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PubMed1990

High molecular weight kininogen-binding site of prekallikrein probed by monoclonal antibodies.

A panel of monoclonal antibodies against human prekallikrein was raised in mice and characterized with respect to the major antigenic epitopes. Of 18 antibodies, nine were directed against the light chain portion performing the proteolytic function of activated kallikrein, and nine recognized the heavy chain mediating the binding of prekallikrein to high molecular weight (H-)kininogen. Among the anti-heavy chain antibodies, one (PK6) interfered with the procoagulant activity of prekallikrein, and prolonged in a concentration-dependent manner the activated partial thromboplastin time of reconstituted prekallikrein-deficient plasma (Fletcher type). Antibody PK6 was subtyped IgG1,k and had an apparent Kass of 6.8 +/- 0.44.10(8) M-1 for prekallikrein. Functional analyses revealed that PK6 does not interfere with prekallikrein activation by activated Hageman factor (beta-F XIIa), and has no effect on the kininogenase function of activated kallikrein. Monoclonal antibody PK6 but none of the other anti-heavy chain antibodies completely prevented complex formation of prekallikrein with H-kininogen, and readily dissociated preformed complexes of prekallikrein and H-kininogen. Likewise, Fab' and F(ab')2 fragments of PK6 blocked H-kininogen binding to prekallikrein. A synthetic peptide of 31 amino acid residues encompassing the entire prekallikrein binding region of H-kininogen effectively competed with PK6 for prekallikrein binding indicating that the target epitope of PK6 is juxtaposed to, if not incorporated in the H-kininogen-binding site of prekallikrein. Extensive cross-reactivity of PK6 with another H-kininogen-binding protein of human plasma, i.e. factor XI, suggested that the structure of the target epitope of PK6 is well conserved among prekallikrein and factor XI, as would be expected for the kininogen-binding site shared by the two proteins. It is anticipated that monoclonal antibody PK6 will be an important tool for the precise mapping of the hitherto unknown kininogen-binding site of prekallikrein.

Antibodies, Monoclonal↗
PubMed1985

The protease specificity of heparin cofactor II. Inhibition of thrombin generated during coagulation.

125I-labeled heparin cofactor II (HCII) was mixed with plasma and coagulation was initiated by addition of CaCl2, phospholipids, and kaolin or tissue factor. In the presence of 67 micrograms/ml of dermatan sulfate, radioactivity was detected in a band which corresponded to the thrombin-HCII complex (Mr = 96,000) upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. No other complexes were observed. The thrombin-HCII complex was undetectable when 5 units/ml of heparin was present or when prothrombin-deficient plasma was used. In experiments with purified proteases, HCII did not significantly inhibit coagulation factors VIIa, IXa, Xa, XIa, XIIa, kallikrein, activated protein C, plasmin, urokinase, tissue plasminogen activator, leukocyte elastase, the gamma-subunit of nerve growth factor, and the epidermal growth factor-binding protein. HCII inhibited leukocyte cathepsin G slowly, with a rate constant of 8 X 10(4) M-1 min-1 in the presence of dermatan sulfate. These results indicate that the protease specificity of HCII is more restricted than that of other plasma protease inhibitors and suggest that the anticoagulant effect of dermatan sulfate is due solely to inhibition of thrombin by HCII.

Cathepsin G↗
PubMed1986

[Procedures for the isolation and characterization of human antithrombin III].

Antithrombin III, the most important inhibitor of activated coagulation factors (IIa, IXa, Xa, XIa, XIIa) was isolated from human plasma by affinity chromatography. The biochemical characterization of this highly purified inhibitor showed, that is was uniform by means of HPLC and PAA gradient gel electrophoresis. The molecular weight was determined to 70000 daltons and the isoelectric point was pH 4,5. The inhibition of factor Xa by AT III had been proofed as competitive by kinetic studies. AT III works as a "dead end inhibitor". Heparin seems to form a ternary complex with AT III and activated coagulation factors, so acting as a catalyst. The therapeutic value of AT III-concentrates will be discussed.

Antithrombin III↗
PubMed1992

Hageman factor and risk of myocardial infarction in middle-aged men.

In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.

Aged↗
PubMed1997

Endothelial cell thrombin receptors and PAR-2. Two protease-activated receptors located in a single cellular environment.

Human endothelial cells express thrombin receptors and PAR-2, the two known members of the family of protease-activated G protein-coupled receptors. Because previous studies have shown that the biology of the human thrombin receptor varies according to the cell in which it is expressed, we have taken advantage of the presence of both receptors in endothelial cells to examine the enabling and disabling interactions with candidate proteases likely to be encountered in and around the vascular space to compare the responses elicited by the two receptors when they are present in the same cell and to compare the mechanisms of thrombin receptor and PAR-2 clearance and replacement in a common cellular environment. Of the proteases that were tested, only trypsin activated both receptors. Cathepsin G, which disables thrombin receptors, had no effect on PAR-2, while urokinase, kallikrein, and coagulation factors IXa, Xa, XIa, and XIIa neither substantially activated nor noticeably disabled either receptor. Like thrombin receptors, activation of PAR-2 caused pertussis toxin-sensitive phospholipase C activation as well as activation of phospholipase A2, leading to the release of PGI2. Concurrent activation of both receptors caused a greater response than activation of either alone. It also abolished a subsequent response to the PAR-2 agonist peptide, SLIGRL, while only partially inhibiting the response to the agonist peptide, SFLLRN, which activates both receptors. After proteolytic or nonproteolytic activation, PAR-2, like thrombin receptors, was cleared from the endothelial cell surface and then rapidly replaced with new receptors by a process that does not require protein synthesis. Selective activation of either receptor had no effect on the clearance of the other. These results suggest that the expression of both thrombin receptors and PAR-2 on endothelial cells serves more to extend the range of proteases to which the cells can respond than it does to extend the range of potential responses. The results also show that proteases that can disable these receptors can distinguish between them, just as do most of the proteases that activate them. Finally, the residual response to SFLLRN after activation of thrombin receptors and PAR-2 raises the possibility that a third, as yet unidentified member of this family is expressed on endothelial cells, one that is activated by neither thrombin nor trypsin.

Endopeptidases↗
PubMedDate not supplied

Contraceptive steroids influence the hemostatic activation state in healthy men.

Hormonal contraception for men requires administration of testosterone and gestagens. The effects of a long-acting testosterone ester and 2 different progestins on hemostatic activation parameters were studied in relation to cardiovascular risk. In phase 1, 7 healthy men aged 28-38 years received a single intramuscular injection of 200 mg norethisterone-enanthate (NET-EN) on Day 0. Plasma samples were obtained on Days 0, 14, 41, and 84. In phase 2, 3 groups of 14 healthy men aged 18-45 years received four injections (every 6 weeks) of 1000 mg testosterone undecanoate (TU), plus daily oral placebo or daily oral levonorgestrel (LNG, 250 microg); or four injections (every 6 weeks) of NET-EN. Treatment lasted 24 weeks. Plasma samples were obtained at weeks 0, 16, 24, and 52. All samples were assayed for levels of coagulation factors VIIc, VIIa, XIIc, and XIIa; prothrombin fragment F1+2 (F1+2); antithrombin; plasmin-alpha(2)-antiplasmin-complex (PAP); and fibrinogen. NET-EN alone led to a depletion of sexual hormones and a marked shift in hemostatic parameters with increasing levels of FXIIc, fibrinogen, antithrombin, and F1+2, whereas FVIIc and FVIIa levels decreased. PAP levels increased significantly. Opposite effects were seen in the TU/placebo group, with a significant down-regulation of fibrinolysis and the hemostatic turnover rate. Testosterone effects were attenuated by additional administration of gestagens. The effect of hormonal male contraception using long-acting testosterone esters with or without gestagens was significantly measurable within the hemostatic system. Down-regulation of the hemostatic system with testosterone alone may indicate an antithrombotic effect, whereas clinical consequences of an additional gestagen compound cannot be derived.

Adult↗
PubMed2000

Activated factor XII levels are dependent on factor XII 46C/T genotypes and factor XII zymogen levels, and are associated with vascular risk factors in patients and healthy subjects.

Coagulation factor XII (FXII) is activated on contact with various biologic surfaces, including subendothelial tissues and lipoprotein particles. Thus, the plasma level of activated FXII (XIIa) might represent vascular lesions or be a marker of abnormal lipid metabolism. A 46C/T polymorphism was recently described in the FXII gene close to the ATG translation initiation codon, which was associated with inter-individual variation of plasma FXII zymogen levels. The present paper reports the association of the 46C/T polymorphism with plasma XIIa levels in apparently healthy subjects, and in patients with ischemic cerebrovascular disease (CVD) and arteriosclerosis obliterans (ASO). XIIa levels were not significantly different between patients and controls, but were strongly dependent on XII 46C/T genotypes (2.07 +/- 0.81, 1.65 +/- 0.63, and 0.93 +/- 0.41 ng/ml for C/C, C/T, and T/T genotypes, respectively; P < 0.0001). This association was evident for each group studied (P < 0.0001 for CVD and controls; P= 0.0007 for ASO). There were positive correlations between plasma FXII clotting activity and XIIa levels. In a univariate analysis, XIIa correlated with total cholesterol, triglycerides, plasminogen activator inhibitor-1, and C-reactive protein (CRP), although the presence of conventional cardiovascular risk factors (male sex, smoking, hypertension, hypercholesterolemia, diabetes) did not significantly increase XIIa. Stepwise regression analyses revealed that the XII clotting activity had the strongest association with XIIa. In conclusion, XIIa levels depended on XII 46C/T genotype and correlated with some cardiovascular risk factors. Thus, the FXII genotype should be taken into consideration for interpretation of plasma XIIa levels.

Aged↗
PubMed1995

Comparative study on the use of anticoagulants heparin and recombinant hirudin in a rabbit traumatic anastomosis model.

Antithrombotic drugs, such as heparin, have been used in the clinics for a long time. Heparin acts by binding with antithrombin III to form a complex thereby enhancing the activity of antithrombin III to inactivate coagulation factors IIa, IXa, Xa, XIa and XIIa. Hirudin is a new antithrombotic agent and is reported to be much more powerful than heparin on a gravimetric basis. When both are administered systemically, one of the common complications seen is bleeding. Some previous studies have shown that local vascular endothelial concentrations of heparin are 30 to 7500 times greater than those found in the circulating blood. In order to avoid such complications, topical administration of antithrombotic drugs may be an ideal route of administration. The rabbit ear arterial crush-avulsion thrombosis model was used in this study. The animals were divided into five groups: one control group and four treatment groups which received varying concentrations of heparin and hirudin. In the saline control group, the patency rate was 19.23% at 24 hrs and 15.38% at 7 days. A higher patency rate at 7 days was obtained in groups treated with high concentration of heparin and hirudin. ACT, PT and APTT performed on samples drawn one hour after drug administration were within the normal range in both the control and the treatment groups. Scanning electron microscopy revealed the different extent of the clots on the injured intimal surfaces of the vessels in different groups. The results indicate that high concentrations of topically administered heparin or hirudin minimize the systemic complications and maximize the antithrombotic effects.

Administration, Topical↗
PubMed1986

Factor XIa-alpha 1 antitrypsin complex--elevation in the patients with DIC.

We developed an assay for the factor XIa-alpha 1 antitrypsin complex (F.XIa-alpha 1AT complex) in plasma. The purified factor XI (F.XI) activated with beta-XIIa and treated with alpha 1 antitrypsin (alpha 1 AT) served as the standard complex. The assay is an enzyme-linked differential antibody immunosorbent assay. The complex level of tested plasma was measured with peroxidase-labeled anti-alpha 1AT Fab' after the addition of 10-fold diluted test plasma (200 microliter) to the anti-F.XI monoclonal antibody beads. To eliminate the effects of plasma, the standard F.XIa-alpha 1AT complex was diluted with F.XI-deficient plasma (10-fold diluted) which did not contain the complex. Purified F.XI (0.08 micrograms/assay, i.e. 100%) was added to the standard F.XIa-alpha 1AT complex, because the absorbance of the standard complex containing F.XI (0.016-0.12 micrograms/assay, i.e. 20-150%) was a little lower than that of the complex alone. The recovery of the F.XIa-alpha 1AT complex added was over 90%. Neither F.XI nor alpha 1AT alone had the color development. The complex level of 25 normal individuals was below the detectable limit (less than 0.18 ng/assay), whereas the 30 patients with disseminated intravascular coagulation (DIC) had a high level complex (0.18-4.2 ng/assay). This assay may be helpful for the diagnosis of DIC.

Disseminated Intravascular Coagulation↗
PubMed1987

Acceleration of surface-dependent autocatalytic activation of blood coagulation factor XII by divalent metal ions.

The effect of divalent metal ions on the rate of dextran sulfate dependent autocatalytic activation of human blood coagulation factor XII was studied at pH 7.4 and 25 degrees C. Zn2+ and Cu2+, but not Co2+, increased the rate of factor XII activation induced by dextran sulfate with optimum effects at approximately 5 and 1 microM, respectively, while Ca2+ acceleration required much higher concentrations (millimolar). Further investigation of the effect of Zn2+ on factor XII activation demonstrated a complete dependence on the presence of dextran sulfate, lack of inhibition by soybean trypsin inhibitor, the appearance of alpha-XIIa as the primary reaction product, and reaction kinetics characteristic of an autocatalytic process. These results were consistent with Zn2+ affecting only the rate of surface-mediated factor XII autoactivation. The initial turnover velocity of dextran sulfate induced factor XII autoactivation increased linearly with factor XII concentration in the absence of Zn2+ up to 0.9 microM factor XII but showed saturation behavior over this same concentration range in the presence of 5 microM Zn2+, indicating that Zn2+ increased the reaction rate primarily by lowering the apparent Km. Comparison of the kinetics of autoactivation at mu = 0.15 and 0.24 revealed that the enhancement in the apparent kcat/Km brought about by Zn2+ increased from 19-fold to 520-fold, respectively, due to a differential dependence of the Zn2+-stimulated and unstimulated reactions on ionic strength.(ABSTRACT TRUNCATED AT 250 WORDS)

Cations, Divalent↗
PubMed1987

[Role of dysfibrinogenemia and disorders of fibrinolysis in the pathogenesis of hemostatic pathology in liver cirrhosis].

A study of 93 patients with liver cirrhosis showed that the most important blood coagulation disorder in this pathology resulting in hypocoagulation, was not decreased synthesis and deficit of the prothrombin complex factors but disturbance of the final stage determined by afibrinogenemia. Considerable depression of XIIa-kallikrein-dependent fibrinolysis and marked increment of an antiplasmin level in the plasma were noted. Positive paracoagulation tests were revealed in 57% of the patients, and as other signs typical of the lingering DIC-syndrome were absent, they were interpreted as the "hypercoagulation syndrome" or "pre-DIC syndrome". The problem of possible relationship of development of both thromboses and hemorrhages with acquired afibrinogenemia in liver cirrhosis was discussed.

Adult↗
PubMed1984

Antithrombotic actions and pharmacokinetics of heparin fractions and fragments.

During the last few years many reports on the antithrombotic actions of low molecular weight fractions (LMF) have become available and are being tested in the experimental and clinical settings. Although derived from commercial heparins, the mode of antithrombotic actions, pharmacokinetics and physiologic disposition of these agents is distinct from the parent materials. The antithrombotic potency of these fractions is generally assigned in terms of their ability to inhibit serine proteases such as factor Xa and thrombin in the presence of antithrombin III (AT III). However, these agents are also reported to exert their antithrombotic actions via non AT III mediated inhibition of serine proteases (XIIa, IXa), activation of fibrinolysis via the release of plasminogen activators and charge transition on vascular surfaces. In order to evaluate the relative pharmacologic actions of heparin and its derivatives, we utilized defined animal models to obtain data in terms of pharmacologic parameters. Significant differences between heparin and its derivatives were evident. Human studies on the pharmacokinetics and the endogenous actions of these agents confirmed our preclinical findings. These studies suggest that well-defined preclinical studies are an essential element in the development of newer antithrombotic agents.

Animals↗
PubMed1992

Dermal dendrocytes and T-cells in canine mycosis fungoides. Support for an animal model of human cutaneous T-cell lymphoma.

BACKGROUND: An extensive upper dermal network of human Thy-1+/Factor XIIa+ dermal dendrocytes (DD) exists in human mycosis fungoides (MF). METHODS: Immunophenotyping and morphologic studies on serial frozen and paraffin sections from 15 cases of canine MF were performed to see if a similar network exists in this disease, as has been proposed as an animal model of human MF. Primary antibodies were anti-human Factor XIIIa, Factor XIIIs, anti-canine Thy-1, CD4, CD8, CD18, CD45RA, Class II, MAC387, KP-1, EBM-11, and several other pan-T, pan-B, and pan monocyte markers. RESULTS: Thy-1+/Factor XIIIa+DD were seen in all cases and confirmed on identical cells by double immunofluorescence. These were seen throughout the upper dermis, similar to DD in human MF. Canine DD expressed the macrophage marker 2A2+, and were Class II+, CD4+, CD8-, CD18+, EBM11-, Factor XIII-, MAC387-, and KP-1. Epidermal and dermal lymphocytes in canine MF were Thy-1-, CD4+, CD8-, CD18+, CD45RA-, EBM11-, MAC387-, Factor XIIIa-, Factor XIIIs- in some cases, whereas others had a predominance of CD8+ lymphocytes. CONCLUSIONS: Thus, canine MF is immunophenotypically similar to human MF. Additional support for this disease as a model of human MF is demonstrated by the rich network of Thy-1+/Factor XIIIa+ DD in the upper dermis of canine MF similar to human MF.

Animals↗
PubMed1987

[In vitro observations on antithrombotic action of urinastatin].

The inhibiting action in vitro of urinastatin on blood coagulation was studied for the purpose of therapeutic application against thrombotic disorders, and the following results were obtained: 1) Partial thromboplastin time of normal human plasma was prolonged dose-dependently by the addition of urinastatin to the reaction mixture, but prothrombin time was little inhibited by the addition of urinastatin. Thrombin time was also prolonged with urinastatin dose-dependently. 2) Using chromogenic synthetic peptide substrates, the amydolytic activities of XIIa, plasma kallikrein and Xa activated with RVV were inhibited by the addition of urinastatin to the reaction mixtures. 3) Activated partial thromboplastin time of normal plasma was prolonged by the addition of urinastatin or heparin, and simultaneous application of both urinastatin and heparin to the reaction mixture resulted in an additional inhibitory effect on APTT. Therefore, it was assumed that the different molecular structures of the clotting factors were concerned with the inhibitory actions of urinastatin and antithrombin III. Furthermore, urinastatin was indicated to have an important role in antithrombotic remedy, since it has no inhibitory action against protein C. 4) In the comparison with purified human plasmin and plasma plasmin activated with streptokinase, the strong inhibitory action of urinastatin on purified plasmin was demonstrated, but the inhibitory action of urinastatin was decreased markedly in plasma. Therefore, it is suggested that plasma may contain an inhibitory factor against the action of urinastatin.

Antithrombin III↗
PubMed2005

Characterization and differentiation-dependent regulation of secreted phospholipases A in human keratinocytes and in healthy and psoriatic human skin.

Secreted phospholipases A2 (sPLA2) expressed in the skin are thought to be involved in epidermal barrier homeostasis as well as in inflammation. We investigated the expression of the novel sPLA2 subtypes in human skin at mRNA and protein levels in the epidermis and primary keratinocytes from healthy human skin, and in skin sections from patients with psoriasis, where the integrity of the epidermis is drastically affected. Immunofluorescence studies using specific antibodies for the different sPLA2 enzymes show that sPLA2-IB, -IIF, and -X are predominantly expressed in suprabasal layers, whereas sPLA2-V and -IID are detected in the basal and spinous layers. sPLA2-IIA is weakly expressed, and sPLA2-IIE and XIIA are not detectable. Accordingly, in differentiated human primary keratinocyte cultures, the expression of sPLA2-IB, -IIF and -X was increased, whereas that of sPLA2-V and -IID was markedly decreased. In psoriatic skin, sPLA2-X was dramatically downregulated in the epidermis, whereas increased amounts of this enzyme together with sPLA2-IIA, -IID, and -IB appeared in the dermis. An enhanced release of these enzymes with the exception of sPLA2-IID was also observed after treatment of HaCaT keratinocytes with tumor necrosis factor-alpha/interferon-gamma. Treatment of HaCaT cells with sPLA2-X and -IB resulted in an increase in prostaglandin E2 formation, suggesting a proinflammatory role of these enzymes during psoriasis. sPLA2-V completely disappeared. The differential locations of the sPLA2 enzymes propose distinct roles of individual enzymes in skin.

Biopsy↗
PubMed2006

Intracellular actions of group IIA secreted phospholipase A2 and group IVA cytosolic phospholipase A2 contribute to arachidonic acid release and prostaglandin production in rat gastric mucosal cells and transfected human embryonic kidney cells.

Gastric epithelial cells liberate prostaglandin E(2) in response to cytokines as part of the process of healing of gastric lesions. Treatment of the rat gastric epithelial cell line RGM1 with transforming growth factor-alpha and interleukin-1beta leads to synergistic release of arachidonate and production of prostaglandin E(2). Results with highly specific and potent phospholipase A(2) inhibitors and with small interfering RNA show that cytosolic phospholipase A(2)-alpha and group IIA secreted phospholipase A(2) contribute to arachidonate release from cytokine-stimulated RGM1 cells. In the late phase of arachidonate release, group IIA secreted phospholipase A(2) is induced (detected at the mRNA and protein levels), and the action of cytosolic phospholipase A(2)-alpha is required for this induction. Results with RGM1 cells and group IIA secreted phospholipase A(2)-transfected HEK293 cells show that the group IIA phospholipase acts prior to externalization from the cells. RGM1 cells also express group XIIA secreted phospholipase A(2), but this enzyme is not regulated by cytokines nor does it contribute to arachidonate release. The other eight secreted phospholipases A(2) were not detected in RGM1 cells at the mRNA level. These results clearly show that cytosolic and group IIA secreted phospholipases A(2) work together to liberate arachidonate from RGM1 cell phospholipids in response to cytokines.

Animals↗