Multidisciplinary management of patients with haemophilia with inhibitors undergoing surgery in the United States: perspectives and best practices derived from experienced treatment centres

Since the 1980s, major surgical interventions in patients with congenital haemophilia with inhibitors have been performed utilizing bypassing agents for haemostatic coverage. While reports have focused on perioperative management and haemostasis, the US currently lacks consensus guidelines for the management of patients with inhibitors during the surgical procedure, and pre‐ and postoperatively. Many haemophilia treatment centres (HTCs) have experience with surgery in haemophilia patients, including those with inhibitors, with approximately 50% of these HTCs having performed orthopaedic procedures. The aim of this study was to present currently considered best practices for multidisciplinary care of inhibitor patients undergoing surgery in US HTCs. Comprehensive haemophilia care in the US is provided by ~130 federally designated HTCs staffed by multidisciplinary teams of healthcare professionals. Best practices were derived from a meeting of experts from leading HTCs examining the full care spectrum for inhibitor patients ranging from identification of the need for surgery through postoperative rehabilitation. HTCs face challenges in the care of inhibitor patients requiring surgery due to the limited number of surgeons willing to operate on this complex population. US centres of excellence have developed their own best practices around an extended comprehensive care model that includes preoperative planning, perioperative haemostasis and postoperative rehabilitation. Best practices will benefit patients with inhibitors and allow improvement in the overall care of these patients when undergoing surgical procedures. In addition, opportunities for further education and outcomes assessment in the care of this patient population have been identified.     

Haemophilia care in South Africa: 2004–2007 look back

Summary.  The South African national haemophilia program (NHP) was officially recognized in 2000 and implemented by the National Department of Health (NDOH), haemophilia specialists of the Medical and Scientific Advisory Council (MASAC) and the South African Haemophilia Foundation (SAHF). This study aims to report on progress and challenges of haemophilia care in SA after implementation of the NHP. Haemophilia care data collected by MASAC from all treatment centres (HTCs) from 2004 to 2007 were reviewed and appraised. Data assessment included evaluation of the number and types of professional haemophilia expertise, diagnostic and human resources available, number and types of HTCs, number and types of haemophilia diagnoses, immunological complications of haemophilia, social, medical and surgical interventions, factor usage and reporting on haemophilia mortality. Over 2200 bleeding diathesis patients in SA were cared for by an average of 79 professionals in 17 HTCs. Fifty-nine per cent were haemophilia A, 21% von Willebrand's disease, 12% haemophilia B and the remainder had rare bleeding diathesis and thrombocytopathies. In 2004–2007, the number of haemophilia professionals stayed the same, clinic visits increased, new patients and inhibitor patients also increased. Surgical and medical interventions were unchanged and per capita factor usage increased from 0.65 to 0.95. National mortality rate remained below 10 deaths per year. Haemophilia care in SA is highly organized and effective in the delivery of haemophilia health services. All diagnosed uncomplicated haemophiliacs have access to state funded factor concentrate. Limited human and diagnostic resources remain major challenges.     

Co‐morbidities and quality of life in elderly persons with haemophilia

The life expectancy and quality of life of persons with haemophilia has dramatically increased since the 1970s, with the exception of the increased rate of deaths observed during the 1980s and the 1990s due to blood‐borne viral infections. Improvements of factor replacement therapy, treatment of infectious diseases and comprehensive health care provided by specialised haemophilia centres are the main determinants of the increasing age of the haemophilia population. As a consequence, a growing number of these patients develop age‐related co‐morbidities, such as cardiovascular disease and cancer. The care of these previously rare conditions is a new challenge for caregivers in haemophilia centres. This review focuses on co‐morbidities in the ageing haemophilia patients, their impact on quality of life and their complex management.     

Trends in clinical management of women with von Willebrand disease: a survey of 75 women enrolled in haemophilia treatment centres in the United States

OBJECTIVE: To assess the management of women with von Willebrand disease( vWD) in an Heamophilia Treatment Center (HTC) setting. METHODS: A total of 75 women with vWd who were registered in HTCs in the United States participated in this study. A telephone interview elicited information about symptoms pertaining to bleeding disorders, diagnostic issues, referral patterns, treatment modalities before and after the enrollment in the HTC, HTC services provided, and satisfaction with care in the HTC. RESULTS: Menorrhagia was the most commonly reported symptom (84%). The average time from the first symptom until clinician recognition was 16 years (range 0-39). In HTC, DDAVP was the most commonly used drug (31%). Of the 75 women, 71 reported a strong positive opinion and satisfaction about their care in the HTCs. DISCUSSION: Women with VWD were typically diagnosed with the condition well into adulthood, in spite of the fact that majority of them experienced several bleeding symptoms beginning in early childhood. In general an HTC setting is appropriate for management of women with bleeding disorders. Diagnosis, treatment and education provided in the HTCs were viewed positively by those surveyed.     

Comprehensive care for hemophilia and related inherited bleeding disorders: why it matters

Comprehensive hemophilia treatment centers (HTCs) were first inaugurated more than 50 years ago. In 1976, a federally funded HTC network was created in the United States, making multidisciplinary care for patients with hemophilia and other inherited bleeding disorders available throughout the country for the first time. Education of the patient and healthcare professional in the management of bleeding became a mainstay of these programs. The HTCs began surveillance of the complications of treatment, such as hepatitis and HIV. The high rate of HIV infection in the hemophilia population from contaminated clotting factor concentrates forced an adaptation of HTCs to manage the medical and psychosocial consequences of these diseases. In addition, expanded surveillance for potential new therapy-associated complications became a legacy of these efforts. From the HIV era until the present, HTCs have undertaken expanded clinical research (drawing on a new scientific understanding regarding hemostasis and new knowledge regarding the management of quality of life) to study new methods to improve the well-being of patients with hemophilia. The further research has extended to phase 1 gene transfer trials for hemophilia A and B. Although the prospect for a complete cure for patients with hemophilia is some time away, HTCs in the 21st century continue to vigorously research a cure. In the interim, the HTC model continues to provide essential services that are being reassessed in light of new scientific information to prevent the complications that have defined the clinical picture of hemophilia.     

The evolution of comprehensive haemophilia care in the United States: perspectives from the frontline

The establishment of dedicated comprehensive treatment centres more than a half century ago transformed the management of haemophilia in the United States. Formerly, a disease associated with crippling disability and premature death, today, persons with haemophilia who are treated appropriately from infancy and do not develop inhibitors can expect a normal life expectancy and relatively few bleeding episodes. The evolution of the comprehensive haemophilia care, while chastened by the viral epidemics of the 1980s, has been marked by ongoing advances, including prophylaxis, immune tolerance induction, new drugs and gene therapy research. Current challenges include sustaining the comprehensive care model despite decreased funding and expanding the delivery and affordability of comprehensive haemophilia care.     

Current challenges of pharmacovigilance in bleeding disorders: converting the burden to benefit

Summary. Safety surveillance studies have proven essential in research and development of new biological therapies for bleeding disorders as well as other diseases. Although product safety regarding HIV, hepatitis, and other blood‐borne infections is currently excellent, potential new infectious agents require continued vigilant monitoring. Inhibitor development is the most common serious side effect of haemophilia replacement therapy. Several aetiological factors associated with inhibitors have been identified, but their true impact is still largely unknown. Moreover, whether plasma‐derived and recombinant factor products differ in their immunogenic profiles is an unresolved issue. Coagulation factor products under development and those currently on the market require uniform, long‐term surveillance. The European Haemophilia Safety Surveillance (EUHASS) project was recently established to meet these goals. The pharmaceutical industry and clinicians face common challenges complying with these requirements. In rare diseases like haemophilia, obtaining adequate patient numbers poses a challenge. Another challenge is a lack of methods for assessing disease severity, a surprising deficiency in the era of modern medical and laboratory technology. National and international registries can be used to gather required safety surveillance information. Simultaneously, clinicians benefit from well‐organized registry data in their daily practice and harmonize the quality of comprehensive haemophilia care by homogeneous follow‐up platforms. Experience with such registries comes, for example, from Europe (PEDNET), the USA (CDC/UDC), the UK (UKHCDO), and Sweden (Malmö). It is important to commit to future pharmacovigilance efforts, aiming at high‐quality safety surveillance programmes at both the pharmaceutical research community and clinical levels.     

The natural history of mild haemophilia: a 30‐year single centre experience

Summary. Although up to 50% of all haemophilic patients followed at haemophilia treatment centres (HTCs) are affected by a mild factor VIII (FVIII) or factor IX (FIX) defect, published data regarding the natural history of these disorders are scarce. To fill this lack of information, a retrospective single centre study was conducted. All cases with mild haemophilia (75 A and 7 B) followed at the regional reference HTC of Parma were evaluated. The patients’ median age at diagnosis was 11.5 years and their median age at first bleeding was 5.5 years; 95% of patients had a history of haemorrhagic problems during their life. Twenty‐three percent of patients were infected by HCV, and none by HIV. Genetic analysis was performed in 80 patients (97% haemophilia A and 100% haemophilia B) and 21 different mutations were characterized. Eleven percent of patients had never received treatment, whereas 67% were treated with plasma‐derived or recombinant FVIII/FIX concentrates (4% developed inhibitors). desmopressin (DDAVP) was used in 80% of the haemophilia A patients. The response to DDAVP was closely related to the patients’ genetic profile, as 60% of non‐responders had a mutation in the F8 promoter region. Patients with mild haemophilia may experience a variety of medical problems, sometimes challenging for the physicians, during their lifetime. The HTCs play an important role in the management of these patients, whose diagnosis is often delayed. The HTCs should improve patients’ knowledge and consideration of their disease and encourage them to maintain regular contact with their haemophilia care provider.     

Geographic variability of hemophilia-associated AIDS in the United States: effect of population characteristics. Hemophilia-Associated AIDS Study Group

National AIDS surveillance suggests that approximately 3.5% of all hemophilic patients in the United States have developed AIDS as of February 1988; however, the cumulative incidence of AIDS among seropositive patients at individual hemophilia treatment centers (HTCs) has been reported to be as high as 12%. The purpose of this study was to examine the reported excess risk of AIDS at selected HTCs. Between July 13 and November 6, 1987, we reviewed medical charts from the 598 hemophilia A and hemophilia B patients receiving comprehensive care as of 1980 at six U.S. hemophilia treatment centers (three identified as low AIDS risk and three identified as high AIDS risk using national hemophilia-associated AIDS surveillance data). The risk of AIDS among all patients was 8% and among seropositive patients was 18%. At the individual HTCs, the risk ranged from 0% to 14% among all patients and 0% to 25% among seropositive patients. Overall incidence rates were higher than those derived from national surveillance data because national estimates include all hemophilic patients (regardless of severity) whereas this study included only patients receiving comprehensive care (who are more likely to be severely affected by their coagulation disorder and receive concentrated clotting factors). The higher incidence of AIDS in the high-risk centers was attributable to the older age of the patients in these HTCs, a factor previously associated with an increased risk of AIDS in seropositive patients. These findings do not support geographic variability in the incidence of AIDS and emphasize the importance of patient characteristics when comparing the incidence of hemophilia-associated AIDS between populations.     

An inventory of healthy weight practices in federally funded haemophilia treatment centres in the United States

In the haemophilia population, obesity has an adverse effect on health care cost, chronic complications and joint disease. Although staff of federally funded Hemophilia Treatment Centers in the United States (HTCs) anecdotally recognize these outcomes, practices to promote healthy weights have not been reported. This evaluation identifies routine practices among HTCs in body mass index (BMI) assessment, perceptions about need to address obesity and roles in offering evidence‐based strategies to promote healthy weights. A telephone survey was developed to assess HTCs practices including patient BMI assessment and counselling, perceptions about the importance of healthy patient weights, and HTCs roles in weight management. Ninety of the 130 federally funded HTCs contacted elected to participate and completed the telephone survey. Of these, 67% routinely calculated BMI and 48% provided results to patients. Approximately one‐third classified obesity correctly for children (30%) and adults (32%), using the Centers for Disease Control and Preventions BMI cut‐offs. Most HTCs (87%) reported obesity as an issue of ‘big’ or ‘moderate’ concern and 98% indicated HTC responsibility to address this issue. Most centres (64%) address patient weight during comprehensive visits. One‐third (33%) of centres include a nutritionist; of those without, 61% offer nutrition referrals when needed. Most (89%) HTCs do not have a protocol in place to address healthy weights; 53% indicated that guidelines are needed. HTCs offer services to help improve weight outcomes. Training programmes for calculating and interpreting BMI as well as identifying appropriate guidelines to apply to the HTC patient population are needed.     

US Hemophilia Treatment Center population trends 1990–2010: patient diagnoses,demographics, health services utilization

For several decades, US government agencies have partially supported regional networks of Hemophilia Treatment Centers (HTC). HTC multidisciplinary teams provide comprehensive and coordinated diagnosis, treatment, prevention, education, outreach and surveillance services to improve the health of people with genetic bleeding disorders. However, national data are scarce on HTC‐patient population trends and services. The aim of the study was to examine national trends over the past 20 years in patient diagnoses, demographics and health services utilization among the Health Resources and Services Administration (HRSA) and Centers for Disease Control and Prevention (CDC)‐supported HTC network. Diagnoses, demographics and health services utilization data from 1990 to 2010 were aggregated from all HTCs using the Hemophilia Data Set (HDS). From 1990 to 2010, the HTC population grew 90% from 17 177 to 32 612. HTC patients with von Willebrand's disease increased by 148%, females by 346%, Hispanic patients by 236% and African Americans by 104%. Four thousand and seventy‐five deaths were reported. From 2002 to 2010, annual comprehensive evaluations grew 38%, and persons with severe haemophilia on a home intravenous therapy programme rose 37%. In 2010, 46% of patients were less than 18 years vs. 24% for the general US population. The Hemophilia Data Set documents the growth and diversity of the US Hemophilia Treatment Center Network's patient population and services. Despite disproportionate deaths due to HIV, the HTC patient base grew faster than the general US population. The HDS is a vital national public health registry for this rare‐disorder population.     

Hepatitis C infection and outcomes in the Scottish haemophilia population

Patients with bleeding disorders previously frequently became infected with hepatitis C virus. We identified the number of patients infected in Scotland and assessed several aspects of the outcomes of HCV infection and its treatment comparing these with cohorts infected for other reasons. We calculated the number of individuals infected in Scotland (cohort A) starting with the total number of patients treated in Scottish haemophilia centres registered on the UKHCDO database between 1970 and 1989. Cases were then removed or added based on additional information from centre records. A second cohort B, consisted of 255 patients from cohort A and 47 patients HCV infected outside Scotland, but with follow‐up data from Scottish centres around their HCV infection. We estimate that 455 patients with bleeding disorders became infected by coagulation factor provided by NHS Scotland. In 302 individuals with documented HCV infection, rates of natural clearance (17.4%), genotype spread (64% genotype 1) and responses to antiviral therapy (14.5% with monotherapy; 38.8% with combination therapy) were similar to those in other cohorts. Thirty‐four liver biopsies were performed without adverse event and liver transplantation has been performed in 11 patients, seven for liver failure, four for hepatocellular carcinoma. Around 455 patients with bleeding disorders became HCV infected in Scotland before 1989. The natural history of HCV infection and responses to treatment are similar to those in other HCV‐infected cohorts. Liver transplantation has been used successfully for the treatment of end‐stage liver failure and hepatocellular carcinoma.     

Comprehensive care in hemophilia

Hemophilia is a chronic and inherited X-linked bleeding disorder that requires life-long medical care. Hemophilia treatment is costly and complex partly because of the cost of the factor concentrates used in replacement therapy. However, the management of hemophilia is not based solely on achieving access to better treatment with safe factor concentrates; it also includes accurately diagnosing the disorder and providing specialized comprehensive care by a multidisciplinary team of specialists trained in hemophilia management. Comprehensive care for the person with hemophilia is defined as the continuous supervision of all medical and psychological aspects affecting the patient and his family and it demands the establishment of specialized centers, called Hemophilia Treatment Centers. The services that should be offered by a comprehensive hemophilia healthcare center are diverse and the multidisciplinary team should be coordinated preferably by a hematologist with the participation of other health professionals. It has been demonstrated that the benefits of establishing hemophilia centers are observed even in developing countries and that changes can be achieved when resources are re-organized, especially when education and training are provided at all levels. To reach these objectives, it is essential to have the participation of the patient and family members, and to strive to obtain the financial and legislative support from the State or Government in order to achieve a national comprehensive care program contemplating all the aspects needed for improving the quality of life for the community of patients with hemophilia and other bleeding disorders.     

Clinical utility of viscoelastic testing (TEG and ROTEM analyzers) in the management of old and new therapies for hemophilia

Hemophilia A and B are rare inherited bleeding disorders resulting from deficiency of coagulation factors VIII and IX respectively. In the past few decades, the field of hemophilia has witnessed pivotal management challenges and therapeutic advances. Routine coagulation and factor assays, while useful in the classification of severity and treatment monitoring in hemophilia patients, have been shown to be of limited use in managing clinical presentations and outcomes. This prompted the investigation of viscoelastic studies in hemophilia care, which have established their utility in various bleeding and thrombotic states. In this review, we will discuss and critically assess the current literature highlighting the use of viscoelastic studies in various aspects of hemophilia including the determination of clinical phenotype, management of patients with inhibitors, perioperative management, and monitoring of novel agents.     

Perceived challenges and attitudes to regimen and product selection from Italian haemophilia treaters: the 2013 AICE survey

Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma‐derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood‐borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non‐inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence‐based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs.     

Plasminogen activator inhibitor type 1 deficiency

Summary. Plasminogen activator inhibitor type 1 (PAI‐1) is an important component of the coagulation system that down‐regulates fibrinolysis in the circulation. Reduced PAI‐1 levels may result in increased fibrinolysis and an associated bleeding diathesis. Clear documentation of PAI‐1 deficiency as a cause of a bleeding disorder has been rare. PAI‐1 was initially identified in the 1980s, and the first reported case of PAI‐1 deficiency appeared in 1989. Several reports followed, although only two identified an underlying genetic defect. These reports of PAI‐1 deficiency suggest that affected individuals exhibit mild to moderate bleeding symptoms, including epistaxis, menorrhagia, and delayed bleeding after trauma or surgical procedures. Affected individuals rarely exhibit spontaneous bleeding events commonly seen in other procoagulant deficiencies. The majority of bleeding events are controlled with antifibrinolytic agents, such as tranexamic acid and ε‐aminocaproic acid. A major issue that contributes to difficulty in establishing an accurate diagnosis of PAI‐1 deficiency is that the activity assay is accurate in detection of elevated levels but not at the lowest range. Reported normal ranges begin at zero, thereby making a deficiency state because of a dysproteinaemia difficult to distinguish from that of a normal unaffected individual. Although the antigen assay may be helpful in some circumstances, it assists only with complete quantitative disorders. Because of lack of standardized commercially available PAI‐1 activity assay sensitive in the lowest range, the true prevalence of this rare condition has not been established.     

Optimal haemophilia care versus the reality

Haemophilia A and B are inherited bleeding disorders whose diagnosis and management is generally well established and best provided by specialists in a comprehensive care setting. Patients may be put at unnecessary risk if appropriate expertise is not sought for the management of accidents and surgery. The delivery of a high quality comprehensive service to patients with bleeding disorders depends upon defined standards and a network of haemophilia centres in the UK with similar models in other countries. In developing countries, despite a shortage or absence of treatment products, development of local expertise results in an improved outlook and reduction in mortality. Optimal care for severe haemophilia includes accurate diagnosis, early and adequate factor replacement for bleeding episodes and the provision of prophylaxis from an early age to prevent joint bleeding and the consequent arthropathy. Haemophilia treatment is expensive resulting in considerable inequity in provision of care across the world. Despite decades of experience, optimal treatment levels are not robustly defined. Transfusion-transmitted infections continue to have a significant impact on patient management. The development of inhibitory antibodies seriously complicates the management both in morbidity and cost. While gene therapy has not yet produced the hoped-for cure, new technologies will produce improved products.     

Risk reduction strategies for variant Creutzfeldt–Jakob disease transmission by UK plasma products and their impact on patients with inherited bleeding disorders

Summary. The appearance and rapid evolution of BSE in UK cattle in the mid 1980s, with compelling data supporting variant Creutzfeldt–Jakob disease (vCJD) as its human manifestation, pose a potentially severe threat to public health. Three clinical cases and one asymptomatic case of vCJD infection have been reported in UK recipients of non‐leucodepleted red cell transfusions from donors subsequently diagnosed with vCJD. Plasma from both these and other donors who later developed vCJD has contributed towards plasma pools used to manufacture clotting factor concentrate. The United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) Surveillance Study has detected asymptomatic vCJD postmortem in a haemophilic patient treated with UK plasma products including two batches of clotting factor linked to a donor who subsequently developed vCJD. Over 4000 bleeding disorder patients treated with UK plasma products are recorded on the UKHCDO National Haemophilia Database. The risk of vCJD transmission by plasma products is not known. However, public health precautions have been implemented since 2004 in all UK inherited bleeding disorder patients who received UK‐sourced plasma products between 1980 and 2001 to minimize the possible risk of onward vCJD transmission. We evaluate vCJD surveillance and risk management measures taken for UK inherited bleeding disorder patients, report current data and discuss resultant challenges and future directions.     

Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres

Summary. Every other day (qod) factor VIII prophylaxis prevents joint bleeds in children with severe haemophilia A. Although three times weekly or qod prophylaxis is recommended by the National Hemophilia Foundation (NHF), how widely these practices have been adopted is not known. We sought to define current prophylaxis practices at US haemophilia treatment centres (HTCs). An email survey was distributed to US HTCs, utilizing web‐based membership rosters of the Centers for Disease Control (CDC) and the Hemostasis Thrombosis Research Society (HTRS). Of 62 HTCs responding, prophylaxis is initiated on a three times weekly schedule in 29 (46.8%), twice weekly in 13 HTCs (21.0%) and once weekly in 20 HTCs (32.2%). Central venous catheters are used to infuse factor prophylactically at 55 HTCs (88.7%), including in 100% of children initiating prophylaxis at 19 HTCs (30.6%) and in 50% of those at 41 HTCs (66.1%), but avoided altogether at seven HTCs (11.3%). Prophylaxis is initiated after one or more bleeds in 56 HTCs (90.3%), but after the first bleed in only 28 HTCs (25.2%). Among 226 newborns with severe haemophilia A in 62 HTCs, 1.82 births/HTC/year, the median age at first bleed, excluding circumcision, is 7 months. Of the 113 (53.5%) newborns who underwent circumcision, 62 (54.9%) bled. Despite a recommended standard of three times weekly prophylaxis, over half of surveyed HTCs do not follow these guidelines, and nearly one‐third begin prophylaxis on a once weekly schedule to delay or avoid the need for central venous access.