Ristocetin cofactor activity

Pharmacokinetic data were collected as well as pharmacodynamic measurements of platelet aggregation support (ristocetin cofactor activity) and cuticle wound blood flow. An important component of these studies was the suitability of the model. These models were chosen because of the biochemical deficiency of the particular factors and the parallel clinical syndromes. Such in vivo data can help in determining activity and dosing when such a product is first used in human trials. The Refacto molecule was also studied in rats and monkeys to determine its no observed adverse effect level, that was more than 10 times normal circulating levels. The major toxicity observed was the development of antibodies to the molecule that blocked activity and resulted in an acquired hemophilia syndrome. Similar findings were demonstrated when plasma-derived material was injected into monkeys [20]. 

Specific laboratory tests to investigate the possible presence of von Willebrand disease include measurement of von Willebrand factor antigen (vWF Ag) level, factor VIII assay, determination of ristocetin cofactor activity, and von Willebrand factor multimer analysis. Plasma concentrations of von Willebrand factor increase with cigarette smoking, exercise, pregnancy, and infection, as well as with the use of certain medications, such as corticosteroids, birth control pills, and desmopressin. Repeated test measurements may be... 

Desmopressin can be administered every 12 to 24 hours, but the response diminishes with repeated treatment. After three to four doses, desmopressin is often no longer effective, and alternative replacement therapy may be necessary if prolonged treatment is required. Laboratory monitoring, including vWF Ag measurements, factor VIII assays, ristocetin cofactor activity assessments, and clinical examinations, will help determine the adequacy of treatment. 

Purified and reduced human Factor VIII exhibits an eight band sub-unit structure (mol. wt. 3.0 X 10 —2.3 x 10 ) as shown by polyacrylamide gel electrophoresis. Rabbit antibody to Factor VIII reacts with all of the sub-units whereas haemophilic antibody reacts with low-molecular-weight sub-units only. Sub-units derived from the largest Factor VIII multimers have a higher binding affinity for D-galactose-specific lectins than have those obtained after reduction of smaller oligomers. Ristocetin cofactor activity of purified Factor VIII is competitively inhibited by two Ricinus communis lectins and by concanavalin A. 

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