The effects of contrast media on coagulation factor XII.
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Standardization of prekallikrein activator (PKA): the 1st British reference preparation for PKA.
A collaborative study on prekallikrein activator (PKA) has been carried out involving four laboratories for the purpose of establishing a British reference preparation for PKA. Samples of two plasma protein fractions (PPF) were assayed against participants' own supplies of the Bureau of Biologics Reference Preparation No. 2 (BoB 2). There was good agreement on the relative PKA activities of the two preparations. One of the preparations, coded 79/572, was established as the 1st British Reference Preparation for Prekallikrein Activator, with an assigned potency of 78.9 units/ml.
Factor XII↗
Standardization of prekallikrein activator (PKA): the 1st International Standard for PKA.
A international collaborative study was carried out to establish an international standard for prekallikrein activator (PKA). The candidate material, coded 82/530, was assayed against the Office of Biologics (FDA) PKA reference preparation No. 2 (OoB 2) and the 1st British Reference Preparation for PKA. There was good agreement between participant laboratories on the relative PKA activity of the three preparations. Preparation 82/530 has been established by the World Health Organization as the 1st I.S. for PKA, with an assigned potency of 85 International Units per ampoule.
Factor XII↗
An animal model for the detection of hypotensive side effects of immunoglobulin preparations.
Intravenous administration of certain immunoglobulin preparations may cause severe adverse reactions, especially in immunodeficient patients. These reactions are generally assumed to be related to the anticomplementary activity of the preparations, caused by IgG aggregates. Because the exact mechanism of the adverse reaction is unknown, we investigated the reactions induced in anesthetized rats on rapid intravenous administration of different human immunoglobulin preparations. The most conspicuous observation was a severe, long-lasting hypotension, induced by standard immunoglobulin preparations (for intramuscular use), which appeared to be independent from the concomitant complement and neutrophil activation. The long-lasting hypotension was not related to the presence of prekallikrein activator, which induced a transient hypotensive reaction only after sensitizing the rats to bradykinin. The reactions appeared to be associated with IgG aggregates. It was found that certain aggregates induced mainly complement activation, whereas others had mainly a hypotensive effect or no effect at all. It was concluded that the rat model provides a sensitive and reproducible test system for vasoactive properties of immunoglobulin preparations for intravenous administration that cannot be predicted from in vitro measurements, such as anticomplementary activity, aggregate content or prekallikrein activator activity. It is suggested that the test may also be used for other plasma products for intravenous administration.
Animals↗
Stability of European anti-D immunoglobulin preparations.
The stability of 18 batches of anti-D immunoglobulin preparations from 7 European manufacturers was studied over 28-day incubation at +37 degrees C and 3-year storage at +4 degrees C. The mean loss of activity after 28 days at +37 degrees C was 12.3 +/- 8.2%, and after 3 years at +4 degrees C 15.2 +/- 9.5%. The correlation coefficient of the loss of activity between these two storages was r = 0.61, p less than 0.05 indicating that short-term incubation can be used to evaluate the shelf life stability of anti-D activity. In general, measurements of IgG fragments or activities of plasmin, plasminogen, or prekallikrein activator were not valuable in predicting the stability of anti-D activity due to the fact that the preparation of each manufacturer has its own unique pattern of enzymes and inhibitors. The anti-D immunoglobulin preparations contained up to at least 7 plasma proteins in addition to IgG. All preparations contained factor B, most of them alpha 2-macroglobulin, alpha 1-antitrypsin, albumin, and alpha 2-HS glycoprotein, alpha-Lysozyme was present in 7, and ceruloplasmin in 2 preparations. Neither purity nor impurity correlated with stability.
Chromatography, High Pressure Liquid↗
An international collaborative study to replace the 1st international standard for prekallikrein activator.
BACKGROUND AND OBJECTIVES: The aim of this study was to replace the 1st International Standard (IS) for prekallikrein activator (PKA) (code 82/530) with a new IS and European Biological Reference Preparation (BRP). The new standards were freeze dried 20% albumin solution containing PKA, the same solution that is tested using these standards. Aspects of the methodology for PKA determination were also examined as part of this study. MATERIALS AND METHODS: A batch of 20% albumin containing approximately 30 IU/ml was donated by a manufacturer of blood products and dispensed into ampoules at the National Institute for Biological Standards and Control (NIBSC) to create the candidate IS (02/168, sample B in the study) and at the European Directorate for the Quality of Medicines (EDQM) to create the candidate BRP (sample C in the study). The concentration of PKA in these preparations was determined in an international collaborative study involving 31 laboratories from 17 countries worldwide in comparison with the 1st IS for PKA (82/530) containing 85 IU of PKA per ampoule. Participants were requested to perform their own in-house method, based on the current Ph. Eur. monograph for determination of PKA in albumin solutions. Participants were provided with sufficient samples to perform two or three assays and were asked to use their local prekallikrein substrate (PKS) and also to use a commercial PKS provided as part of the study, in order to investigate the importance of the source of PKS on the final potency values. RESULTS: Samples B and C emerged with identical PKA concentrations of 29 IU/ml, very close to the expected value. This figure was determined using a variety of statistical methods, with the participants' own calculated values and values calculated centrally at the EDQM using raw data. The value of 29 IU/ml was consistent and independent of the method of calculation, although interlaboratory variability was more sensitive to the statistical analysis method. There was no statistically significant difference in mean potencies when comparing results with the laboratories' own local substrate and the substrate provided for the study. All stability studies indicate that these lyophilized preparations of PKA in 20% albumin are extremely stable. CONCLUSIONS: Samples B and C were established as the 2nd IS (code 02/168) and PKA activator in albumin BRP batch 1 (Y0000263), respectively, with a potency of 29 IU per ampoule. Results from this study indicate that testing for PKA in albumin may be less sensitive to the source of PKS than previously feared. The study highlights a number of methodological issues that may need revising in the Ph. Eur. general chapter 2.6.15.
Cooperative Behavior↗
Effect of surface-immobilized heparin on the activation of adsorbed factor XII.
Two different heparin surfaces, structurally closely related and of similar negative charge characteristics, were compared with regard to adsorption and activation of coagulation Factor XII (FXII). One surface was prepared by immobilization of unfractioned heparin, which yielded a surface containing both heparin molecules with high and with low affinity for antithrombin (unfractioned [UF] heparin surface). The other surface consisted of a fraction of heparin molecules with low affinity for antithrombin (LA heparin surface) and essentially devoid of antithrombin-binding as well as anticoagulant activity. Both surfaces adsorbed FXII from plasma to a similar extent, and essentially the same quantities of bound factor could be recovered from the surfaces. The two heparin surfaces, however, differed markedly with regard to activation of the adsorbed FXII. On the LA heparin surface, a major portion of the surface-bound FXII was recovered in its enzymatically active form (FXIIa), but only trace amounts of the FXII taken up by the UF heparin surface had undergone activation. When FXII-deficient plasma was used instead of normal plasma, no surface-associated enzyme activity could be recovered on either surface. The presence of free standard heparin or low molecular weight heparin in the plasma exposed to the LA heparin surface did not prevent conversion of FXII to FXIIa.
Adsorption↗
Factor XIIIa+ dendritic cells and S-100 protein+ Langerhans' cells in adult periodontitis.
OBJECTIVE: The purpose of this study was to evaluate the presence of factor XIIIa+ dendritic cells and S-100 protein+ Langerhans' cells in the gingival epithelium and connective tissue of periodontal pockets, before and after non-surgical periodontal therapy. BACKGROUND: The microbial flora in periodontal pockets provokes complex immune reactions. Dendritic cells play a critical role in primary and secondary immune responses and are considered as antigen-presenting cells. Factor XIIIa positive dendritic cells and S-100 protein positive Langerhans' cells identified by immunoreactivity against factor XIIIa antigen and S-100 protein, respectively, are two distinct subpopulations of dendritic cells. METHODS: Fifty-four gingival tissue samples were obtained from periodontal pockets of initial depth 4-5 mm and > or = 6 mm. Each group was subdivided in to three subgroups. The first subgroup consisted of samples taken on baseline day and used as control. The second and third subgroups included those obtained 1 month after plaque and calculus removal, and 1 month after scaling and root planing, respectively, additionally to oral hygiene instructions. The tissues were removed from the palatal gingiva under local anaesthesia during routine periodontal surgery. Immunohistochemical staining with antibodies against factor XIIIa and S-100 protein was performed to identify dendritic cells positive and Langerhans' cells positive, respectively. RESULTS: Factor XIIIa+ dendritic cell numbers decreased compared to controls after plaque and calculus removal, oral hygiene instructions and scaling and root planing in periodontal pockets of 4-5 mm, but not in those of > or = 6 mm depth. S-100+ Langerhans' cell numbers decreased after periodontal treatment in the periodontal pockets > or = 6 mm. CONCLUSION: These results may reflect a tendency for reduction of these two distinctive subpopulations of dendritic cells after non-surgical periodontal therapy.
Adult↗
Activation of factor XII in rat plasma: protection by benzamidine of the cofactor function of high molecular weight kininogen.
Factor XII has been assayed as kaolin-activated prekallikrein activator in rat citrated plasma pretreated with acetone (Briseid et al. 1978 & 1979; Briseid & Berstad 1979). In the present work benzamidine added during blood collection increased the extent of activation by a factor of 6. Rat high molecular weight kininogen (HMWK) added to acetone-treated citrated plasma likewise increased the activation, providing evidence of the protection by benzamidine of the cofactor function of HMWK. All cofactor capacity was retained after the removal of the kinin part of HMWK. Experiments carried out with plasminogen-free plasma showed that plasmin could hardly be the the factor responsible for the destruction of HMWK. The stoichiometric factor XII concentration-effect curve obtained by diluting acetone-treated rat plasma with acetone-treated human factor XII deficient plasma showed that factor XII is present in functional excess, the concentration of HMWK deciding the extent of activation. By diluting acetone-treated rat plasma with buffer, HMWK concentration-effect curves were obtained which were approximately linear over a range of 0.03-0.40 microgram (bradykinin equivalents) per ml kaolin incubate. No further activation of factor XII was obtained at 0.80 microgram/ml.
Amidines↗
Effect of serotonin antagonists on the dextran-induced anaphylactoid reaction in the rat.
Dextran injected intravenously into rats causes a rapid lowering of the extent of activation of factor XII and of the plasma levels of prekallikrein and plasminogen, and at the same time a profound fall in blood pressure. The effects on these dextran-induced reactions of three serotonin antagonistic lysergic acid derivatives were studied in the rat: bromolysergic acid diethylamide (BOL 148), methysergide, and ergotamine. BOL 148 was found to be the only effective inhibitor of the blood pressure fall, possessing an inhibitory effect over the dose range 1.0-4.0 mg/kg intravenously. The finding supports the assumption that part of the dextran-induced blood pressure fall is mediated by serotonin through D-receptors. All three serotonin antagonists showed a serotonin-like lowering effect on the activation of factor XII and on the level of prekallikrein in plasma (BOL 148 1.0-4.0 mg/kg; methysergide 0.10-0.60 mg/kg; ergotamine 0.10-0.60 mg/kg). The results with the serotonin antagonist alone and in combination with dextran provided evidence that the serotonin-mediated part of the blood pressure fall can not be secondary to the effect of dextran on the plasma parameters assayed.
Anaphylaxis↗
Are cardiovascular and sympathoadrenal effects of human "new pressor protein" preparations attributable to human coagulation beta-FXIIa?
"New pressor protein" (NPP) derived from normal human plasma is an extra renal enzyme that shares strong sequence homology with human coagulation beta-FXIIa. Under our bioassay conditions, human NPP (10-20 microl plasma equivalent/ approximately 300 g rat iv) can raise the systolic blood pressure (SBP) by 40-50 mmHg, the diastolic blood pressure (DBP) by 15-20 mmHg, and the heart rate (HR) by 70-90 beats/min. Plasma epinephrine (of adrenal medullary origin) and norepinephrine rise by about 50- and 10-fold, respectively. Because beta-FXIIa is not normally associated with pressor properties, we endeavored to substantiate that the hypertensive effects of impure NPP preparations used in our experiments are attributable to their content of beta-FXIIa. We carried out comparisons with highly purified (>90%) commercial human beta-FXIIa and found that by gel filtration (Sephadex G-100 and G-75), NPP bioactivity appeared in the approximately 30-kDa elution zone, consistent with the molecular mass of beta-FXIIa. Retention time using fast-protein liquid chromatography anion exchange chromatography was identical. Molecular mass and comigration were confirmed by SDS-PAGE gel electrophoresis, and the recovered approximately 30-kDa protein bands yielded beta-FXIIa fragments identified by mass spectrometry. Matched doses of the NPP preparations produced dose-response curves very similar to those elicited by beta-FXIIa with respect to increments of SBP, DBP, and HR, whereas plasma catecholamine increments were generally comparable. We propose that beta-FXIIa is substantially, if not exclusively, responsible for the observed effects of our NPP preparations and that this points to a novel axis connecting the FXII coagulation cascade and the sympathoadrenal gland to other cardiovascular regulatory mechanisms.
Amino Acid Sequence↗
Extrinsic coagulation factors and tissue factor pathway inhibitor in end-stage chronic renal failure.
The relationship between extrinsic coagulation factors, tissue factor pathway inhibitor (TFPI) and activated factor XII (FXIIa) was examined in 71 patients with end-stage chronic renal failure. They had chronic stable uremia due to regular hemodialysis. The patients were divided into two age- and sex-matched groups with and without diabetes mellitus. As extrinsic coagulation parameters, FVIIa and FVII antigen (FVIIag), tissue factor antigen and TFPI (the activity and antigen) were measured. FXIIa was measured as a marker of contact activation, and thrombin generation was evaluated using the two markers thrombin-antithrombin III complex and prothrombin fragment 1 + 2. In both hemodialysis groups with and without diabetes, significant elevations of FXIIa, FVIIa and tissue factor, with high levels of TFPI, were found. Thus, hyperactivation of the coagulation system was in part compensated by TFPI, and a significant increase in FXIIa could not directly affect FVIIa hyperactivation. No differences of these parameters, except for FVIIag and fragment 1 + 2, were found between the groups with and without diabetes. It is suggested that the long-term hemodialysis might have masked any differences due to the underlying disease in these two subgroups.
Aged↗
Alpha 2-macroglobulin-kallikrein potentiates contact system activity: possible effect in asthma.
Bradykinin release, an end product of contact system activation, is thought to play a significant role in the pathophysiology of asthma. We have found an increased level of native alpha 2-macroglobulin-kallikrein (alpha 2M-KK) in asthma plasmas, and have demonstrated increased levels of contact system activity in these plasmas under certain laboratory conditions. We investigated the possible role of alpha 2M-KK as a modulator of the contact system activity. Alpha 2M-KK potentiated the factor XII activation on kaolin and the kallikrein production in a dextran-sulfate-mediated assay. This potentiation presumably involves a proteolytic effect of alpha 2M-KK on high molecular weight kininogen.
Asthma↗
Assembly of the human plasma kinin-forming cascade along the surface of vascular endothelial cells.
The generation of bradykinin by contact activation requires autoactivation of factor XII (Hageman factor) upon initiating surfaces, conversion of prekallikrein to kallikrein, and digestion of high-molecular-weight (HMW) kininogen. Endothelial cells have a high-affinity receptor that binds either HMW kininogen or factor XII in a zinc-dependent interaction, and activation of factor XII can occur along this surface to initiate kinin formation. Tissue injury, exposure of proteoglycans, or release of mast cell heparin will markedly accelerate these reactions. The bradykinin released binds to endothelial cell B-2 receptors along the inner surface of blood vessels which results in dilatation and increased vascular permeability.
Bradykinin↗
Characterization of various immunoglobulin preparations for intravenous application. I. Protein composition and antibody content.
In this comparative study we investigated 14 immunoglobulin (Ig) preparations for intravenous application; they were prepared by various manufacturers who used either placental or venous blood as the starting material. The pepsin- and plasmin-treated products and a preparation which, according to the manufacturer, was not degraded enzymatically, contained 17-86% of IgG split products. On the other hand, three chemically modified preparations, one preparation treated at pH 4, for products treated with poly(ethylene glycol) (PEG) and one preparation protected by albumin contained 90% or more of non-fragmented IgG. The IgG subclass distribution corresponded to the distribution of subclasses in normal serum only in the nonmodified and not enzymatically degraded preparations. All samples except one contained 0.1 mg/ml IgA or more, all contained only traces of IgM. No product had clinically relevant titers of irregular antibodies against erythrocyte antigens. The content of those antiviral and antibacterial antibodies that were tested for was similar in all preparations. Only the anti-HBs activity exhibited large variations. Some PEG-treated preparations showed an elevated prekallikrein activator (PKA) level, whereas all other preparations contained, if any, only traces of PKA.
ABO Blood-Group System↗
Endothelial cells express a matrix protein which binds activated factor XII in a zinc-independent manner.
Recent studies have shown that peptides identified as surface binding regions of high molecular mass kininogen (HK) and factor XII (FXII) inhibit the Zn(2+)-dependent binding of FXII to confluent layers of human umbilical vein endothelial cells (HUVEC). This indicates that negatively charged FXII binding surfaces, such as sulfatides and dextran sulfate, may interfere with the binding of FXII to confluent layer of HUVEC. Upon investigating this hypothesis it was unexpectedly found that sulfatides enhanced a specific binding of FXII to a matrix protein expressed during growth of the endothelial cells and that this binding was independent of the presence of Zn(2+). The function of sulfatides was partly to minimize nonspecific electrostatic binding and partly to induce and enhance autoactivation of FXII generating alphaFXIIa. Western blot analysis of the extracts of the matrix incubated with FXII and sulfatides showed that the binding was specific for alphaFXIIa. The dissociation constant for binding alphaFXIIa was 12.8 +/- 0.4 nM (n = 4). The binding of alphaFXIIa to ECM was mapped to the heavy chain as no binding was observed of the light chain containing the catalytic domain. HK, which previously has been shown to completely abolish the Zn(2+)-dependent binding of FXII to confluent layers of HUVEC, did not inhibit the binding of alphaFXIIa to the matrix but sulfatides enhanced binding of FXII to ECM. This suggests that HK interferes with the binding of FXII to sulfatides and thereby the autoactivation of FXII. Trypsin treatment of the matrix protein completely abolished the binding, and fibronectin but not laminin was found to be a suitable target. The binding of activated FXII to the ECM suggests that FXIIa may be a modulator of cellular adhesion, migration and vascularization.
Endothelial Cells↗
Mechanisms of activation of the classical pathway of complement by Hageman factor fragment.
The mechanism by which a fragment of activated Hageman factor (HFf) activates the classical pathway of complement in serum or platelet-poor plasma has been further delineated. When serum or platelet-poor plasma was incubated with various concentrations of HFf, the total complement hemolytic activity was reduced in a dose-dependent manner. This activation appears to be due to the direct interaction of HFf with macromolecular C1, since incubation of purified C1 with HFf resulted in dissociation of the subunits with concomitant reduction of C1r antigenicity that is indicative of C1 activation. HFf-dependent activation was prevented by prior treatment of HFf with the active site-directed inhibitor, H-D-proline-phenylalanine-arginine chloromethyl ketone or with a specific inhibitor of activated HF derived from corn. Incubation of HFf with highly purified C1r also resulted in activation of C1r as assessed directly using a synthetic substrate or indirectly by activation of C1s and consumption of C2. However, incubation of HFf with highly purified C1s resulted in formation of activated C1s (C1s-) but this was less efficient than HFf activation of C1r. We therefore conclude that activation of C1 in macromolecular C1 is the result of HFf conversion of C1r to C1r; activation of C1s then occurs primarily by C-1r and to a lesser degree by the direct action of HFf.
Amino Acid Chloromethyl Ketones↗
Anaphylactic release of a prekallikrein activator from human lung in vitro.
We have demonstrated the in vitro IgE-mediated release of a prekallikrein activator from human lung. The lung prekallikrein activator was partially purified by sequential chromatography on sulfopropyl-Sephadex, DEAE-Sephacel, and Sepharose 6B. Purified human prekallikrein was converted to its active form (kallikrein) by the lung protease. The generated kallikrein was shown to be biologically active; that is, it generates bradykinin from purified human high-molecular weight kininogen and also cleaves benzoyl-propyl-phenyl-arginyl-p-nitroanilide, a known synthetic substrate of kallikrein. The lung prekallikrein activator differs from the known physiologic activators of prekallikrein (the activated forms of Hageman factor) with respect to: (a) size (it has a mol wt of approximately 175,000); (b) synthetic substrate specificity (D-propyl/phenyl/arginyl-p-nitroanilide is a substrate for the activated forms of Hageman factor, but not the lung protease); (c) antigenic specificity (an anti-Hageman factor immunoadsorbent column did not remove significant amounts of the lung protease, while it removed most of the activity of activated Hageman factor fragments); and (d) inhibition profile (the lung proteases was not inhibited by corn trypsin inhibitor). This prekallikrein activator provides a physiologic mechanism by which prekallikrein can be directly activated during IgE-mediated reactions of the lung. While the role of this lung prekallikrein activator in immediate hypersensitivity reactions and in other inflammatory processes is not clear, it does represent a first and important interface between IgE-mediated reactions and the Hageman factor-dependent pathways of the inflammatory response.
Anaphylaxis↗