Origin of the high molecular weight activator of prekallikrein.

Two lines of evidence suggest that the high molecular weight activator of prekallikrein (large activator) (BAGDASARIAN, A., TALAMO, R. C., AND COLMAN, R. W. (1973) J. Biol. Chem. 248, 3456-3463) is derived from coagulation factor XII (Hageman factor). Large activator could not be isolated from plasma congenitally deficient in factor XII, and partial immunologic identity was demonstrated between factor XII and the large activator. When the factor XII molecule was denatured, reduced, and run in disc gels containing sodium dodecyl sulfate, no molecule the size of large activator was obtained. This observation suggested that the large activator might be formed by the digestion of factor XII by a plasma proteolytic enzyme. Incubation of plasmin with factor XII resulted in the formation of the large activator which accounted for 22 % of the total activators formed. Whether isolated from plasma or generated by plasmin digestion of factor XII, the large activator was not further attacked by plasmin, indicating that it is an end product. In contrast, kallikrein digestion of factor XII failed to produce large activator but did yield low molecular weight activators. Thrombin, even at very high concentrations, failed to generate any activator. Pancreatic trypsin also formed the large activator, which comprised only 10% of the total activators of prekallikrein produced. The results suggest that factor XII exhibits differential susceptibility to plasma proteolytic enzymes with both quantitative and qualitative changes in the prekallikrein activators formed. Moreover, the kallikrein formed might exert positive feedback control by converting factor XII to low molecular weight prekallikrein activators.