Mary Lou Damiano

Prevalence and risk factors associated with decreased bone mineral density in patients with haemophilia

Summary.  Osteoporosis in adult males is an under‐recognized problem. Patients with haemophilia have several predisposing factors for developing decreased bone mineral density (BMD) including prolonged periods of immobility, reduced weight bearing and co‐morbidities associated with bone loss. To establish prevalence and risk factors associated with decreased BMD in patients with haemophilia. Adults with moderate or severe haemophilia A or B underwent dual‐energy X‐ray absorptiometry (DXA). BMD was correlated to laboratory values, joint mobility measurements and physical activity questionnaires. Thirty patients completed evaluations. The median age was 41.5 years (range 18–61). Median lowest T‐score by DXA was −1.7 (range: −5.8 to +0.6), with the femoral neck being the site of the lowest T‐scores. Based on World Health Organization criteria, 70% of patients had decreased BMD. Twenty‐seven per cent of the participants (n = 8) had osteoporosis and 43% (n = 13) had osteopenia. Variables associated with increased bone loss included lower serum 25‐hydroxyvitamin D levels (P = 0.03), lower body mass index (P = 0.047), lower activity scores (P = 0.02), decreased joint range of motion (P = 0.046), HIV (P = 0.03), HCV (P = 0.02), history of inhibitor (P = 0.01) and age (P = 0.03). Adults with haemophilia are at increased risk for developing osteoporosis. A history of HCV and HIV infections, decreased joint range‐of‐motion, decreased activity levels, history of an inhibitor and low body weight predict bone loss and suggest a population to target for screening. A high prevalence of vitamin D insufficiency was observed. Future studies should investigate interventions, including vitamin D supplementation, to prevent bone loss and fractures for this at‐risk population.

Prevalence of conditions associated with human immunodeficiency and hepatits virus infections among persons with haemophilia, 2001-2003

Summary.  Before the mid‐1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV‐1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV‐seropositive patients, age 13–88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross‐sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV‐1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV‐1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV‐1‐positive participants had ≥200 CD4+ cells μL−1, only 59% were on HAART. HIV‐1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti‐HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV‐1‐positive than HIV‐1‐negative participants (85% vs. 70%, P < 0.0001). HIV‐1‐positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV‐negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self‐reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non‐Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV‐1, HCV or both.

Overweight and obesity in hemophilia: a systematic review of the literature.

CONTEXT As life expectancy in individuals with congenital hemophilia approaches that of the general population, we hypothesize that public health risks, including overweight and obesity, also follow a similar trend. EVIDENCE ACQUISITION A search of the literature included terms relating to overweight, sequelae of being overweight, and hemophilia. Studies were included if they reported the frequency or clinical significance of known complications of overweight and obesity, including musculoskeletal disease, aerobic capacity, cardiovascular disease, diabetes, hyperlipidemia, decreased quality of life, and change in pharmacokinetics of infused clotting factor in hemophilia. Recommendations from medical organizations were searched for preventive and management strategies applicable to this population. EVIDENCE SYNTHESIS Overweight and obesity are now more prevalent in the hemophilia population than previous generations, with rates similar to and, in certain subsets even higher, than that of the general population. Increased BMI leads to limitations in joint range of motion in the general population and even more so in persons with hemophilia. CONCLUSIONS Overweight and obesity in hemophilia are an increasing problem. Simple steps can be taken to encourage patients to decrease caloric intake and increase physical activity. Prevention and management of overweight, obesity, and their sequelae must be addressed in clinical practice in order to maximize the overall health of the hemophilia population.

Treatment of chronic haemophilic synovitis in humans with D-penicillamine.

Summary. Chronic proliferative synovitis secondary to haemathroses is a major complication in patients with severe haemophilia. Current management strategies include prophylactic infusions of the missing coagulation factor, corticosteroids, synoviorthesis and/or synovectomy with variable degrees of benefit. In addition, patients with coagulation factor inhibitors are not amenable to the invasive therapeutic modalities. The gross and microscopic findings of the synovitis in haemophilic arthritis are remarkably similar to those seen in patients with rheumatoid arthritis, although the pathophysiology of these two conditions are quite different. Haemophilic arthropathy, in the later stages, resembles degenerative rather than inflammatory joint disease. Oral d‐penicillamine, a drug effective in the proliferative synovitis of rheumatoid arthritis, was evaluated in 16 patients. Ten patients had an unequivocal response, while three had a reduction in palpable synovium and three had no response. Thus 81% of the patients had a beneficial response. Minor reversible drug side‐effects occurred in two patients (proteinuria in one and a rash in the second). The results of this study suggest that d‐penicillamine is an effective and safe drug for the treatment of haemophilic chronic synovitis.

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.

Danazol-induced factor VIII and IX by passing activity in hemophiliacs

Danazol, a synthetic androgen reported to increase factor VIII and IX activity levels, was given to 6 hemophiliacs. With danazol therapy (600 mg/da) the APTTs shortened by 30-45% of pre-treatment times. However, the activity levels of the deficient factors did not increase significantly nor consistently with the APTT change. The prothrombin times and activity levels of factors XI and XII also did not change during the study period. Addition of plasma from danazol-treated patients to plasma with a known factor VIII inhibitor and to plasma from an untreated severe hemophilia A patient caused a similar shortening of the respective APTTs. Absorption of the danazol plasma with precipitating antibody against factor VIII and IX did not remove the APTT correcting principal. The data suggest that danazol may cause the de novo appearance of an intrinsic coagulation pathway activator having factor VIII and IX bypassing activity.

DANAZOL-INDUCED FACTOR IX AND VIII BYPASSING ACTIVITY

Danazol, a synthetic androgen reported to increase factor VIII and IX activity levels, was given to 5 hemophiliacs who were >17 years old (3 with severe hemophilia A, one moderate hemophilia A and one moderate hemophilia B). With danazol therapy (600 mg/da) the PTTs shortened 20-30% of pre-treatment times. The prothrombin times and activity levels of factors VIII, IX, and XII did not change during the study period. Addition of plasma from danazol-treated patients to plasma with a known factor VIII inhibitor and to plasma from an untreated severe hemophiliac A patient caused a similar shortening of the respective PTTs. A typical mixing experiment is shown in the Table (IP=inhibitor plasma; NP=normal plasma; HP=hemophilia A control; HP-D=danazol plasma in hemophilia A. The PTTs, in secs, are shown using 1 vol to 1 vol mixing, incubating for 4 min @ 37°C).Absorption of the danazol plasma with precipitating antibody against factor VIII and IX did not remove the PTT correcting principal. The data suggest that danazol may cause the de novo appearance of an intrinsic coagulation pathway activator having factor VIII and IX bypassing activity.

EFFECT OF DANAZOL ON APTT, COAGULANT FACTOR ACTIVITY AND BLEEDING IN HEMOPHILIA

Danazol has been reported to raise several plasma proteins. Danazol was given orally at 600 mg/day in 3 divided doses to 6 hemophiliacs for 8-14 weeks. Factor levels, APTT and other laboratory parameters were measured every 2 weeks. Five patients had classic hemophilia (1 mild-moderate, 3 severe, 1 with inhibitor) and 1 had Christmas disease. All patients showed a significant decrease an APTT beginning with the first measurement (2 weeks) and persisting till the drug was discontinued. However, a corresponding increase in the deficient factor activity could not be consistently demonstrated. Typical results for a severe classic hemophiliac are shown.Despite the shortened APTT bleeding episodes continued in the severe hemophiliacs and the patient with Christmas disease. In 4 patients bleeding appeared to either increase in severity or change in pattern. In 2 patients bleeding did not respond to their usual factor infusions, but responded to discontinuation of danazol and further factor replacement. In 3 patients the drug was discontinued because of bleeding. These results differ from those recently reported. Increased fibrinolytic activity may be responsible for the altered bleeding.

PENICILLAMINE TREATMENT IN HEMATHROSIS-INDUCED CHRONIC ARTHRITIS

Current medical management for established hemophilic arthritis is unsatisfactory and does not modify the eventual outcome. D-Penicillamine (PEN), an anti-inflammatory drug effective in rheumatoid arthritis, has not been evaluated in hemarthroses-induced joint disease. 83 NZ white rabbits had weekly intra-articular injections of citrated autologous blood (right knee) and citrated saline (left knee) for 6 months. PEN 15 mg or 50 mg/kg/da, IM, was begun early (day 1) or late (at 8 wks). Controls were saline treated rabbits. The animals were killed at 6 mo. Analysis included joint fluid WBC counts, gross and histologic examination of the synovia (acute and chronic inflammatory cells, synovial hyperplasia, and iron deposition). The saline-injected knees showed no inflammatory change and the blood-injected knees had iron deposition in all animal groups. The early high and low dose, and late low dose PEN treated groups showed no difference from untreated animals. Late high dose PEN treatment showed marked suppression of the synovitis. Four hemophiliacs with synovitis were given PEN, 5-10 mg/kg/da, p.o. for>2 months. All have had significant reduction in the synovial thickening with concurrent increased range-of-motion and decreased number of bleeds into the affected joint. These studies suggest that PEN is beneficial in the chronic arthritis induced by hemarthroses. Its anti-inflammatory mechanism is not known but may be inhibiting free radical formation, not by removing iron by its chelating ability.