The Jamaican Haemophilia Registry: Describing the burden of disease.

INTRODUCTION: Jamaica has an estimated 200 persons with haemophilia (PWH), who face significant constraints in access to specialized haemophilia care, including access to clotting factor concentrates. AIM: The aim of this paper is to establish the current burden of disease in PWH in Jamaica. METHODS: PWH were enrolled through the University Hospital of the West Indies, Jamaica. The impact of haemophilia was assessed using a comprehensive battery of heath outcome measures that included the following: laboratory, clinical information and validated outcome measures of joint structure and function, activity, and health-related quality of life (HRQoL) to provide a health profile of the Jamaican haemophilia population. RESULTS: In all, 45 PWH were registered (mean age: 29, range: 0.17-69 years), including 13 children (<18 years of age) and 32 adults. In this sample, 41 had haemophilia A (30 severe) and 4 had haemophilia B (3 severe); 10 patients with haemophilia A were inhibitor positive. The results indicate that adults with haemophilia in Jamaica have significant joint damage: mean Haemophilia Joint Health Score (HJHS) = 42.1 (SD = 17.3); moderate activity levels - mean Haemophilia Activities List (HAL) score = 64.8 (SD = 17.8); and low HRQoL scores - mean Haemo-QoL-A score = 62.3 (SD = 19.4). Results for children are also reported but should be interpreted with caution due to the small sample size. CONCLUSIONS: There is a very high burden of disease in PWH in Jamaica. The health profiles reported in this paper are an essential first step in advocating for a multidisciplinary Comprehensive Care Program for assessment and care of PWH in Jamaica.

Supply and demand for hemophilia treatments-Systems-based approaches to mitigate the risk.

Treatment of hemophilia consists of replacement of the missing coagulation factor, either prophylactically or at the time of injury or bleeding. Because of the high cost of these products, which can present a barrier to care, different procurement strategies have been developed at national and regional levels. The emergence of novel therapeutic agents adds complexity to these strategies. This paper examines the benefits and challenges of these strategies, with primary reference to the Canadian context and a consideration of the concepts of value-based care.

Pilot study of once-a-day prophylaxis for youth and young adults with severe haemophilia A.

INTRODUCTION: Standard prophylaxis has been shown to be an effective treatment for severe haemophilia A. According to pharmacokinetic principles, daily factor infusions of smaller doses can maintain similar trough factor VIII (FVIII) levels, and perhaps the same protection as standard prophylaxis. AIM: This multicentre study examined the feasibility of daily prophylaxis for youth and young adults with severe haemophilia A in Montreal and Toronto. METHODS: Bleeding rates, joint status, quality of life and physical activity were monitored for 14 patients during this study. At baseline, subjects continued their regular treatment regimen and switched to daily prophylaxis after 4 months; nine had begun daily prophylaxis before enrolment. Additional visits occurred at 8 and 12 months which included a physical examination, inhibitor testing, HJHS and FISH assessments, the CHO-KLAT/Haemo-QoL-A and PDPAR. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication ver.II and perceived difficulty questions at the end of study. RESULTS AND CONCLUSIONS: There were no significant changes in quality of life except for concerns with the demanding daily infusion schedule. The number of bleeds did not statistically differ from the initial 4 months of the study to the last 8 months. Monthly bleeding rates from the year prior to the study and during the intervention phase were not statistically different. It was also found that daily prophylaxis used 24% less FVIII compared to standard prophylaxis. Taking all of this into account, we have found that providing daily prophylaxis is feasible and that it is feasible to prospectively study daily prophylaxis in youth and young adults.

First analysis of 10-year trends in national factor concentrates usage in haemophilia: data from CHARMS, the Canadian Hemophilia Assessment and Resource Management System.

The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1,009,097,765 IU) and FIX (272,406,859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs.

Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010.

The objective of this study was to evaluate the inhibitor development (ID) in previously untreated patients (PUPs) with severe haemophilia A (FVIII ≤ 0.01 IU mL(-1) ). All Canadian Haemophilia Treatment Centres completed a questionnaire on patients born between September 2005 and August 2010 and followed for up to 7 years. Eligible patients had at least 20 exposure days (ED) or had developed an inhibitor. The odds ratio (OR) and 95% confidence intervals (95% CI) for risk factors to develop an inhibitor were estimated using unconditional logistic regression. A total of 99 haemophilia A PUPs were studied. Thirty-four (34%) developed an inhibitor (24/34 of high titre). Inhibitors developed in 25/63 (40%) patients with a high-risk mutation. ID was most frequent in Aboriginals (86%). Dose intensity (IU kg(-1)  day(-1) X number of ED) at first exposure to factor VIII (FVIII) was associated with a crude OR increase of 1.10 (95% CI: 0.99-1.23) with each increase of 100 dose-intensity units. Haemarthrosis and intracranial bleeding as the indication for first exposure to FVIII concentrate were associated with a crude OR for ID of 7.63 (95% CI: 2.14-27.17) and 5.08 (95% CI: 1.11-23.31) respectively. ID according to FVIII concentrate used was: Advate (®) 18/50 (36%), Kogenate FS(®) or Helixate FS(®) 15/36 (42%), Wilate(®) 0/11 and Xyntha(®) 1/2. In multivariate analysis, Aboriginal ethnicity (OR = 11.69; 95% CI: 1.11-122.86) and haemarthrosis (OR = 4.49; 95% CI: 1.08-18.61) were statistically significant. The cumulative incidence of ID in severe haemophilia A PUPs was 34% and varied according to ethnicity, type of bleeding at first ED, type of FVIII product and dose intensity at first exposure.

Low prevalence of inhibitor antibodies in the Canadian haemophilia population.

Annual reporting of inhibitors to factors (FVIII) and IX (FIX) to the Canadian Haemophilia Registry has suggested a lower prevalence than that published in the literature. We performed a prospective study to determine the prevalence of patients with inhibitors directed against either FVIII or FIX. Patients with inhibitors were classified as: (i) inhibitor test positive; (ii) inhibitor test negative but on immune tolerance induction (ITI); (iii) inhibitor test negative but bypass treatment recommended; or (iv) inhibitor resolved. One year later, the cohort was re-classified. The prevalence of inhibitors on 1 May, 2007 was 3.3% for haemophilia A, 0.6% for haemophilia B and 8.9% and 2.1% for severe haemophilia A and B. One year later 17 individuals gained and 11 individuals lost inhibitor status (10 of these with ITI). This study suggests that the prevalence of inhibitors in our population is lower than that was previously published. We hypothesize that this is primarily due to the increased use of ITI, but other factors may be the unselected nature of the cohort and the restriction of the study to one date thereby conforming as close as practical to the definition of prevalence rather than incidence. The classification system used in this study was easy for clinics to apply and was important in defining the population with inhibitors.

A consensus statement on clinical trials of bypassing agent prophylaxis in inhibitor patients.

The haemophilia literature increasingly contains reports describing the use of bypassing agent prophylaxis (BAP) in patients with severe haemophilia A and inhibitors. However, it is difficult to interpret and compare the results and draw conclusions about treatment efficacy because of small patient numbers and a lack of standardization among BAP studies. This article presents consensus recommendations for standardizing future BAP clinical trials developed by an international panel of haemophilia opinion leaders.

Orthopaedic surgery in haemophilia patients with inhibitors: a practical guide to haemostatic, surgical and rehabilitative care.

All but essential surgery is generally avoided in haemophilia patients with inhibitor antibodies, because of concern about the reliability with which haemostasis can be achieved and maintained in such patients. Orthopaedic surgical procedures which are not required to preserve life fall under this category. As a result, patients with inhibitors may be denied operations, which could greatly enhance their quality of life, and which are routinely offered to other haemophilia patients. While caution is appropriate in recommending surgery in any circumstance, we believe that the threshold for offering validated surgical procedures to patients with inhibitors should be re-evaluated in the light of current surgical and rehabilitative techniques, and the long experience with safe and effective factor VIII inhibitor bypassing agents, namely activated prothrombin complex concentrates and recombinant activated factor FVII. In this article, we review the haematological, surgical and rehabilitative considerations relevant to orthopaedic surgery in haemophilia patients with inhibitors, and provide recommendations for carrying out such procedures.

A prospective surveillance study of factor VIII inhibitor development in the Canadian haemophilia A population following the switch to a recombinant factor VIII product formulated with sucrose.

The introduction of new factor concentrates has, at times, resulted in an increase in inhibitor development; hence large systematic surveys of inhibitor development are necessary whenever new products are introduced. This study presents the results of a surveillance study conducted by the Inhibitor Subcommittee of the Association of Hemophilia Clinic Directors of Canada that evaluated inhibitor development in patients with haemophilia A following the switch to a second generation recombinant FVIII product (rFVIII-FS; Kogenate((R)) Bayer). Four hundred and sixty haemophilia A paediatric and adults patients from 17 Canadian Comprehensive Hemophilia Care Centers were enrolled in the study. Of these, 274 patients had evaluable data. Blood samples collected at baseline (prior to the switch to rFVIII-FS), and at 12 and 24 months following conversion were tested for inhibitors by the Nijmegen-modified Bethesda assay. Four subjects had positive inhibitor titres at baseline, with values ranging from 3.3 to 160 BU. Of the 274 patients who had baseline samples collected, 225 had postswitch samples collected at 12 months and 189 subjects had samples collected at 24 months. Only patients with positive baseline inhibitor titres (n = 4) had positive inhibitor titres at either the 12- or 24-month postswitch time points; therefore no de novo inhibitors developed over the 2-year evaluation period in this patient population. The results of this surveillance study suggest that the altered formulation of this recombinant FVIII concentrate was not associated with an increased incidence of inhibitor formation.

Protection of factor Xa from neutralization by the heparin-antithrombin complex.

We have studied the accessibility of Factor Xa to neutralization by the heparin-antithrombin complex within plasma and whole blood. This serine protease was detected by measuring the concentrations of activation fragments (F2/F1+2) cleaved from prothrombin. The levels of F2/F1+2) were quantitated by means of a sensitive and specific radioimmunoassay. Our findings indicate that the binding of Factor Xa to "activated" platelets but not to phospholipid micelles results in the protection of the above enzyme from inactivation by the heparin-antithrombin complex. This sequestration of Factor Xa is not affected by the liberation of platelet release proteins or the molecular heterogeneity of the mucopolysaccharide preparations used. The magnitude of enzyme protection is strongly correlated with the extent of prothrombin activation at the time of heparin addition. On this basis, we suggest that high in vivo rates of thrombin generation may lead to the sequestration of Factor Xa on the platelet surface and hence allow this serine protease to resist the action of heparin until the complex is cleared from the circulation.

Effect on hematologic risk factors for coronary heart disease of a cholesterol reducing diet.

BACKGROUND: A dietary portfolio of cholesterol-lowering ingredients has proved effective in reducing serum cholesterol. However, it is not known whether this dietary combination will also affect hematologic risk factors for coronary heart disease (CHD). Reductions in hematocrit and polymorphonuclear leukocytes have been reported to improve cardiovascular risk. We, therefore, report changes in hematological indices, which have been linked to cardiovascular health, in a 1-year assessment of subjects taking an effective dietary combination (portfolio) of cholesterol-lowering foods. METHODS: For 12 months, 66 hyperlipidemic subjects were prescribed diets high in plant sterols (1.0 g/1000 kcal), soy protein (22.5 g/1000 kcal), viscous fibers (10 g/1000 kcal) and almonds (23 g/1000 kcal). Fifty-five subjects completed the study. RESULTS: Over the 1 year, data on completers indicated small but significant reductions in hemoglobin (-1.5+/-0.6 g/l, P=0.013), hematocrit (-0.007+/-0.002 l/l, P<0.001), red cell number (-0.07+/-0.02 10(9)/l, P<0.001) and neutrophils (-0.34+/-0.13 10(9)/l, P=0.014). Mean platelet volume was also increased (0.16+/-0.07 fl, P=0.033). The increase in red cell osmotic fragility (0.05+/-0.03 g/l, P=0.107) did not reach significance. CONCLUSIONS: These small changes in hematological indices after a cholesterol-lowering diet are in the direction, which would be predicted to reduce CHD risk. Further research is needed to clarify whether the changes observed will contribute directly or indirectly to cardiovascular benefits beyond those expected from reductions previously seen in serum lipids and blood pressure.

Induction versus noninduction antiviral therapy for chronic hepatitis C virus in patients with congenital coagulation disorders: a Canadian multicentre trial.

BACKGROUND: Patients with congenital coagulation disorders and chronic hepatitis C virus (HCV) infection have multiple risk factors (ie, infection predominantly with genotype-1 HCV, long duration of the disease, HIV coinfection and male sex) for poor response to antiviral therapy. The present study compared induction therapy with interferon-alpha (IFN-alpha)-2b with standard IFN-alpha2b therapy. Pegylated IFN was not available at the time that the study was initiated. PATIENTS AND METHODS: A randomized study was performed comparing the efficacy of traditional IFN-alpha2b therapy (group A -- three million units, three times weekly for 24 to 48 weeks) and daily ribavirin (1.0 g to 1.2 g according to weight for 24 to 48 weeks), with induction IFN-alpha2b therapy (group B -- three million units, daily for eight weeks followed by the same dose administered three times a week for a further 16 to 40 weeks) and daily ribavirin (same dose as above) in IFN-naive patients with congenital coagulation disorders and chronic HCV infection. RESULTS: Between 2000 and 2003, 54 HIV-negative patients were recruited and randomly assigned to group A or B (n=27 each). Both groups were comparable in terms of age, sex, ethnicity, body mass index, baseline HCV RNA titre, viral genotype, liver fibrosis stage and type of coagulation disorder. Induction therapy did not significantly alter sustained virological response rates (group A 50%, group B 50%; P=1.0). Multiple logistic regression analysis indicated that induction therapy did not benefit individuals with difficult-to-treat infection (ie, those infected with genotypes 1 and 4, or those with high baseline viral loads). CONCLUSIONS: There was no benefit with induction antiviral therapy for HCV infection in individuals with congenital coagulation disorders.

Plasma urokinase antigen and plasminogen activator inhibitor-1 antigen levels predict angiographic coronary restenosis.

BACKGROUND: The fibrinolytic system is intimately involved in several processes that contribute to restenosis, including clot dissolution, cell migration, and tissue remodeling. However, the role of the individual activators (urokinase [uPA] and tissue plasminogen [tPA] activators) and inhibitors (plasminogen activator inhibitor [PAI-1]) of the fibrinolytic system in maintaining patency after coronary artery angioplasty and stenting is unclear. METHODS AND RESULTS: We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty (n=110) or stenting (n=49) of de novo native coronary artery lesions. Plasma samples were drawn at baseline (before angioplasty) and serially after angioplasty (immediately afterward and 6 hours, 24 hours, 3 days, 7 days, 1 month, 3 months, and 6 months afterward). Antigen and activity assays were performed for uPA, tPA, and PAI-1. Follow-up quantitative coronary angiography was performed in 92% of eligible patients. The overall angiographic restenosis rate (diameter stenosis >50%) was 31% (37% in PTCA patients, 17% in stented patients). At all time periods, including baseline, uPA antigen levels were significantly higher and PAI-1 antigen levels were significantly lower in patients with restenosis. Restenosis rates for patients in the upper tertile of baseline uPA antigen levels were 2-fold higher than for those in the lower 2 tertiles (46% versus 24% and 22%, respectively; P<0.004). In a stepwise regression multivariate analysis, obstruction diameter after the procedure and uPA antigen were significant predictors of follow-up diameter stenosis. CONCLUSIONS: Plasma uPA antigen levels and PAI-1 antigen levels identify patients at increased risk for restenosis after percutaneous coronary revascularization.

Use of porcine factor VIII for surgical procedures in hemophilia A patients with inhibitors.

We have described the use of polyelectrolyte fractionated porcine factor VIII (HYATE:C, Porton Speywood Ltd, Wrexham, UK) to provide hemostasis in 45 patients with hemophilia A complicated by inhibitor antibodies. The cases were collected from hemophilia care providers in seven nations and represent some of the experience with porcine factor VIII generated over the past 12 years. A wide variety of procedures was performed with varying degrees of associated hemostatic challenge in a difficult treatment group. The patients were representative of the hemophilia population in general and ranged in age from 1 to 67 years. The results of our survey should encourage clinicians to consider use of porcine factor VIII to provide hemostatic coverage in hemophilia patients with inhibitors who require surgical procedures. Hemostatic coverage was satisfactory in the vast majority of episodes; there have been only a small number of easily controlled, well-tolerated adverse reactions, which were usually self-limited in nature. No life-threatening reactions to porcine factor VIII were seen during coverage for surgical procedures in our survey, although serious reactions can occur as noted above. This is remarkable, since surgical patients usually are treated with higher doses of porcine factor VIII for greater periods of time than most other hemophilic patients treated for hemarthroses or soft-tissue bleeding, for example. Thrombocytopenia in association with porcine factor VIII therapy has been a major concern since the first crude preparations were used in the 1950s. Modern series, however, note the incidence of thrombocytopenia in only a minority of patients treated with the current polyelectrolyte fractionated preparations of porcine factor VIII. In our series, thrombocytopenia with platelet counts of less than 150 x 10(9)/L occurred in 11 of 54 treatment episodes (20%). The mechanism for thrombocytopenia demonstrated in a previous study involves porcine von Willebrand factor, which may copurify with porcine factor VIII and cause platelet aggregation and/or clearance from the circulation. The phenomenon of thrombocytopenia appears to be related to the administration of high doses of porcine factor VIII in some cases; however, in other patients, it may develop inconsistently at modest doses. It may be that there are idiosyncratic differences between patients that determine the dose of porcine factor VIII likely to cause thrombocytopenia. As yet, there is no way to predict which patient will develop thrombocytopenia while being treated with porcine factor VIII.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of psyllium in hypercholesterolemia at two monounsaturated fatty acid intakes.

We performed two studies to determine whether the lipid-lowering effect of viscous soluble fiber was modified by monounsaturated fatty acid (MUFA). First, psyllium (1.4 g/MJ) was compared with wheat bran (control) in 1-mo metabolic diets by using a randomized crossover design (n = 32 hyperlipidemic subjects). The background diet contained approximately 6% of energy as MUFA (20% of total fat). The second study (n = 27 hyperlipidemic subjects) was similar to the first but the background diet contained approximately 12% MUFA (29% of total fat) because of the addition of canola oil. At both fat intakes, psyllium resulted in significant reductions in total, low-density-lipoprotein (LDL), and high-density-lipoprotein (HDL) cholesterol compared with the wheat bran control. For the psyllium diet at 6% compared with 12% MUFA, the decreases in LDL cholesterol were 12.3 +/- 1.5% (P < 0.001) and 15.3 +/- 2.4% (P < 0.001), respectively. With the higher-MUFA diet triacylglycerol fell significantly over the control phase (16.6 +/- 5.5%, P = 0.006) and the ratio of LDL to HDL cholesterol fell significantly over the psyllium phase (7.3 +/- 2.8%, P = 0.015). Psyllium and MUFA intakes were negatively related to the percentage change in the ratio of LDL to HDL cholesterol (r = -0.34, P = 0.019 and r = -0.44, P = 0.002, respectively). Chenodeoxycholate synthesis rate increased (30 +/- 13%, P = 0.038) with the psyllium diet in the 12 subjects in whom this was assessed. We conclude that psyllium lowered LDL- and HDL-cholesterol concentrations similarly at both MUFA intakes. However, there may be some advantage in combining soluble fiber and MUFA to reduce the ratio of LDL to HDL cholesterol.

Isolation and characterization of cell lines with reduced urokinase binding.

Six cell lines have been generated from the human fibrosarcoma HT-1080 by mutagenesis. They were selected on the basis of reduced urokinase (uPA) binding on replicate polyester filters. Single cell clones were then isolated by limited dilution cloning. All cloned cells showed less uPA binding on filters, and as cell monolayers. These cell lines were able to bind only 10 to 65% as much uPA as the wild-type HT-1080 cells. Surface-bound uPA proteolytic activity and surface activation of plasminogen from these cells were also reduced relative to the wild-type. uPA could activate MAP kinases in the wild-type and two of the cell lines with the least uPA-binding, but the amount of the activated forms of the signalling molecules were reduced. Immunoblotting using two different anti-uPA receptor antibodies showed two cross-reacting protein species of approximately 53 kDa and approximately 38 kDa. The proportion of the lower Mr band to the higher Mr band was found to be reduced in all the cell lines relative to the wild-type. Chemical cross-linking with single-chain urokinase (scuPA) showed only one high-molecular-weight adduct, with Mr approximately 90 kDa, in all the cell lines tested. Similarly, cross-linking with the amino terminal fragment of uPA yielded a single approximately 70 kDa adduct. These would indicate that only the approximately 53 kDa band was responsible for cross-linking reactions. Equilibrium binding experiments showed that only one set of high-affinity binding sites for the wild-type cells. However, the binding of scuPA to two of these cell lines was best fitted to a two-site model, one of which was similar to the high-affinity binding sites of the wild-type, although the number of sites was reduced, while the other was of much lower affinity but was large in number. These results are discussed in relation to changes in the structure of ligand binding machinery in these cells, which affect other cellular functions.