Hageman Factor (HF) Dependent Fibrinolysis

Abstract

The HF dependent fibrinolytic pathway is initiated by binding of HF (M. W. 80,000) and a complex of prekallikrein and high molecular weight (HMW) kininogen (M. W. 280,000) to negatively charged surfaces. A reciprocal reaction proceeds in which HFA converts prekallikrein to kallikrein and kallikrein activates HF. The rate of each enzymatic reaction is augmented by HMW kininogen. The active site of HF, as assessed by incorporation of 3H-DFP, in the surface bound enzyme does not form upon binding in the presence or absence of HMW kininogen, but is generated upon activation by kallikrein. The product, HFA (M. W. 80,000), is subsequently cleaved to liberate the active Hageman factor fragments (M. W. 28,000). Two forms of prekallikrein (M. W. 88,000 and 85,000) are cleaved by HFA to yield kallikreins in which a heavy chain (M. W. 52,000) is disulfide linked to a light chain (36,000 or 33,000) and, for each molecular form, the active site is in the light chain. Kallikrein activates plasminogen (M. W. 94,000) to yield a plasmin consisting of a heavy chain (M. W. 58,000) disulfide linked to a light chain (M. W. 27,000) and again, the active site is in the light chain. Digestion of prekallikrein by kallikrein yields proenzymes of molecular weight 78,000 and 75,000 that appear to represent the previously described plasminogen proactivator. Factor XI circulates bound to HMW kininogen, is activated by HFA in the presence of HMW kininogen, and factor XIA-HMW kininogen activates HF. Thus factor XI may contribute to the gradual activation of HF and evolution of fibrinolytic activity in prekallikrein deficient plasma. A further role for factor XIA as a plasminogen activator will be discussed.