The mechanism by which the light chain of cleaved hmw-kininogen augments the activation of prekallikrein, factor XI and hageman factor

Abstract

HMW-kininogen binds prekallikrein and factor XI to form two bimolecular complexes in plasma; upon addition of certain negatively charged surfaces, it functions as a coagulation cofactor and facilitates the activation of Hageman factor, prekallikrein and factor XI. We have investigated the mechanism by which HMW-kininogen functions in each of these steps. HMW-kininogen was found to augment the binding of prekallikrein and factor XI to kaolin in a plasma system sùggesting that the prekallikrein-HMW kininogen complex and the factor XI-HMW kininogen complex are attached to surfaces via HMW-kininogen. The attachment was shown to be mediated by the light chain derived from cleaved HMW-kininogen and is consistent with previous data demonstrating that the light chain is the coagulant part of the molecule. Prekallikrein can be readily activated when bound to the surface by this HMW-kininogen linkage; however, when an equal quantity of prekallikrein was bound directly to the surface, it was not activatable even after the addition of HMW-kininogen. Thus, binding of prekallikrein (and factor XI) to the surface via HMW-kininogen appears to place them in a conformationally favorable position for activation by activated Hageman factor. This appears to be the major function of HMW-kininogen as a coagulation cofactor. In addition, HMW-kininogen attachment of prekallikrein (kallikrein) to the surface is a reversible interaction which is not the case when direct binding to the surface occurs. In this fashion, a portion of the kallikrein formed can dissociate and interact with other Hageman factor molecules. These data suggest that the effect of HMW-kininogen upon Hageman factor activation is indirect and acts to increase the effective concentration of kallikrein available for Hageman factor cleavage.