Contact-activated factors: contaminants of immunoglobulins preparations with coagulant and vasoactive properties

Abstract

The intramuscular or intravenous administration of ISG prepared from human plasma by ethanol fractionation can elicit such reactions as pain at the injection site, flushing, and even hypotension. Similar adverse reactions to plasma protein fraction, a volume expander also made by ethanol fractionation, have been associated with PKA (Hageman factor fragments) in the product. Twenty-five lots of commercial ISG were therefore analyzed for PKA and kallikrein, components of the contact activation system which could mediate such reactions through the generation of kinins in recipients. Kallikrein activity ranged from undetectable levels to > 60% of the total potential kallikrein activity in normal plasma. PKA, which was measured by its ability to catalyze the conversion of prekallikrein to kallikrein, ranged from 5% to 3950% of the activity in a reference plasma protein fraction that had caused hypotension. All but five lots increased vascular permeability in the guinea pig. The five lots which caused no increased were also the lowest in PKA and kallikrein activity. When ISG ws subjected to gel chromatography to separate the enzymic contaminants from immunoglobulin G, only the fractions containing PKA and/or kallikrein increased vascular permeability. Several lots of ISG shortened the nonactivated partial thromboplastin time of normal plasma fro 236 sec to 38 to 55 sec. During gel chromatography, coagulation activity was eluted in a position corresponding to a molecular weight of 150,000; it was inhibited by antibody to human factor XI. These data indicate that factor XIa is responsible for the coagulant activity observed and that PKA and/or kallikrein are potential mediators of vasoactive reactions to ISG.