Characterization of human high molecular weight kininogen. Procoagulant activity associated with the light chain of kinin-free high molecular weight kininogen.

Abstract

High molecular weight (HMW) 1 kininogen has been shown to be a critical factor which functions at the initial step of the Hageman factor-dependent pathways. Thus, plasmas deficient in HMW kininogen have a markedly prolonged partial thromboplastin time and diminished kaolin-activatable fibrinolysis (1-4). The Hageman factor substrates, prekallikrein and factor XI, circulate bound to HMW kininogen (5, 6) and are adsorbed to negatively charged surfaces where they interact with surface-bound Hageman factor. HMW kininogen augments the ability of activated Hageman factor or Hageman factor fragments to activate prekallikrein (7-10) and factor XI (7-11), and it also augments the rate of Hageman factor activation (8) and cleavage (7, 12) by kallikrein. Kallikrein also cleaves the HMW kininogen to liberate the vasoacrive peptide bradykinin.We have previously reported that kinin-free HMW kininogen could still function as a coagulation factor (2) and this observation was confirmed by Schiffman et al. (13). However, Chan et al. (14) reported that kallikrein digestion of human HMW kininogen progressively diminished its coagulant activity, while Matheson et al. (15) assessed bovine HMW kininogen in human HMW kininogen-deficient plasma and found that the kinin-free protein possessed <1% of the coagulant activity of the native molecule. In this report we investigate the structural changes that occur in purified human HMW kininogen as a consequence of kallikrein digestion. The critical portion of the molecule that is responsible for its coagulant activity has been isolated, as reported in preliminary form (6), and is shown to possess an antigenic determinant that distinguishes HMW kininogen from low molecular weight (LMW) kininogen.

Inactivation of Factor XIa by Plasma Protease Inhibitors

“…Upon reduction, the two polypeptide chains are separated. LMW kininogen, which is antigenically similar to the heavy chain of HMW kininogen, and does not exhibit coagulant activity (35), did not modulate the inhibition of Factor XIa. In contrast, the light chain, which contains the coagulant activity of HMW kininogen (24,35) (35) and our present data may be due to either a higher affinity of HMW kininogen for the zymogens in that study than for the enzymes in our study.…”

“…LMW kininogen, which is antigenically similar to the heavy chain of HMW kininogen, and does not exhibit coagulant activity (35), did not modulate the inhibition of Factor XIa. In contrast, the light chain, which contains the coagulant activity of HMW kininogen (24,35) (35) and our present data may be due to either a higher affinity of HMW kininogen for the zymogens in that study than for the enzymes in our study. Alternatively, it may reflect the difference between functional kinetic determinations in the fluid-phase vs. physical binding measured in the presence of a plastic surface (36).…”

Protection by recombinant alpha 1-antitrypsin Ala357 Arg358 against arterial hypotension induced by factor XII fragment.

“…1 C). 5 min after the end of pretreatment, the animals received an intravenous bolus of 1.0 ,ug of (-Factor XIIa (Fig. 1, vertical arrows).…”

“…When zymogen activation takes place on a negatively charged surface, highmolecular-weight kininogen functions as a cofactor because it increases the rate of reciprocal activation of Factor XII by kallikrein and ofprekallikrein by Factor XIIa (4). High-molecularweight kininogen also serves as a substrate for a-and fl-kallikrein and for Factor XIIa (5)(6)(7). At an early stage of high-molecularweight kininogen proteolytic cleavage, kinins such as the nonapeptide bradykinin are released (5)(6)(7).…”

“…High-molecularweight kininogen also serves as a substrate for a-and fl-kallikrein and for Factor XIIa (5)(6)(7). At an early stage of high-molecularweight kininogen proteolytic cleavage, kinins such as the nonapeptide bradykinin are released (5)(6)(7). These peptides are potent inflammatory mediators that enhance vascular permeability and cause arterial vasodilation and venous constriction (8).…”