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.

Utilization of recombinant activated factor VII in southern Ontario in 85 patients with and without haemophilia.

Recombinant activated factor VII (rFVIIa) is licensed for the treatment of bleeding in individuals with haemophilia and inhibitors. The use of rFVIIa appears to be increasing, and an increase in unlicensed use is suspected. There are currently few data about the specific indications for its use. The aim of this study was to describe the patterns of utilization of rFVIIa. We performed a retrospective cohort study using rFVIIa infusion data collected prospectively and clinical data collected retrospectively. Patients were identified using a tracking system designed to account for use of all coagulation factor concentrates issued in southern Ontario. Between 1 January 2001 and 31 December 2005, 85 patients received rFVIIa. 1164 infusions were given (8246.4 mg). Haemophilia patients with inhibitors accounted for 82.9% of rFVIIa infused and represented 8.2% of patients. The total amount of rFVIIa used increased each year from 2001 to 2004 and then decreased in 2005. The total number of infusions of rFVIIa administered annually increased. Both on-label and off-label use of rFVIIa increased. The number of patients with haemophilia receiving rFVIIa remained small and constant. The number of patients receiving rFVIIa for off-label indications increased markedly. Most rFVIIa infusions were given for licensed indications; however, these infusions represented <10% of patients treated. Overall, the utilization of rFVIIa is increasing, mostly for approved indications; however, the number of patients being prescribed rFVIIa for off-label indications has increased. The tracking system used in this study is a valuable tool to describe ongoing utilization patterns of rFVIIa.

Fermi-liquid breakdown in the paramagnetic phase of a pure metal.

Fermi-liquid theory (the standard model of metals) has been challenged by the discovery of anomalous properties in an increasingly large number of metals. The anomalies often occur near a quantum critical point--a continuous phase transition in the limit of absolute zero, typically between magnetically ordered and paramagnetic phases. Although not understood in detail, unusual behaviour in the vicinity of such quantum critical points was anticipated nearly three decades ago by theories going beyond the standard model. Here we report electrical resistivity measurements of the 3d metal MnSi, indicating an unexpected breakdown of the Fermi-liquid model--not in a narrow crossover region close to a quantum critical point where it is normally expected to fail, but over a wide region of the phase diagram near a first-order magnetic transition. In this regime, corrections to the Fermi-liquid model are expected to be small. The range in pressure, temperature and applied magnetic field over which we observe an anomalous temperature dependence of the electrical resistivity in MnSi is not consistent with the crossover behaviour widely seen in quantum critical systems. This may suggest the emergence of a well defined but enigmatic quantum phase of matter.

Evolution of Fermi-liquid interactions in Sr2RuO4 under pressure.

We have measured the temperature and field dependence of the resistivity of the unconventional superconductor Sr2RuO4 at pressures up to 3.3 GPa. Using the Shubnikov-de Haas effect, we find that the Fermi surface sheet believed to be primarily responsible for superconductivity becomes more two-dimensional with increasing pressure, a surprising result that is, however, consistent with a recent model of orbital-dependent superconductivity in this system. Many-body enhancements and the superconducting transition temperature all fall gradually with increasing pressure, contrary to previous suggestions of a ferromagnetic quantum critical point at approximately 3 GPa.

Loss of factor VIII activity during storage in PVC containers due to adsorption.

Recombinant factor VIII concentrates are stable when administered in a reconstituted form according to the manufacturer's specifications, and undiluted via infusion with syringe mini-pumps. However many Haemophilia centres administer recombinant factor VIII further diluted in intravenous fluids for greater ease of administration. To investigate the stability of recombinant factor VIII during administration as a diluted infusion, reconstituted factor VIII was stored in polyvinylchloride (PVC) mini-bags undiluted (146 IU mL-1) and at factor VIII concentrations of 10 IU mL-1 and 2 IU mL-1. After 48 h of storage at room temperature in PVC mini-bags, the recoveries of factor VIII activity were 41.9% of the initial activity for the undiluted (146 IU mL-1) product and 43.7% of the initial activity for factor VIII diluted to 10 IU mL-1. For factor VIII diluted to 2 IU mL-1, the amount of factor VIII activity remaining at 48 h was only 1.8% of the initial activity. In contrast, 100% of factor VIII activity was recovered after 48 h when undiluted reconstituted product (146 IU mL-1) was stored in a syringe. To investigate the mechanism of factor VIII activity loss during storage, factor VIII samples collected after 0, 3 and 48 h of storage were analysed by immunoblotting with factor VIII antibodies. No evidence of factor VIII proteolytic degradation during storage was found, however, large amounts of factor VIII antigen were recovered from the empty PVC mini-bags following elution with denaturing detergent. We conclude that clinically significant losses of factor VIII activity occur during storage in PVC mini-bags and that the loss of activity is most likely due to protein adsorption onto the plastic surface. This loss of factor VIII activity during storage in PVC containers may substantially affect the safety and potential cost savings of administering recombinant factor VIII by continuous infusion.

Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A.

To determine whether the factor V Leiden mutation is associated with decreased bleeding in individuals with severe hemophilia A, factor concentrate utilization, maximum annual number of bleeding episodes, and the prevalence of hemophilic arthropathy between carriers and non-carriers of the factor V Leiden mutation were compared. Heterozygosity for the factor V Leiden mutation was found in 6 of 137 subjects (4.4%). Carriers of the factor V Leiden mutation utilized less factor concentrate (geometric mean: 310 vs. 1185 units/kg/year) and had fewer bleeding episodes than non-carriers (proportion with 10 or fewer bleeding episodes in their worst year: 50 vs. 11%). However, the factor V Leiden mutation was not associated with the absence of arthropathy. The intron 22 inversion mutation of the factor VIII gene was tested for in a subgroup of 80 subjects, but it was not found to be a significant variable for any of the bleeding endpoints. The results of this small study are consistent with the hypothesis that the factor V Leiden mutation imparts a protective effect; however, a larger confirmatory study in which the factor VIII molecular defects can be controlled for is needed. Furthermore, most severe hemophiliacs who used fewer than 200 units/kg/year of factor concentrate or who had experienced 10 or fewer bleeding episodes per year did not carry the factor V Leiden mutation, suggesting that the proportion of severe hemophiliacs whose mild clinical course can be attributed to the factor V Leiden mutation is small.

Radiotherapy to control CNS lymphomatoid granulomatosis: a case report and review of the literature.

Lymphomatoid granulomatosis (LG) is an uncommon but potentially fatal disease. The disease primarily involves the lungs; however, skin, renal, and central nervous system (CNS) are seen in varying proportions. Neurological involvement occurs in one third of the patients, and confers a worse prognosis. The use of radiotherapy to treat CNS involvement in LG has not been well studied. We report a case of a 33-year-old man with multiple CNS lesions treated successfully with radiotherapy and review 6 other cases in the literature using similar treatment. These cases support the use of radiotherapy for CNS involvement in LG.

Causes of death in Canadians with haemophilia 1980-1995. Association of Hemophilia Clinic Directors of Canada.

The life expectancy of individuals with haemophilia was close to that of the general population in the early 1980s. Since then, life expectancy has decreased, due to transfusion-transmitted virus infections. Deaths in individuals with haemophilia were investigated by analysing 2450 records from the Canadian Hemophilia Registry, for the years 1980-1995. Deaths were tabulated by age, year and cause, and compared with that of the Canadian male population by calculating standardized mortality ratios (SMRs). The median life expectancy at 1 year of age was calculated for various subpopulations and the impact of various population characteristics was assessed by survival regression modelling. There were 359 deaths and the annual number of deaths increased significantly after 1986. Risk factors were seropositivity to human immunodeficiency virus (relative risk 16.7, 95% CI 11.1-25.1), severe haemophilia (1.9, 1.3-2.7) and moderate haemophilia (1.8, 1.2-2.6). In HIV antibody negative individuals, the overall death rate was not increased (SMR 0.9, 95% CI 0.7-1.1) and only haemorrhage was significantly increased. In HIV antibody positive individuals, causes of death which were significantly increased were acquired immunodeficiency syndrome, liver failure, haemorrhage, lymphoma, liver cancer, nonspecific infections, and trauma or violence. Deaths due to the acquired immunodeficiency syndrome accounted for only 66% of the excess deaths in individuals who were HIV antibody positive. Life expectancy has markedly decreased since the onset of the HIV epidemic. The impact of HIV is underestimated by considering only deaths due to the acquired immunodeficiency syndrome; other HIV-linked causes need also to be considered.

Clinical and economic analysis of allogeneic peripheral blood progenitor cell transplants: a Canadian perspective.

Allogeneic peripheral blood progenitor cell (PBPC) transplants are an alternative to BMT, although G-CSF mobilization dose, timing of pheresis and risk of GVHD are not well defined. We compared harvest characteristics, donor and recipient outcomes and costs of two PBPC transplant strategies with historical controls who received BMT. Twenty donors mobilized with four daily s.c. G-CSF doses (5 microg/kg/day) (group 1) and 20 mobilized with 10 microg/kg/day G-CSF (group 2) were compared with 20 BM controls (group 3). G-CSF and phereses were well tolerated. Four of 40 PBPC donors required femoral catheter placement. At least 2.5 x 10(6) CD34+/kg recipient weight were collected with two phereses in 19/20 donors (group 1) and 18/20 donors (group 2). Time to neutrophil (18 vs 20 vs 22 days, P = 0.02) and platelet (21 vs 24 vs 27 days, P = 0.005) engraftment was shorter in the PBPC groups (group 2 vs group 1 vs group 3) but secondary engraftment outcomes were not different. The incidence of grade 2-4 aGVHD was higher in the low-dose G-CSF group (group 1) but there was no difference in cGVHD, 100-day or 1-year survival. The mean PBPC transplant cost (group 1) at first hospital discharge was less than BM (group 3) ($34,643 vs $37,354) but the mean overall cost for both groups was similar at 100 days ($46,334 vs $46,083). Allogeneic PBPC transplant with short course, low-dose G-CSF mobilization is safe, feasible and cost equivalent to allogeneic BMT.

Reinduction of remission of chronic myeloid leukemia by donor leukocyte transfusion following relapse after bone marrow transplantation: recovery complicated by initial pancytopenia and late dermatomyositis.

A significant proportion of patients relapse after allogeneic BMT for CML. These relapses have been treated by induction of a graft-versus-leukemia effect by transfusing donor leukocytes. We have treated a 27-year-old woman with interferon and donor leukocyte transfusion and a complete haematological and cytogenetic remission was obtained coincident with the onset of GVHD. Her course was complicated by prolonged and profound pancytopenia which was fully reversed by the administration of rGM-CSF. She remains in CR with mild dermatomyositis due to chronic GVHD 17 months after the procedure.

B-cell lymphoma of recipient origin 9 years after allogeneic bone marrow transplantation for T-cell acute lymphoblastic leukaemia.

A 25-year-old woman developed an immunoblastic lymphoma 9 years after HLA-identical allogeneic bone marrow transplantation for T-cell acute lymphoblastic leukaemia in second remission. The B-cell origin of the second malignancy was confirmed by gene rearrangement studies. Despite continued donor engraftment, two separate genotypic analyses identified the lymphoma to be of recipient origin. This is the longest latency of a post-transplant recipient lymphoma yet reported and illustrates that recipient B-cells may survive the transplant conditioning regimen and undergo malignant transformation in the presence of donor haemopoiesis.

A pilot study of carboplatin augmentation therapy for patients with poor risk acute non-lymphocytic leukemia.

Eleven patients with acute non-lymphocytic leukemia and persistent leukemia on a bone marrow done 6 days after the start of standard induction chemotherapy with daunorubicin and cytosine arabinoside were given augmentation chemotherapy with carboplatin as a continuous intravenous infusion over 3 days. Nine of the 11 patients (82%) entered complete remission. The hematologic and non-hematologic toxicities encountered by these patients were similar to those seen after conventional therapy alone with the exception of peripheral neuropathy in one patient. Of the two induction failures, one patient died of treatment-related toxicity and one patient had resistant leukemia.

Polymyositis: a manifestation of chronic graft-versus-host disease.

Polymyositis developed in a patient who had had bone marrow transplants for the treatment of acute myeloid leukemia. There was no previous evidence of graft-versus-host disease. Polymyositis has previously been reported to be associated with graft-versus-host disease; this article suggests that polymyositis may represent its sole manifestation.

Allerod--younger dryas lake temperatures from midge fossils in atlantic Canada.

Remains of freshwater midges are abundant in lake sediments, and their species distributions are closely related to the surface-water temperature of lakes; their distributions thus provide a powerful tool for paleoclimatology. The distribution of species in a core from Splan Pond in Atlantic Canada indicates that there were abrupt transitions in late-glacial temperatures between warm and cold states. The transitions are correlative with the well-known warm Allerød and cold Younger Dryas events in Europe. These data thus confirm the inference from palynological data that these events affected regions on both sides of the Atlantic.

Orthotopic liver transplantation in a patient with combined hemophilia A and B.

A 38-year-old man with severe factor IX and mild factor VIII deficiencies complicated by cirrhosis secondary to chronic non-A non-B hepatitis underwent orthotopic liver transplantation as treatment for both the cirrhosis and his congenital coagulopathy. Intraoperative hemostasis was obtained with factor VII-depleted prothrombin complex concentrate and fresh frozen plasma. Factor VIII and factor IX levels were assayed frequently in the perioperative period, and both returned to normal within 24 hr and remained normal postoperatively. Liver transplantation can be considered as definitive therapy for hemophilia A and/or B with transfusion-related liver disease.

The bleeding disorders: current concepts and management.

Bleeding disorders are relatively uncommon, and most bleeding episodes occur as a result of local factors. Therefore a positive history of bleeding usually does not accurately predict the presence of a bleeding disorder. In a few cases the existence of certain patterns of bleeding, such as hemarthroses and petechiae, does allow an accurate prediction. On the other hand, the absence of bleeding following significant challenge is very helpful indeed in excluding a bleeding disorder. However, a negative history of bleeding in the absence of hemostatic challenge does not exclude a bleeding disorder. Accurate clinical analysis of suspected bleeding disorder requires acquaintance with the common causes of bleeding; these are described along with a clinical approach to diagnosis. The laboratory investigation starts with the performance of the "hemostasis screen". A normal hemostasis screen excludes by far the majority of acquired defects, and further investigation, other than a repeat of the bleeding time, is rarely needed. When hereditary disorders are suspected, specific assay of individual factors, usually factors VIII (hemophilia A), IX (hemophilia B) and Von Willebrand factor, is advised. Recent advances in the understanding and the management of some disorders are described.