The diagnosis and management of von Willebrand disease in Canada.

In Canada, care for individuals with inherited bleeding disorders, including Von Willebrand disease, is provided by 26 tertiary care multidisciplinary Inherited Bleeding Disorders clinics geographically spread across the country. The Association of Hemophilia Clinic Directors of Canada, the Canadian Association of Nurses in Hemophilia Care, the Canadian Physiotherapists in Hemophilia Care, the Canadian Social Workers in Hemophilia Care, and the Canadian Hemophilia Society all collaborate to provide optimal management for patients with inherited bleeding disorders. The standards of care for these patients were explicitly laid out in a 2007 document published by the Canadian Hemophilia Standards Group (with representation from all of the groups just mentioned) entitled Canadian Comprehensive Care Standards for Hemophilia and Other Inherited Bleeding Disorders. Separate Canadian guidelines for the management of patients with Hemophilia and Von Willebrand disease also exist, focused on diagnosis, comprehensive care, assessment, and treatment.

Theories of blood coagulation.

Although the concept of the coagulation cascade represented a significant advance in the understanding of coagulation and served for many years as a useful model, more recent clinical and experimental observations demonstrate that the cascade/waterfall hypothesis does not fully and completely reflect the events of hemostasis in vivo. The goal of this article is to review the evolution of the theories of coagulation and their proposed models to serve as a tool when reviewing the research and practice literature that was published in the context of these different theories over time.

Genetic basis of familial Meniere's disease.

The genetic basis of familial Meniere's disease (MD) is unclear. We present a genetic investigation of six individuals in two families with familial MD. Linkage analysis was performed using polymorphic DNA markers linked to the human leukocyte antigen (HLA) locus that map to chromosome 6p. We have demonstrated the presence of anticipation in successive generations and the absence of HLA association. This is the second report of anticipation in familial MD in the literature, and it suggests that efforts should be directed toward finding a trinucleotide expansion as a possible genetic lesion in this uncommon disorder.

Naked DNA transfer of Factor VIII induced transgene-specific, species-independent immune response in hemophilia A mice.

The development of antibodies to a previously unexpressed protein product may limit the success of human gene therapy approaches. We inserted B-domain-deleted factor VIII (FVIII) cDNA of human, canine, or murine origin into the multiple cloning site of a liver-specific vector, pBS-HCRHPI-A, to yield plasmids pBS-HCRHPI-FVIIIA, pBS-HCRHPI-cFVIIIA, and pBS-HCRHPI-mFVIIIA, respectively. Fifty micrograms of each plasmid in 2 ml of solution was rapidly injected into the tail vein of three groups of hemophilia A mice. Factor VIII levels ranging from 3 to 12 IU/ml were obtained from all three groups (normal is 1 IU/ml in human plasma) 3 days after treatment. These initial very high levels of functional human, canine, or murine factor VIII, however, fell gradually to undetectable levels within 2-3 weeks, and their disappearance correlated with the generation of high-titer, inhibitory anti-FVIII antibodies. Notably, this immune response occurred independent of the species of origin of the exogenous factor VIII. Antibody titers to factor VIII were detected beginning at 2 weeks, reached a plateau and remained at high levels for over 6 months. The majority of anti-hFVIII IgG was IgG1 isotype specific, suggesting a humoral response mediated by Th2-induced signals. Consistent with this idea, in a separate group of mice treated with pBS-HCRHPI-FVIIIA, transient immunosuppression by cyclophosphamide significantly delayed (5/6) or abolished (1/6) inhibitory antibody formation against the transgene.