The intrinsic coagulation/kinin pathway, the classical complement pathway and their interactions

Activation of the Hageman factor (HF) dependent pathways in normal human plasma occurs by interaction of Hageman factor, prekallikrein and high molecular weight (HMW) kininogen with initiating surfaces. Human Hageman factor autoactivates upon binding to certain negatively charged surfaces as assessed using the synthetic substrate D-pro-phe-arg-p-nitroanilide. A concave upward accelerating rate of substrate digestion is obtained when the reaction is performed in glass rather than plastic cuvettes. Activated HF (HFa) can digest HF to form more HFa by cleavage within a disulfide bridge while Hageman factor fragment (HFf), a later cleavage product retains kinin forming ability, loses much of its coagulant activity and cannot digest HF. When an active site in native HF was sought, a lower limit of activity seen was about 1/4,000 that of HFa but we could not distinguish at trace activity present in the zymogen from a very low level of HFa present in the preparation. When HF and prekallikrein are mixed, they attack each other and a dramatic acceleration is seen relative to the autoactivation reaction. Kallikrein digests HF to HFa and then to HFf. HFa consists of a 50,000 MW heavy chain containing the surface binding site, disulfide linked to a 30,000 MW light chain with the active site. In HFf the 30,000 MW chain is disulfide linked to either a 500 or 2500 MW chain derived from the C-terminal end of the HFa heavy chain. HFa of HFf convert prekallikrein to kallikrein and kallikrein digests HMW-kininogen to release bradykinin. HMW-kininogen circulates bound to prekallikrein or to coagulation factor XI, attaches them to surfaces and is required for an optimal rate of conversion of prekallikrein to kallikrein or factor XI to factor XIa by HFa. This is a function of the light chain derived from cleaved HMW kininogen. The heavy chain has been recently shown to be a cysteine protease inhibitor. The Cl INH is the critical control protein of this cascade since it inhibits HFa, HFf, and kallikrein. The first component of complement (Cl) is also stabilized by the present of Cl INH and in its absence the Clr subcomponent undergoes an intramolecular autoactivation and Clr then activities Cls to initiate the classical complement pathway HFf can also enzymatically activate Clr. Thus in hereditary angioedema (Cl INH deficiency) both cascades appear to activate <<spontaneously<< and cross interactions between them appear likely. If hereditary angioedema plasma is incubated in a plastic tube for prolonged periods in the presence of kinniase inhibitors, evolution of bradykinin is seen while normal plasma requires addition of an exogenous surface or incubation in a glass tube.