E. P. Mauser-Bunschoten

Guidelines for the management of hemophilia.

Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence‐based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion‐transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

Sexual transmission of hepatitis C virus

We tested 50 heterosexual partners of hepatitis C viraemic (HCV) individuals, using second generation HCV antibody assays and a validated polymerase chain reaction assay. In none of them were HCV antibodies or HCV-RNA detected. The median duration of the sexual relationship was 13 years. This study, with the most sensitive techniques for detection of HCV, indicates that the risk of sexual transmission of HCV is absent or very low.

Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study

Summary.  Background: Clotting factor products have been safe for HIV since 1985, and for hepatitis C since 1992. Few studies have reported on mortality in the total population of hemophilia patients after the period of risk of viral infection transmission. Objectives: We studied the mortality, causes of death, and life expectancy of hemophilia patients between 1992 and 2001. We compared these findings with those of previous cohorts, together spanning the periods before, during, and after the use of potentially contaminated clotting products. Patients and methods: We performed a prospective cohort study among 967 patients with hemophilia A and B. Death rates, overall and cause‐specific, were compared with national mortality figures for males adjusted for age and calendar period as standardized mortality ratio (SMRs). Results: Between 1992 and 2001, 94 (9.7%) patients had died and two patients were lost to follow‐up (0.2%). Mortality was 2.3‐times higher in hemophilia patients than in the general male population (SMR 2.3 95% confidence interval 1.9–2.8). In patients with severe hemophilia, life expectancy decreased from 63 (1972–1985) to 59 years (1992–2001). Exclusion of virus‐related deaths resulted in a life expectancy at birth of 72 years. Conclusions: AIDS was the main cause of death (26%) and 22% of deaths were because of hepatitis C. In patients not affected by viral infections, there still appeared to be a trend toward a moderately increased mortality compared with the Dutch male population. Thus, mortality of patients with hemophilia is still increased; this is largely because of the consequences of viral infections.

Prophylactic versus on‐demand treatment strategies for severe haemophilia: a comparison of costs and long‐term outcome

Summary.  A multicentre study was performed to compare clotting factor use and outcome between on‐demand and prophylactic treatment strategies for patients with severe haemophilia. Data on treatment and outcome of 49 Dutch patients with severe haemophilia, born 1970–80, primarily treated with prophylaxis, were compared with those of 106 French patients, who were primarily treated on demand. Dutch patients received intermediate dose prophylaxis, for a median duration of 12.7 years. Patients primarily treated with prophylaxis had fewer joint bleeds per year (median 2.8 vs. 11.5), a higher proportion of patients without joint bleeds (29% vs. 9%), lower clinical scores (median 2.0 vs. 8.0), and less arthropathy as measured by the Pettersson score (median 7 points vs. 16 points). Mean annual clotting factor use was equal at 1488 ± 783 IU kg−1 year−1 (mean ± standard deviation) for patients primarily treated with prophylaxis and 1612 ± 1442 IU kg−1 year−1 for patients primarily treated on demand. These findings suggest that, compared with a primarily on‐demand treatment strategy, a primarily prophylactic treatment strategy leads to better outcome at equal treatment costs in young adults with severe haemophilia.

Long-term outcome of individualized prophylactic treatment of children with severe haemophilia.

The development of arthropathy is a serious complication of severe haemophilia. With the use of prophylaxis, bleeds can be prevented and arthropathy delayed. We investigated whether an individually tailored prophylactic regimen can prevent arthropathy and whether it had a similar effect on orthopaedic outcome compared with that of a high‐dose regimen. Efficacy was determined clinically and by radiographs of six major joints. Prophylaxis was started in 70 patients at a mean age of 4·1 years. Mean follow‐up was 15·6 years (range 8–24·5 years). The mean factor VIII consumption was 2319 IU/kg/year. The mean number of joint bleeds was 3·5/year and the mean clinical score (maximum score 90) was 1·0, with a mean Pettersson joint score (maximum score 78) of 3·0 at a mean age of 13·5 years. In conclusion, long‐term, early‐onset, individualized prophylaxis in haemophilia is feasible and prevents arthropathy.

Changes in treatment strategies for severe haemophilia over the last 3 decades: effects on clotting factor consumption and arthropathy

A cohort study was performed among 214 patients with severe haemophilia, born 1944–1994, to describe changes in treatment over the last 3 decades and its effects on clotting factor consumption and haemophilic arthropathy. Data on treatment strategy, clotting factor consumption, and outcome were collected for 3567 patient years (from 1972 to 1998), and 493 Pettersson scores were analysed. Median follow up was 17 years (range 6–27 years), and median age in 1998 was 27.6 years. Since 1965, replacement therapy, prophylaxis, and home treatment have been used and treatment intensified. Over the last 3 decades, annual clotting factor consumption increased by 260%, for both prophylactic and on‐demand treatment. Annual clotting factor consumption kg–1 increased during childhood and appeared to stabilize in early adulthood for patients born 1965–79, who were treated with early replacement therapy or early prophylaxis. In contrast, clotting factor consumption increased continuously for patients born before 1965, who had had no access to replacement therapy during the early years of their life. The annual number of joint bleeds decreased over the years. Arthropathy as measured by the Pettersson score generally became apparent around the age of 15 years and was lowest in patients treated with primary prophylaxis. In conclusion, clotting factor consumption has increased and haemophilic arthropathy has decreased due to the intensification of treatment for severe haemophilia over the last 3 decades. Annual clotting factor consumption stabilizes in adulthood for patients who receive early intensive treatment.

The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleedings in patients with haemophilia A with an inhibitor to Factor VIII

A double blind study was carried out on 15 haemophilia A patients with inhibitors using FEIBA (Immuno) as the investigational drug and prothrombin complex (Prothromplex, Immuno) as the alternate therapy.

Cardiovascular disease in patients with hemophilia

Summary.  Mortality due to ischemic heart disease in hemophilia patients is lower as compared to the general male population. Differences in the prevalence of cardiovascular risk factors cannot explain this finding. The hypocoagulable state of hemophilia patients might have a protective effect on thrombus formation, which precipitates infarction. It remains unclear whether the deficiency of coagulation factor VIII or IX exerts a protective effect on the development of atherosclerosis. Despite the relative protection against cardiovascular events, the incidence of ischemic cardiovascular disease in hemophilia patients is increasing, because life expectancy of these patients now approaches that of the general population. This review focuses on what is currently known about cardiovascular risk factors, atherosclerosis, arterial thrombosis and ischemic cardiovascular disease in hemophilia patients.

Discontinuation of prophylactic therapy in severe haemophilia: incidence and effects on outcome.

A cohort study was performed to assess adherence to early prophylactic therapy and its effects on outcome in 49 patients with severe haemophilia born 1970–1980. Median age at start of prophylaxis was 5.5 years. The majority (69%) of patients interrupted prophylactic treatment one or more times of their own accord (median total interruption 2.2 years). Patients who discontinued prophylaxis at any point tended to have more arthropathy as measured by the Pettersson scale (median 8 points versus 4 points). One‐third of these patients interrupted prophylaxis for longer periods and had permanently stopped taking prophylaxis at a mean age of 20.1 years (mean ± SD duration 4.1 ± 4 years) and consequently experienced 5.4 ± 3.4) joint bleeds per year. This subgroup could be identified by a predictive score based on age at start of prophylaxis, weekly dose of prophylaxis, and joint bleed frequency on prophylaxis. In conclusion, while on prophylaxis, more than two‐thirds of patients with severe haemophilia try to discontinue treatment, resulting in slightly more arthropathy. One‐third of these patients permanently discontinue prophylaxis in adulthood, while maintaining a low number of joint bleeds.

Co-morbidity in the ageing haemophilia patient: the down side of increased life expectancy

Summary.  Because of an increased life expectancy, (age‐related) co‐morbidity is becoming a common occurrence in haemophilia patients. In this review, haemophilia‐related and non‐haemophilia‐related medical problems, treatment recommendations and psychosocial consequences in ageing haemophilia patients are discussed. Haemophilic arthropathy is an important cause of pain and disability, and a frequent indication for surgery in haemophilia patients. In addition, many adult patients are infected with hepatitis C or HIV, the consequences and treatment of which can add to physical and mental discomfort. Moreover, inhibitors against factor VIII can also develop in adulthood, especially in patients with mild haemophilia. Hypertension is reported to occur more often in haemophilia patients than in the general population. Other internal problems, like renal abnormalities, overweight, diabetes mellitus and hypercholesterolemia are discussed. Haemophilia seems to protect against cardiovascular disease, although the incidence is increasing. Recommendations are given on dealing with tooth extractions, surgical interventions and sexuality problems in patients with haemophilia. In addition to haemophilia in itself, co‐morbidity has a major psychological impact, and an important effect on quality of life. It can also result in complex treatment regimens, in which coordination between health care workers is essential.