentration dependent, ranging from 0.66 to 1.30. The SSC plasma standard was similar in both. Assay variability was similar for both compounds. The results show that N8 can be reliably measured in plasma without the need for a separate N8 standard.

Treatment related factors and inhibitor development in children with severe haemophilia A.

Abstract: With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.

Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres.

Abstract: Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.

Prevalence and risk factors of cardiovascular disease (CVD) events among patients with haemophilia: experience of a single haemophilia treatment centre in the United States (US)

Abstract: The primary objective of the study was to examine the prevalence of cardiovascular disease (CVD) events and their known risk factors among persons with haemophilia (PWH). This cross-sectional study, covering a 5-year period, included PWH aged ≥35 years who were cared for at a single haemophilia treatment centre in the United States. Medical records were extensively reviewed to collect the information about CVD events and their risk factors such as obesity, hypertension, diabetes, hypercholesterolemia and smoking. Prevalence rates were compared with national population estimates and associations between risk factors and CVD events were examined using logistic regression. The study cohort comprised 185 PWH (102 haemophilia A and 83 haemophilia B). Lifetime prevalence of a CVD event was 19.5% (36/185, 95% confidence interval [CI] 13.8-25.2%). CVD mortality was 5.4% (10/185, 95% CI 2.7-8.1). Compared with US non-Hispanic White males (NHWH), PWH had about twice the prevalence of coronary artery disease, stroke and myocardial infarction. The prevalence of CVD risk factors for PWH was similar to that for US NHWM with 39.5% of PWH exposed to two or more of these risk factors. Both hypertension and smoking were associated significantly with CVD events, with odds ratios of 4.9 and 6.3, respectively. In conclusion, this study revealed that both CVD events and its risk factors were at least equally prevalent among PWH and might have been even higher than among the US NHWM in the United States. Therefore, it is imperative to implement strategies for CVD prevention among PWH.

Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors.

Abstract: Some 10-20% of bleeding events in haemophilia patients with high-responding inhibitors cannot be controlled with bypassing agents. However, sequential combined bypassing therapy (SCBT) has been reported to be successful in five children. To extend this observation, a survey was undertaken by the European Haemophilia Treatment Standardisation Board (EHTSB) in children and adults. Data were collected from all centres belonging to the EHTSB network by a retrospective medical record review. SCBT courses were defined as the administration of both recombinant activated factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within 12 h. A web-based database was prepared to collect data on SCBT courses in a standardized and anonymous manner from patients' files. Eleven inhibitor patients underwent SCBT (nine haemophilia A; two haemophilia B). Two children had refractory knee haemarthrosis and one, an unresponsive calf haematoma. Five adults had significant bleeds following major surgery, one had lower limb compartmental syndrome and one a post-traumatic upper limb haematoma and haemarthrosis. SCBT administration alternated one APCC dose to 1-3 rFVIIa doses: dosing intervals ranged between 3 and 6 h; APCC (20-80 U kg(-1) ) was given every 8-12 h; rFVIIa (90-270 μg kg(-1) ) was given every 3-12 h. Bleeding control was achieved in 12-24 h in all patients. SCBT was discontinued after 1-15 days. No clinical adverse events were observed, but a significant increase in D-dimer levels was seen in three/five patients who were assessed. SCBT was efficacious without adverse events; nevertheless, due to potential risks, it remains a salvage treatment. A prospective clinical trial is needed to provide further evidence.

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

Abstract: 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.

Comparing bleed frequency and factor concentrate use between haemophilia A and B patients

Abstract: Haemorrhagic manifestations in patients with haemophilia A and B are considered quite similar for comparable level of factor deficiency. We investigated the bleeding frequency and factor usage between HA and HB patients with comparable disease severities. We collected data on frequency of bleeds and factor concentrate utilization over 3 years, from January 2001 to December 2003. Information was gathered from home infusion logs recorded by patients or their parents, and treatment records from the Hemophilia Clinic or the Hospital Emergency Department. Data were available on 58 patients with severe HA (FVIII 0.05). The decrease in bleed frequency in haemophilia B indicates that the conclusions from randomized trials of prophylaxis in HA may not be accurately applied to HB.

Role of exercise and physical activity on haemophilic arthropathy, fall prevention and osteoporosis.

Abstract: In older men with haemophilia, arthropathy resulting from a lifetime of intra-articular bleeding contributes to the loss of independence and increased morbidity that occurs with age. A regular exercise programme that incorporates aerobics, strength training and balance and flexibility activities is a key component of successful ageing, helping to improve functional mobility and reduce the risk of falls, osteoporosis and osteoporotic fractures. Because of the special challenges associated with haemophilia, which include both the underlying coagulopathy and, in many cases, extensive joint damage, patients beginning an exercise regimen should be referred to appropriately trained physiotherapists (preferably someone associated with a haemophilia treatment centre) for evaluation, education and instruction and follow-up. Various assistive devices may make exercise easier to perform and more comfortable.

A systematic review of the management and outcomes of pregnancy in Glanzmann thrombasthenia.

Abstract: Glanzmann Thrombasthenia (GT) is a rare autosomal recessive disorder which usually manifests as severe mucocutaneous bleeding and is caused by deficiency of the platelet glycoprotein IIb-IIIa. Pregnancy in women with GT presents particular challenges as there is increased risk of both maternal and foetal bleeding. To improve understanding and clarify the optimum management of pregnancy in this disorder, we performed a systematic review of the world literature of pregnancy and GT. This identified three single-centre case series of patients with GT that included brief descriptions of women in pregnancy and 31 detailed case reports of 40 pregnancies in 35 women that resulted in 38 live births. Among the detailed case reports, ante-natal bleeding was described in 50% of pregnancies but was usually mild and occurred at mucocutaneous sites. Primary postpartum haemorrhage (PPH) was reported in 34% of pregnancies and secondary PPH in 24%. PPH was frequently severe and occurred up to 20 days after delivery. There was a wide variation in approach to prevention and treatment of PPH but most women received platelet transfusion, sometimes with additional recombinant FVIIa and anti-fibrinolytics. Maternal alloimmunization against platelet antigens was reported in 73% of pregnancies and was associated with four neonatal deaths. These data emphasize the need for multidisciplinary management of pregnancy in women with GT. Delivery plans should recognize the need for prevention and aggressive treatment of PPH and should minimize foetal bleeding risk in pregnancies complicated by alloimmunization.

von Willebrand factor/factor VIII concentrate (Humate-P) for management of elective surgery in adults and children with von Willebrand disease.

Abstract: von Willebrand disease (VWD) is the most common inherited bleeding disorder. Treatment guidelines recommend the use of von Willebrand factor/factor VIII (VWF/FVIII) concentrate for VWD patients with type 2 or 3 VWD undergoing surgery, and type 1 patients undergoing surgery who are unresponsive, or for whom desmopressin acetate is contraindicated. This prospective, open-label, multinational study evaluated the safety, efficacy and optimal dosing of a VWF/FVIII concentrate (Humate-P) in subjects with VWD undergoing elective surgery. Dosing was based on VWF ristocetin cofactor (VWF:RCo) and FVIII pharmacokinetic assessments performed before surgery. Pharmacokinetic assessments were completed in 33 adults and 9 children. Haemostatic efficacy was assessed on a 4-point scale (excellent, good, moderate/poor or none). Overall effective haemostasis was achieved in 32/35 subjects. Median terminal VWF:RCo half-life was 11.7 h, and median incremental in vivo recovery was 2.4 IU dL(-1) per IU kg(-1) infused. Major haemorrhage occurred after surgery in 3/35 cases despite achieving target VWF and FVIII levels. Median VWF/FVIII concentrate loading doses ranged from 42.6 IU VWF:RCo kg(-1) (oral surgery) to 61.2 IU VWF:RCo kg(-1) (major surgery), with a median of 10 (range, 2-55) doses administered per subject. Adverse events considered possibly treatment-related (n = 6) were generally mild and of short duration. The results indicate that this VWF/FVIII concentrate is safe and effective in the prevention of excessive bleeding during and after surgery in individuals with VWD.

The power of a standardized bleeding score in diagnosing paediatric type 1 von Willebrand's disease and platelet function defects.

Abstract: A predictive standardized bleeding questionnaire (Vicenza score), previously validated for identifying individuals with type 1 von Willebrand's disease (VWD), has never been prospectively validated in tertiary care paediatric settings. The aim of this study was to assess the Vicenza score's predictive power in identifying type 1 VWD, low von Willebrand factor (VWF) and platelet function defects (PFD) in a prospective cohort of patients, 0-17 years old, referred to a paediatric haematology clinic for evaluation of a bleeding disorder. Before the initial visit, caregivers consented to answer the questionnaire via telephone. Patients' medical records were reviewed after haematological evaluation. VWF:Ag or VWF:RCo 2 bleeding symptoms) and quantitative (Vicenza score ≥ 2) criteria. The Vicenza score has limited predictive value in paediatric tertiary care settings. While the NPV of excluding 'definite type 1 VWD' is high, simpler qualitative criteria is similarly predictive.

Association between phenotype and genotype in carriers of haemophilia A.

Abstract: Summary. Female carriers of haemophilia might suffer from increased bleeding tendency therefore the assessment of the bleeding risk is very important for improving care. This single-centre study documents the occurrence of bleedings in 46 carriers of haemophilia A including bleeding after tooth extraction (77%), easy bruising (67%), postsurgical bleeding (61%), menorrhagia (50%) or prolonged postpartum bleeding (43%). The F8 gene mutation of all 46 carriers (median age: 36.5 years, 15–80 years; mean FVIII:C activity: 59 ± 24.45%; normal range: 64–167%) was determined, and family history of haemophilia was recorded. For analysis, the bleeding tendency of the carriers was differentiated by severity into three groups. There was no statistically significant difference of FVIII:C between these groups. However, a correlation was found between the severity of bleeding tendency and the type of F8 gene mutation (P < 0.05) as well as the severity of haemophilia in affected male relatives (P < 0.0005). Results show that even carriers with a FVIII:C activity as high as 50–60% are at increased risk of bleeding. Incidence and intensity of bleeding symptoms of haemophilia A carriers are high and correlated with the phenotype of the male haemophilic relative and the underlying F8 gene mutation.

The longitudinal effect of body adiposity on joint mobility in young males with Haemophilia A

Abstract: Although body adiposity and disease severity in haemophilia have been found in cross-sectional studies to be negatively associated with joint mobility, it is not clear how these two factors affect the rate of joint mobility loss over time. Over a 10-year period, repeated measures of joint range of motion (ROM) were collected annually using universal goniometers on bilateral hip, knee, ankle, shoulder and elbow joints in 6131 young males with haemophilia A aged ≤ 20 years. Body mass index (BMI) was calculated using data on weight and height during follow up. The effect of body adiposity, adjusted for disease severity, on the rate of joint mobility loss over time was assessed using a longitudinal model. Compared with haemophilia males with normal BMI, those who were obese had lower ROM at initial visit and a faster rate of joint mobility loss in the lower limbs. Overweight subjects experienced similar loss in ROM, although to a lesser degree. A decline in ROM with age was also observed in upper limb joints but the rate was not significantly affected by body adiposity. Haemophilia severity, joint bleeding and the presence of an inhibitor were other significant contributors to joint mobility loss in both upper and lower limb joints. Excess body adiposity accelerates joint mobility loss in weight bearing joints particularly among those with severe haemophilia. Our findings suggest that body weight control and effective treatment of bleeds should be implemented together to achieve better joint ROM outcomes in males with haemophilia.

The relative burden of haemophilia A and the impact of target joint development on health-related quality of life: results from the ADVATE Post-Authorization Safety Surveillance (PASS) study

Abstract: Studies with haemophilia A (HA) patients have shown burden in health-related quality of life (HRQOL) when compared with general population norms. In the current study, HA patients' SF-36v2 health survey scores were compared with general population norms and to patients with other chronic conditions. The impact of target joints (TJs) on HRQOL was also examined. The sample was a subset of HA patients enrolled in the Post-Authorization Safety Surveillance (PASS) programme: a prospective open-label study in which ADVATE [Antihaemophilic Factor (Recombinant), Plasma/Albumin-Free Method] was prescribed. A total of 205 patients who were ≥ 18 years old and had SF-36v2 baseline scores were selected for this study. To measure the burden of HA on HRQOL, manova analyses compared these SF-36v2 scores to age- and gender-matched general population US and EU norms and to patients from other chronic condition groups. manova and correlational analyses examined the relations among TJ, age and SF-36v2 scores. Comparisons with general population norms confirm that HA negatively impacts physical, but not mental, HRQOL. Comparison with other chronic conditions shows the physical burden of HA is greater than for chronic back pain but similar to diabetes and rheumatoid arthritis, while the mental burden of HA is less than for all three patient groups. The presence of TJs was negatively associated with physical HRQOL, although this association was much larger for older patients (45+ years) than for younger ones. Physical, but not mental, HRQOL is diminished in HA patients. Target joints are associated with lower physical HRQOL, although this effect is moderated by age.

Assessment of acute and persistent pain management in patients with haemophilia

Abstract: A descriptive survey was conducted in Region V-E of the United States to bridge the gap in available information on pain issues in the bleeding disorders population. The aim of this study was to a) determine language used by patients to describe and differentiate acute and persistent pain, b) describe pharmacological and non-pharmacological strategies utilized to control pain, c) determine the providers of pain management to this population and d) evaluate quality of life incorporating the SF-36 QOL tool. A total of 202 surveys were returned. For the purposes of this paper, it was decided to analyse only haemophilia data (n = 114). Average persistent daily pain levels were 5/10 (P < 0.001). The three most common word descriptors for both acute and persistent pain were the same - achy, throbbing and tender; the most utilized pain medications were NSAIDs and acetaminophen. Factor replacement was used for what respondents described as acute pain management 79% of the time and for persistent pain management 38% of the time. Participants described acute and persistent pain with the same pain descriptors leading to the conclusion that patients have difficulty distinguishing between acute and persistent pain. This lack of differentiation was further displayed by the use of factor replacement to treat persistent pain associated with arthritic discomfort (38%) which would be viewed as inappropriate, as well as lack of factor replacement use by 21% of respondents who identified pain as from an acute bleed. Opportunities exist to improve pain management through patient and provider-directed educational programs.

Comparative study of dual energy X‐ray absorptiometry and quantitative ultrasonography with the use of biochemical markers of bone turnover in boys with haemophilia

Abstract: Our aim was to evaluate bone status in boys with haemophilia using dual energy X-ray absorptiometry (DXA) and quantitative ultraSonography (QUS), and in addition, to compare these two methods with the use of biochemical markers of bone turnover Twenty-six boys with a mean decimal age of 1208 ± 444 years were included in the study which included a DXA scan at lumbar spine and radial, as well as tibial QUS Serum levels of soluble receptor activator of nuclear factor κB ligand (sRANK-L), osteoprotegerin (OPG) and osteocalcin (OC) were measured and joint evaluation was performed using the Hemophilia Joint Health Score (HJHS) With regard to the study results, only 2 of 26 patients (77%) had bone mineral density (BMD) Z-scores < -2, and 4 patients (154%) had BMD Z-scores between -1 and -2 Only one patient had radial and other two had tibial QUS Z-scores < -2 No agreement was recorded between QUS and DXA in identifying patients at risk for osteoporosis (k = 0275, P = 0063) Haemophiliacs had significantly higher serum levels of sRANK-L (2104 ± 478 vs 1858 ± 228 ng mL(-1), P = 0038) and of OC (535 ± 229 vs 309 ± 061 ng mL(-1), P = 0002) and significantly decreased levels of OPG (1578 ± 253 vs 2379 ± 439 pg mL(-1), P < 0001) compared with controls QUS Z-scores at tibia significantly correlated with HJH Scores (r = -0450, P = 0040), whereas lumbar BMD Z-scores significantly correlated with body mass index Z-scores (r = 0500, P = 0009) More studies are warranted to identify the most accurate densitometric method for assessing bone status in haemophiliacs

Bioequivalence between two serum-free recombinant factor VIII preparations (N8 and ADVATE®)--an open-label, sequential dosing pharmacokinetic study in patients with severe haemophilia A.

Abstract: Recombinant coagulation factor VIII (rFVIII) concentrates provide a safe and efficacious replacement therapy for treatment and prevention of bleeding in patients with severe haemophilia A. The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of two serum-free rFVIII products: N8, a new rFVIII manufactured by Novo Nordisk and Advate(®), a marketed product. Patients with severe haemophilia A with >150 exposure days to FVIII, without current or past inhibitors, were enrolled in an open-label, first human dose (FHD), multicentre trial. Twenty-three patients first received a single dose of 50 IU kg(-1) body weight Advate(®) followed by 50 IU kg(-1) body weight N8 at the next visit. A 4-day washout period was required prior to each dosing. Blood samples for PK and safety analyses were drawn prior to dosing and at intervals up until 48 h postdosing. The PK parameters were based on FVIII clotting activity (FVIII:C) measurements. Occurrence of adverse events was closely monitored. The mean profiles of FVIII:C and all primary and secondary parameters for Advate(®) and N8 were comparable. The 90% CI for the treatment ratio (Advate(®)/N8) for all primary endpoints (incremental recovery, t(1/2), AUC and Cl), and the secondary endpoints (AUC(last) and C(max)) were within the bioequivalence interval of 0.8-1.25. There were no safety concerns in the study and no reports of inhibitor formation in the 72-h period following exposure to a single N8 dose. In conclusion, N8 is bioequivalent to Advate(®). Furthermore, N8 is well tolerated in the FHD trial.

Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials.

Abstract: Replacement therapy or prophylaxis, has become the standard of care for the treatment of severe haemophilia A. To describe bleeding patterns in children, adolescents and adults on prophylaxis and their observed relationships to times of infusion (during the week and during the day) as well as season of the year. Data from Advate pre-licensure prospective clinical trials from 145 patients with factor VIII (FVIII) <1%, were used. All patients underwent a 48-h pharmacokinetic study. The 10-65 year group had ≥ 75 exposure days on fixed prophylaxis (25-40 IU kg(-1) 3-4x per week). Prophylaxis was not fixed but similar for 1-6 year olds. Bleeding patterns were analysed. Overall, 700 bleeds were observed in 110/145 patients. All were treated with prophylaxis, mean dose 108 IU kg(-1) week(-1) in on average 2.9 infusions (1-6 years), 86 IU kg (-1) week(-1) in 2.7 infusions (10-17 years), and 75 IU kg (-1) week(-1) in 2.6 infusions (18-65 years), respectively. On prophylaxis, median total bleeds per year were low at 3.1 for patients aged 1-6 years, 3.3 for those aged 10-17 years and 2.1 for patients aged 18-65 years. Patients aged 1-6 years had predominantly soft tissue bleeds (79%). Incidence of joint bleeding was not associated with season, but was significantly lower in patients who infused FVIII in the mornings: median 0 per year (IQR 0.0-0.4) compared to those who infused later [median 1.8 per year (IQR 0.0-5.2)]. Older patients predominantly experienced joint bleeds (50% and 62%, respectively). More joint bleeds occurred during the summer [43 and 46% respectively, (P < 0.01)]. Bleeding patterns in patients on prophylaxis varied according to age. In addition, the 10-65 year olds showed increased bleeding during the summer. After confirmation in prospective studies, this information may be used to improve tailoring of prophylactic treatment.