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1. Activated human plasma factor XIII was 65% inhibited by iodo[(14)C]acetate and incorporated 0.6 mol of label into the alpha subunit, which eventually was allowed to form a precipitate. 2. All the label was recovered as S-carboxymethylcysteine in a tetra-peptide of sequence Gly-Gln-Cys-Trp.
A commercially available, disposable blade in a spring-loaded cassette was used to measure oral mucosa bleeding times (OMBT) of ketamine/acepromazine-anesthetized cats. The OMBT were determined in cats homozygous for Chediak-Higashi syndrome (CHS, n = 7), cats heterozygous for CHS (n = 6), and cats homozygous for Hageman factor (factor XII) deficiency (n = 5). In addition, OMBT were determined in three groups of normal cats: random-source cats (n = 14), inbred normal relatives of the cats with CHS (n = 7), and inbred normal relatives of Hageman factor deficient cats (n = 9). No significant differences were found in the OMBT of the three groups of normal cats. The mean OMBT for all 30 normal cats was 1.9 minutes +/- 0.5 minutes s.d. Compared to the normal cats, those homozygous for CHS had significantly prolonged OMBT (14.1 +/- 3.3 minutes; p < 0.05). The mean OMBT of cats heterozygous for CHS (2.6 +/- 0.8 minutes) was also significantly longer than the OMBT of the combined normal group. The mean OMBT of the CHS heterozygotes, however, was not significantly longer than that of their normal relatives (OMBT = 1.8 +/- 0.5 minutes), probably because of the low number of cats in this subgroup of normals. As expected, the OMBT of cats homozygous for Hageman factor deficiency (2.3 +/- 0.3 minutes) were not significantly prolonged.
A secific, sensitive, and reproducible radioimmunoassay for human Hageman factor (HF, factory XII) has been developed with purified human HF and monospecific rabbit antibody. Precise measurements of HF antigen were possible for concentrations as low as 0.1% of that in normal pooled plasma. A good correlation (correlation co-efficient = 0.82) existed between the titers of HF measured by clot-promoting assays and radioimmunoassays among 42 normal adults. Confirming earlier studies, HF antigen was absent in Hageman trait plasma, but other congenital deficient plasmas, including those of individuals with Fletcher trait and Fitzgerald trait, contained normal amounts of HF antigen. HF antigen was reduced in the plasmas of patients with disseminated intravascular coagulation or advanced liver cirrhosis, but it was normal in those of patients with chronic renal failure or patients under treatment with warfarin. HF antigen was detected by this assay in plasmas of primates, but not detectable in plasmas of 11 nonprimate mammalian and one avian species.
The reactive center of C1-inhibitor, a plasma protease inhibitor that belongs to the serpin superfamily, is located on a peptide loop which is highly susceptible to proteolytic cleavage. With plasma kallikrein, C1s and beta-Factor XIIa, this cleavage occurs at the reactive site residue P1 (Arg444); with neutrophil elastase, it takes place near P1, probably at residue P3 (Val442). After these cleavages, C1-inhibitor is inactivated and its conformation is modified. Moreover, in vivo, cleaved C1-inhibitor is removed from the blood stream more rapidly than the intact serpin, which suggests that proteolysis unmasks sites responsible for cellular recognition and the uptake of the cleaved inhibitor. In the study reported here, we show, using an MAb, that an identical neoepitope is created on C1-inhibitor after the cleavage of its exposed loop by plasma kallikrein, C1s, beta-Factor XIIa, and by neutrophil elastase.
It is now well recognised that antiphospholipid antibodies are associated with thrombosis and recurrent fetal loss. Some antiphospholipid antibodies (aPAs) have been shown to require a cofactor, beta 2 glycoprotein-I (beta 2 GPI), for binding to phospholipids, and recently beta 2 GPI has been identified as the antigenic target for some aPAs. beta 2 GPI possesses in vitro anticoagulant properties and modulation of beta 2 GPI function may therefore result in altered haemostatic regulation. In the present study, the influence of plasma derived aPAs and beta 2 GPI on factor XII activation on the surface of very low density lipoprotein (VLDL) was investigated. Factor XIIa generation was dependent on lipoprotein lipase treatment of VLDL and beta 2 GPI inhibited the factor XIIa generation in a concentration dependent manner. No consistent effects on factor XIIa generation were demonstrated with the IgG fractions from patients with aPAs. Inhibition of the beta 2 GPI activity was demonstrated by some antibodies, and study with cardiolipin affinity purified antibody indicated that antibody concentration is critical. These results suggest that perturbation of beta 2 GPI function may contribute to the pathogenic mechanism for thrombosis in some patients with aPAs.
Purified precursor Hageman factor has been demonstrated to bind to soluble bacterial lipopolysaccharide (LPS, endotoxin) isolated from Escherichia coli 0111:B4, and this complex has been shown to have the capacity to convert prekallikrein to its active form. In addition, LPS-activated Hageman factor substantially reduces clotting times in XII-deficient plasma. The capacity to activate Hageman factor has been demonstrated to reside in the lipid A region of the LPS molecule. Activation of Hageman factor by LPS contrasts with fluid-phase activation (e.g., by kallikrein or trypsin) in that no cleavage to lower molecular weight fragments occurs. High concentrations of LPS inhibit the activity of Hageman factor, probably by a direct LPS-Hageman factor interaction.
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Few data exist on the effects of n-3 polyunsaturated fatty acids (PUFAs) on the initiators and endstage products of coagulation following an acute myocardial infarction (MI). We assessed the long-term effects of n-3 PUFAs on postinfarct variations of tissue factor (TF), activated factor XII (FXIIa) and fibrin monomer (FM), and expected additional statin treatment to modify thrombogenicity. Acute MI patients (n = 300) were randomly allocated to a high dose of n-3 PUFAs or corn oil for at least one year. Plasma concentrations of TF, FXIIa and FM were unaffected by n-3 PUFAs as compared to corn oil, and were uninfluenced by additional statin treatment in subgroup analyses. TF decreased (p = 0.0001), while FXIIa increased during the first 6 weeks (p = 0.001). FM remained essentially unchanged during the entire observation period. In conclusion, TF, FXIIa and FM were unaffected by long-term treatment with high- dosed n-3 PUFAs and by additional statin treatment.
Effects of Hageman factor fragment (factor XIIf) administration on shock induction were studied in anesthetized male Wistar rats with hemorrhagic shock. Administration of factor XIIf in non-hemorrhaged rats resulted in an immediate decrease of mean arterial pressure (MAP) for 5 min and in significant increases of blood glucose, lactate and hematocrit (Hct) as well as in a strong tendency for plasma kallikreinogen (KKN) to decrease. At the beginning of bleeding (15 min after factor XIIf administration) MAP has been normalized again. During subsequent hemorrhage pretreated rats showed a sharper decrease in MAP which remained significantly lower up to 25% of estimated blood volume (EBV) and recovered more slowly to normal level after hemorrhage. Blood glucose, lactate and Hct were significantly higher in pretreated animals after hemorrhage of 30% EBV. KKN depicted significant lower values during hemorrhage and in the posthemorrhagic period. Mortality within the observation time increased from 20% (control group) to 60% (pretreated animals). The results demonstrate that prehemorrhagic kallikrein-kinin system (KKS) activation induced an increased severity of shock state with higher mortality.
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A bovine Hageman factor cDNA was cloned from a liver cDNA library. The nucleotide sequence was analyzed and the amino-acid sequence was deduced. The sequence deduced was consistent with the partial amino-acid sequences of bovine Hageman factor protein. The sequences for three portions including the amino terminal had been previously reported (Fujikawa et al. (1977) Biochemistry 16, 2270-2278). In comparison with the primary structures of human and guinea pig Hageman factors, the putative domain structures were totally conserved. Each domain possessed high sequence homology with the human molecule (66-88%) and the guinea pig one (63-81%) except for the proline-rich region (less than 10%) which connects the amino-terminal five domains with a serine proteinase portion. Significant heterogeneities were observed among the three species around the essential cleavage sites for the conversion to the activated Hageman factors. Bovine Hageman factor has no suitable amino-acid sequence as the substrate for the trypsin-type proteinases at the proline-rich region in difference from the human and guinea pig molecules. Probably this is the reason why the beta-form activated Hageman factor (the proteinase moiety) is not liberated in the activation of the bovine molecule with trypsin or plasma kallikrein.
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The aim of the present investigation was to clarify whether immobilized heparin does, as previously suggested, prevent triggering of the plasma contact activation system. Purified FXII in the absence or presence of antithrombin and/or C1 esterase inhibitor as well as plasma was exposed for 1 to 600 seconds to a surface modified by end-point immobilization of heparin. With purified reagents, a process including surface adsorption and activation of FXII occurred within 1 second. In the presence of antithrombin, the resulting surface-bound alpha-FXIIa was inhibited within that time. Likewise, the adsorption of native FXII from plasma was a rapid process. However, the inhibition of surface-bound alpha-FXIIa was slightly slower than with purified components. Nevertheless, neither beta-FXIIa nor FXIa were found in the plasma phase. Exposure of a surface prepared from heparin molecules, lacking antithrombin binding properties, to plasma resulted in surface-bound alpha-FXIIa within 1 second. In the liquid phase, beta-FXIIa was detected after 2.5 seconds and, 12 seconds later, FXIIa and FXIa in complex with the C1 esterase inhibitor appeared. Addition of heparin to plasma prior to surface exposure did not prevent activation of surface-bound FXII, nor did it increase the beta-FXIIa inhibition rate and prevent FXI activation in plasma, although beta-FXIIa and FXIa-AT complex formation occurred. It is concluded that surface-immobilized heparin, unlike heparin in solution, effectively inhibits the initial contact activation enzymes by an antithrombin-mediated mechanism, thereby suppressing the triggering of the intrinsic plasma coagulation pathway.
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