Polyglutamic and Polyaspartic Acids: Synthetic Polypeptides with Predominantly Factor VIII-like Coagulant Activity 1

Abstract

Summary and discussion

We have shown that polyglutamic and polyaspartic acids are quite active in specific assays for F. VIII, much less so in specific assays for F. IX, and inactive in four other systems (Table I). The F. VIII and IX activities are demonstrable only when the deficient substrate plasmas have been activated previously with kaolin and when phospholipid is also present (Tables II and III). Furthermore, polyglutamic acid “potentiates” F. VIII activity, two- to fivefold, when it is added to normal human plasma or F. VII-rich fractions of normal human plasma (Table IV).

“Potentiation” of F. VIII by PGA is apparently different from activation or enhancement of F. VIII activity by thrombin. Very low concentrations of thrombin are known to activate F. VIII in a time-dependent reaction in which maximum activation does not occur until several minutes after mixing (8). This increase in F. VIII activity is unstable, decreasing to the original value upon further incubation. In contrast, the “potentiating” effect upon plasma F. VIII of polyglutamic acids (as well as kidney AHF and AHF₃ prepared from albumin) is observed immediately upon mixing and remains stable for hours at room temperature (unpublished observations).

Our experiments suggest that polyglutamic acid does not decrease clotting times by activating factors XII, XI, or IX, but that, once these factors have been activated by kaolin, polyglutamic acid is able to “substitute” for F. VIII. The fact that the PGA shows a slight corrective effect in previously activated F. IX deficient plasma suggests a possibly even wider role, i.e., that polyglutamic acid may mimic the “intrinsic F. X activator.”

Kaolin-activation of the F. VIII deficient substrate is an absolute requirement for expression of the activity of the polypeptides.