Discontinuing early prophylaxis in severe haemophilia leads to deterioration of joint status despite low bleeding rates.

Prophylaxis is the recommended treatment for children with severe haemophilia A, but whether prophylaxis should be continued in adulthood is still under debate. Previous studies with limited follow-up have suggested that some patients may be able to stop prophylaxis in adulthood, while maintaining good joint health. This single-centre observational cohort study examined patients with severe haemophilia A born 1970-1988 without inhibitor development, and assessed the long-term consequences of discontinuing prophylaxis.

IL-1β, in contrast to TNFα, is pivotal in blood-induced cartilage damage and is a potential target for therapy.

Joint bleeding after (sports) trauma, after major joint surgery, or as seen in hemophilia in general leads to arthropathy. Joint degeneration is considered to result from the direct effects of blood components on cartilage and indirectly from synovial inflammation. Blood-provided proinflammatory cytokines trigger chondrocytes and induce the production of cartilage-degrading proteases.

The detrimental effects of iron on the joint: a comparison between haemochromatosis and haemophilia.

Joint damage due to (recurrent) joint bleeding in haemophilia causes major morbidity. Although the exact pathogenesis has not been fully elucidated, a central role for iron is hypothesised. Likewise, in hereditary haemochromatosis joint destruction is caused by iron overload.

Deferasirox limits cartilage damage following haemarthrosis in haemophilic mice.

Joint bleeds in haemophilia result in iron-mediated synovitis and cartilage damage. It was evaluated whether deferasirox, an iron chelator, was able to limit the development of haemophilic synovitis and cartilage damage. Haemophilic mice were randomly assigned to oral treatment with deferasirox (30 mg/kg) or its vehicle (control) (30 mg/kg).

Hemarthrosis in hemophilic mice results in alterations in M1-M2 monocyte/macrophage polarization.

Introduction: Joint bleedings result in iron-mediated synovitis and cartilage destruction. Monocyte/macrophage polarization affects their role in iron homeostasis. This study evaluates the effects of hemarthrosis on monocyte/macrophage polarization.

Blood-Induced Joint Damage: The Devastating Effects of Acute Joint Bleeds versus Micro-Bleeds.

Objective: Four days of blood exposure leads to irreversible cartilage damage in vitro. In contrast, intermittent intra-articular blood injections twice a week during 4 weeks (mimicking micro-bleeds) in a canine model resulted in transient damage only. In this study, it was evaluated whether acute joint bleeds are more harmful than micro-bleeds in a canine model of knee arthropathy.

Haemarthrosis stimulates the synovial fibrinolytic system in haemophilic mice.

Recurrent joint bleeding is the most common manifestation of haemophilia resulting in haemophilic arthropathy (HA). The exact pathophysiology is unknown, but it is suggested that arthropathy is stimulated by liberation of fibrinolytic activators from the synovium during haemarthrosis. The aim of this study was to test the hypothesis that haemarthrosis activates the local synovial fibrinolytic system in a murine haemophilia model.

A short time window to profit from protection of blood-induced cartilage damage by IL-4 plus IL-10.

Objective: IL-4 plus IL-10 prevents blood-induced cartilage damage. The aim of the present study was to evaluate whether cartilage damage can still be averted by addition of IL-4 plus IL-10 when added after the onset of a bleed and whether aspiration of blood prior to addition of IL-4 plus IL-10 is of additive protective value.

Methods: Healthy canine hip and human shoulder cartilage was exposed to whole blood for 4 days.

A single intra-articular injection with IL-4 plus IL-10 ameliorates blood-induced cartilage degeneration in haemophilic mice.

The combination of interleukin (IL)-4 and IL-10 protects against blood-induced cartilage damage in vitro. It has been hypothesized that the combination of these cytokines is effective if applied early in the process of cartilage damage. The present study investigated whether a single intra-articular injection of IL-4 plus IL-10 immediately after a joint bleed limits cartilage damage in an in vivo haemophilia mouse model of blood-induced joint damage.

Unfavourable cardiovascular disease risk profiles in a cohort of Dutch and British haemophilia patients.

Cardiovascular disease (CVD) mortality is reported to be decreased in haemophilia patients, but reports on the prevalence of CVD risk factors are conflicting. A cross-sectional assessment of CVD risk profiles was performed in a large cohort of haemophilia patients. Baseline data on CVD risk factors of 709 Dutch and UK haemophilia patients aged ≥30 years were analysed and compared with the general age-matched male population.

Increased prevalence of hypertension in haemophilia patients.

An increased prevalence of hypertension is reported in haemophilia patients, but data from large, unbiased studies are lacking. The aim of our study was to cross-sectionally assess the prevalence of hypertension in a large cohort of 701 haemophilia patients. Blood pressure (BP) measurements performed in 386 Dutch and 315 UK haemophilia patients aged 30 years or older were analysed and compared with the general age-matched male population.

History of non-fatal cardiovascular disease in a cohort of Dutch and British patients with haemophilia.

Objective: Cardiovascular disease (CVD) mortality is reported to be lower in haemophilia patients than in the general population, but information on the occurrence of non-fatal CVD is lacking. The aim of our study was to assess CVD history in a cohort of living haemophilia patients.

Methods: Retrospective data on the occurrence of myocardial infarction, angina pectoris, ischaemic stroke and intracranial bleeding in 709 living Dutch and British haemophilia patients aged 30 yr or older were analysed and compared with the general age-matched male population.

Coagulation aggravates blood-induced joint damage in dogs.

Objective: Joint bleeding due to trauma, major joint surgery, or hemophilia leads to joint damage. It is unclear if there are differences between coagulating blood and anticoagulated blood with respect to joint degeneration, especially in vivo. Therefore, we undertook this study to evaluate in a canine in vivo model whether intraarticular exposure to coagulating blood is more destructive than exposure to anticoagulated blood, and whether inflammation plays a role in the cartilage- damaging process.

Non-fatal cardiovascular disease, malignancies, and other co-morbidity in adult haemophilia patients.

Introduction: With increasing life expectancy, more haemophilia patients will be confronted with age-related problems. To ensure optimal care, it is important to know the occurrence of both fatal and non-fatal cardiovascular disease, malignancies and other types of co-morbidity in these patients. Our aim was to retrospectively assess the occurrence of co-morbidity and causes of death in a substantial birth-cohort of haemophilia patients.

Coronary artery calcification in hemophilia A: no evidence for a protective effect of factor VIII deficiency on atherosclerosis.

Objective: Ischemic heart disease mortality is lower in hemophilia patients than in the general male population. As coagulation plays a role in the inflammatory pathways involved in atherogenesis, we investigated whether the clotting factor deficiency protects hemophilia patients from developing atherosclerosis.

Methods And Results: Coronary artery calcification, measured with multidetector-row computed tomography, was compared between 42 men, ≥59 years, with severe or moderate hemophilia A, and 613 nonhemophilic men from the Rotterdam Study, a prospective population-based study.

The combination of the biomarkers urinary C-terminal telopeptide of type II collagen, serum cartilage oligomeric matrix protein, and serum chondroitin sulfate 846 reflects cartilage damage in hemophilic arthropathy.

Objective: Hemophilic arthropathy, with characteristics of inflammatory (rheumatoid arthritis) and degenerative (osteoarthritis) joint damage, occurs at an early age, is associated with minor comorbidity, and is restricted to 3 pairs of large joints. The aim of this study was to determine whether commonly used serum and/or urinary biomarkers of cartilage and bone turnover for which assay kits are commercially available are associated with the severity of joint damage in patients with various degrees of hemophilic arthropathy and, thus, whether this disease could be useful in the identification and evaluation of such biomarkers.

Methods: Blood and urine samples were collected from 36 patients with various degrees of hemophilic arthropathy.

Understanding haemophilic arthropathy: an exploration of current open issues.

Haemophilic arthropathy is joint damage evolving from recurrent joint bleeds that occur in patients suffering from the clotting disorder haemophilia. Insight into the pathogenetic mechanism of this blood-induced arthropathy yields possible treatment targets and modalities useful to reduce this invalidating co-morbidity of haemophilia. Joint bleeding leads to initially independent adverse changes in both the synovial tissue and the articular cartilage.

Interleukin-10 protects against blood-induced joint damage.

Despite prophylactic treatment, haemophilia patients suffer from spontaneous joint bleeds, which lead to severe joint damage. Also after joint trauma, an intra-articular haemorrhage can add to joint damage over time. This study evaluated interleukin 10 (IL-10) in the search for possible interventions to prevent or limit the damaging effects of joint bleeds.

Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: an in vitro study.

Objective: Joint bleeding, or hemarthrosis, leads in time to severe joint damage. This study was carried out to test the in vitro thresholds of exposure time and concentration that lead to irreversible joint damage, to add to the discussion on the usefulness of aspiration of the joint after a hemorrhage.

Methods: Explants of healthy human articular cartilage tissue were cultured in the presence or absence of 50% (volume/volume) blood for 1, 2, 3, or 4 days or in the presence of 0%, 5%, 10%, 20%, 30%, or 50% (v/v) blood for 4 days, followed by a 12-day period of recovery after withdrawal of blood.

Factor VIII half-life and clinical phenotype of severe hemophilia A.

Background And Objectives: Patients with severe hemophilia A have considerably different factor VIII half-lives. Whether this is associated with their clinical characteristics has not been reported. The aim of this study was to describe the association of factor VIII half-lives with treatment and clinical characteristics of patients with severe hemophilia A, who have been treated with individually tailored prophylaxis.

Successful treatment of severe bleeding in hemophilic target joints by selective angiographic embolization.

Bleeding into the joints is common in patients with hemophilia. After total knee or elbow replacement, profuse intraarticular bleeding unresponsive to high-dose clotting factor replacement sometimes occurs. In some patients who have severely damaged elbow or knee joints the same profuse bleeding pattern can be seen.

Initiation of degenerative joint damage by experimental bleeding combined with loading of the joint: a possible mechanism of hemophilic arthropathy.

Objective: To investigate the effect of a limited number of experimental joint bleedings, combined with loading of the affected joint, on the development of progressive degenerative joint damage.

Methods: The right knee of 8 mature beagle dogs was injected with freshly collected autologous blood 3 times per week for 4 weeks, to mimic a limited number of joint hemorrhages occurring over a short period. To ensure loading of the experimental joint, the contralateral control knee of the animals was fixed to the trunk 4 hours per day, 3 days per week.

Blood-induced joint damage in hemophilia.

Hemophilia is a X chromosome-linked disease characterized by an increased tendency to hemorrhage. Because of recurrent hemarthrosis, specific changes occur in synovium and cartilage. This process is called hemophilic arthropathy.