Heparin and Protamine Sulfate are charged substances which are widely used clinically. Recently it has been appreciated that protamine may cause serious adverse reactions when it is given to reserve the anticoagulant effects of heparin. In the first part of this project, we will examine the mechanism by which protamene may exert these reactions. We will study whether they are due to Type I hypersensitivity and/or whether the effect may be mediated through complement. We will examine the prevalence of positive immediate or delayed skin tests and IgG and IgE anti-protamine in patients who have received protamine containing insulin; in diabetics who have not received protamine containing insulin; in men who have had vasectomy; in other patients who have received protamine; in patients with Type I hypersensitivity to fish; and in a normal population. We will determine the true incidence and the mechanism(s) of hypersensitivity to protamine when the drug is given, to reverse the anticoagulant effect of heparin, to patients who will undergo cardiac catheterization and to patients who will undergo open heart surgery. In the second part of the project, we will examine heparin more fully to determine the Structure Activity Relationship between its fragments and complements. We will study the following polysaccharide mixtures to see which fragments are active in regulating complement: tetrasaccharides, hexasaccharide, octasaccharide, decasaccharide and larger polysaccharides. We will search for heparin fragments of very low MW which have the minimum structure necessary to regulate complement as actively as does commercial heparin. We will examine other heparin-like molecules to determine if they are able to exert the same effects on complement. We will examine other polycations to determine whether they have the same effect. Finally, we will determine if Major Basic Protein, an important constitutent of the eosinophil, may similarly modulate the complement system.
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