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PubMed1987

Plasma kallikrein-kinin system in patients with uncomplicated sepsis and septic shock--comparison with cardiogenic shock.

Alterations of the kallikrein-kinin system consistent with activation and increased consumption have been reported in septic patients and it has been suggested that this activation could contribute to the development of septic shock. The aim of this work was to confirm these alterations in septic patients and to investigate the possible existence of similar changes in subjects developing cardiogenic shock secondary to myocardial infarction as a model of non septic shock. Patients with septic shock, especially in fatal cases, showed a highly significant decrease in levels of factor XII, prekallikrein, high molecular weight kininogen (HMW-kininogen), alpha 2-macroglobulin (alpha 2-M) and antithrombin III (AT-III). C1-esterase inhibitor (C1-INH) activity was increased in uncomplicated sepsis but came back to normal or was slightly decreased in septic shock. Components and inhibitors of the kallikrein-kinin system were within normal limits in patients with cardiogenic shock. Our findings support the idea of a contribution of the kallikrein-kinin system to the development of septic shock though this system does not seem to play a significant role in the pathogenesis of cardiogenic shock or seem to be altered as a consequence of it.

Adolescent↗
PubMed1998

Effect of C1 inhibitor on inflammatory and physiologic response patterns in primates suffering from lethal septic shock.

We evaluated the effect of C1 inhibitor (C1-inh), an inhibitor of the classical pathway of complement and the contact system, on the physiologic and inflammatory response in baboons suffering from lethal Escherichia coli sepsis. Five animals pretreated with 500 U/kg C1-inh (treatment group; n = 5), followed by a 9-h continuous infusion of 200 U/kg C1-inh subsequent to bacterial challenge, were compared with five controls receiving E. coli alone. Of the treatment group, one animal survived and another lived beyond 48 h, whereas all control animals died within 27 h. In four of five treated animals, less severe pathology was observed in various target organs. C1-inh administration did not prevent the hemodynamic or hematologic changes observed upon E. coli infusion. The activation of fibrinolysis and the development of disseminated intravascular coagulation were essentially unaffected by C1-inh. However, C1-inh supplementation significantly reduced decreases in plasma levels of factor XII and prekallikrein and abrogated the systemic appearance of C4b/c, indicating substantial inhibition of activation of the contact system and the classical complement pathway, respectively. Furthermore, treated animals displayed a reduced elaboration of various cytokines including TNF, IL-10, IL-6, and IL-8. Thus, the administration of C1-inh may have a beneficial but modest effect on the clinical course and outcome of severe sepsis in nonhuman primates. We suggest that activated complement and/or contact system proteases may, at least in part, contribute to the attendant manifestations of septic shock through an augmentation of the cytokine response.

Animals↗
PubMed1987

Organization of the fibronectin gene provides evidence for exon shuffling during evolution.

We report the organization of the two ends of the rat fibronectin gene which encode the type I and II repeating units of the protein. We show that each of these modular structural units is encoded by a separate exon. Homologous type I and II repeats are known to occur in tissue plasminogen activator, factor XII and a bovine seminal plasma protein. Comparison of these sequences and the exon structures of the fibronectin and tissue plasminogen activator genes indicates that exons encoding type I and type II repeats have reassorted during evolution. We also report analyses of the extreme 5' and 3' ends of the fibronectin gene including the promoter region and the exon encoding the prepro sequence of fibronectin and we show that the gene is transcribed from a single initiation site to a single polyadenylation site. These data provide information pertinent to the transcriptional regulation of the gene, the alternative splicing of the primary transcript and the structure of the primary translation product.

Amino Acid Sequence↗
PubMed1994

Assembly of contact-phase factors on the surface of the human neutrophil membrane.

H-kininogen (HK), a major factor involved in contact-phase activation, was recently immunolocalized on the external surface of human neutrophils. Experiments were, therefore, designed to consider the question of whether the complete assembly of contact factors occurs on the outer surface of the neutrophil membrane. By immunolocalization techniques, and using specific antibodies directed against the various contact factors, we now demonstrate that plasma prekallikrein (PK), factor XI (FXI), and factor XII (FXII) are present on the exterior face of the human neutrophil. Failure to localize HK, PK, or FXI by monoclonal antibodies directed to their reciprocal binding sites, and displacement of PK/FXI by peptide HK31, which mimics the relevant binding site(s) of HK, suggested that prekallikrein and FXI are anchored to the neutrophil membrane through attachment to the kininogen molecule. Probing of the kinin moiety by a specific antibody showed that kininogen molecules bound to the neutrophil cell membrane contain the kinin sequence, which can be released by plasma kallikrein or by tissue kallikrein. Our results led us to the novel conclusion that neutrophils provide a circulating platform for the components of the contact-phase system.

Cell Membrane↗
PubMed1998

Effect of neurotropin on the binding of high molecular weight kininogen and Hageman factor to human umbilical vein endothelial cells and the autoactivation of bound Hageman factor.

Bradykinin is generated by activation of the plasma kallikrein-kinin (K-K) cascade and contributes to the symptoms of allergic reactions and the perception of pain. Neurotropin is a biological material obtained from inflamed rabbit skin inoculated with vaccinia virus, which is widely used clinically in Japan as an effective agent for these disorders. Factor XII (FXII) and high molecular weight kininogen (HK), two critical constituents of the plasma K-K cascade, bind to endothelial cells, and bound FXII is autoactivated in the presence of zinc ions. We have investigated the effects of Neurotropin on the interactions of FXII and HK with endothelial cells. Neurotropin inhibited the binding of both proteins to cultured human umbilical vein endothelial cells (HUVEC) and inhibited autoactivation of FXII upon HUVEC in a concentration-dependent manner. These data suggest that the ameliorating effects of Neurotropin in allergic disorders and pain syndromes may be related to this ability to inhibit activation of the K-K cascade and, consequently, the formation of bradykinin.

Binding, Competitive↗
PubMed1994

Activation of the coagulation cascade in severe falciparum malaria through the intrinsic pathway.

The mechanisms involved in the activation of the coagulation cascade in severe falciparum malaria were studied in 22 adult patients (19 male, three female) aged 18-45 (mean +/- SD 31 +/- 11) years. Of these, nine had multiple vital organ dysfunction, and bleeding occurred in four patients, two of whom died. During acute illness the reduction in plasma antithrombin III (AT III) concentrations and elevation in thrombin-AT III complexes were associated with significant reductions in factor XII and prekallikrein activities, and an increase in the C1 inhibitor antigen/activity ratio. Serial plasminogen activity remained within the normal range in all patients while protein C activity was significantly reduced. All patients had markedly elevated plasma polymorphonuclear leucocyte elastase (PMN-elastase) levels with mild depletion of alpha-2 macroglobulin but normal concentrations of alpha-1 antitrypsin. There was no correlation between PMN-elastase concentrations and any of the coagulation parameters or concentrations of proteinase inhibitors. These results suggest that the intrinsic pathway of the clotting cascade is activated in severe malaria. This may cause activation of the complement system and release of bradykinin and PMN-elastase and could contribute to the pathogenesis of severe malaria.

Adolescent↗
PubMed1976

Procoagulant and platelet aggregating properties of antilymphocyte sera.

Ten anti-human lymphocyte sera in clinical use at six transplant centers and five anti-nonhuman lymphocyte sera were studied for their procoagulant and platelet-aggregating properties. This investigation was initiated following the observation of a clinical episode of renal artery thrombosis, associated with the use of one of the sera in a patient who had received a cadaveric renal transplant. The procoagulant from this serum shortened the clotting times of individual samples deficient, respectively, in factors XII, XI IX, X VIII, and VII. Esterolytic activity, demonstrated on the substrate benzoylarginine ethyl ester, was completely inhibited by phenylmethylsulfonyl fluoride, but coagulant activity was variably affected. The platelet-aggregating activity (PAA) has been identified as a complement-fixing gamma G antibody that was absorbed from the antilymphocyte serum (ALS) with human spleen lymphocytes. Five of the ten anti-human lymphocyte sera showed varying procoagulant activity (PCA), and six sera demonstrated PAA. Three sera contained both activities. The presence of both PCA and PAA in the same preparation may predispose patients to thrombotic events, particularly if administered intravenously. Sera should be screened for PCA and PAA prior to clinical use, and sera with these properties should be used with caution.

Animals↗
PubMed1999

Correlation between coronary morphology and molecular markers of fibrinolysis in unstable angina pectoris.

BACKGROUND: In acute coronary syndromes, marked alterations of coagulation and fibrinolysis have been observed, but no data are available concerning a possible relation to coronary stenosis morphology. METHODS: Thirty one patients with unstable angina pectoris were included. Culprit stenosis morphology judged from coronary angiography was graded using the modified ACC/AHA classification. Molecular and functional markers of hemostasis and fibrinolysis were determined from venous plasma samples obtained at admission. RESULTS: Patients with unstable angina pectoris had a moderate procoagulant state, especially a contact phase activation compared with age-matched controls (factor XII 93.9 +/- 5.6 vs 112.8 +/- 5.4%; P < 0.05; high molecular weight kininogen 55.3 +/- 5.4 vs 86.1 +/- 6.5%; P < 0.01). Thrombin-antithrombin (TAT) was not significantly elevated (7.6 +/- 1.9 vs 4.0 +/- 0.5 microg/l). Elevated plasminogen activator mass concentration (16.6 +/- 2.1 vs 5.4 +/- 0.6 ng/ml; P < 0.01) and plasminogen activator inhibitor (PAI) activity (9.9 +/- 3.0 vs 5.6 +/- 3.0 AU/ml; P < 0.05) indicated an alteration of the fibrinolysis. Complexity of coronary stenosis was positively correlated with tissue-type plasminogen activator (TPA) mass concentration (P < 0.01) and PAI activity (P < 0.05). No association was found to markers of a hypercoagulative state. CONCLUSION: These findings indicate a relation between alterations of the fibrinolytic system and coronary morphology, whereas the acute changes of coagulation occur independently of culprit stenosis complexity.

Adult↗
PubMed1975

Evaluation of the plasma kinin system in dengue hemorrhagic fever.

The role of the plasma kinin system in the pathogenesis of dengue hemorrhagic fever (DHF) ws explored by simultaneously measuring factor XLL (Hageman), prekallikrein, kallikrein inhibitors, bradykinin, and complement (C3) in the blood of Thai children with DHF and acute febrile illnesses other than dengue. Prekallikrein, factor XII, and C3 levels were significantly lower in DHF patients compared to fever control patients with the lowest mean levels found in dengue patients with shock. However, bradykinin concentrations were not elevated and mean activity levels of kallikrein inhibitors were not depressed in dengue patients. Two dengue patients first studies at least 2 days before onset of shock had falling C3 levels which were more closely related temporally to the onset of shock than were their rising levels of prekallikrein. The results fail to provide convincing evidence ofr activation of the plasma kinin system leading to free bradykinin or a significant role for bradykinin in the immunopathogenesis of DHF. By contrast, the results refocus attention on complement as a potentially important humoral mediator of the dengue shock syndrome.

Antigens, Viral↗
PubMed1982

Oral contraceptives and fibrinolysis among female cyclists before and after exercise.

The effect of oral contraceptives on a number of plasma fibrinolytic variables and antithrombin III was studied in 20 highly trained women before and immediately after exhaustive exercise on a bicycle ergometer. Two groups were studied, 11 women using an oral contraceptive agent (OCA group) and 9 women not using an oral contraceptive (control group). Factor XII, prekallikrein, plasminogen, alpha 2-antiplasmin, and antithrombin III activities were determined in plasma as well as a number of cardiovascular, respiratory, and metabolic components. Resting values showed a significantly higher level of prekallikrein and plasminogen in the OCA group compared with the control group. Exercise plasma values of components of the fibrinolytic system were significantly higher than resting values in both groups. However, when corrected for plasma volume changes, the exercise levels of prekallikrein and antithrombin III were significantly decreased in the OCA group only, whereas alpha 2-antiplasmin exercise level was significantly lower in both groups. Our results indicate that use of OCA even with an estrogen dosage as low as 30 micrograms has an effect on resting and exercise fibrinolytic variables; an effect, however, which does not seem to interfere with maximal performance in trained women.

Adolescent↗
PubMed1989

Effect of human mast cell tryptase on human plasma proenzymes.

The effect of human skin mast cell tryptase on human plasma proenzymes (prothrombin, coagulation factor XII, complement C1s, protein C and plasminogen) was investigated. Tryptase had no effect on these proenzymes, when incubated with them at 37 degrees C for up to 90 min, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by the ability to hydrolyze specific peptide p-nitroanilide substrates. After prolonged treatment with tryptase, proenzymes could be fully activated with their specific activators. The results indicate that tryptase neither activates these plasma proenzymes nor inactivates the corresponding active enzymes. As a positive control, the tryptase preparation was also incubated with human fibrinogen and rat thymus histones. Prolonged treatment with tryptase increased the thrombin-induced clotting time of fibrinogen. Tryptase also efficiently hydrolyzed histone H1 from rat thymus. Histones H3/H2B and H2A were hydrolyzed less efficiently than H1, and no hydrolysis of histone H4 by tryptase was detected under the experimental conditions.

Animals↗
PubMed1982

Plasma arginine esterase in cystic fibrosis: kinetics of activation, identification as plasma kallikrein, reaction with alpha 2-macroglobulin and comparison with levels in normal plasma.

Treatment of normal plasma with chloroform and ellagic acid yielded esterase activity against tosylarginine methyl ester, which reached a maximum within 2 h. After 2 h most or all of the activity as resistant to inhibition by soybean trypsin inhibitor (STI), but was still sensitive to the low molecular weight inhibitors di-isopropyl fluorophosphate, aprotinin and prolyl-phenylalanyl-arginyl chloromethane. The activity ran in gel chromatography with alpha 2 macroglobulin (ampha 2M), as if it were due to an alpha 2M proteinase complex. The generation of the arginine esterase activity by chloroform and ellagic acid was apparently dependent on the activation of factor XII, being blocked by Polybrene. In plasma pretreated with methylamine-HCl (an inactivator of alpha 2M), the arginine esterase was 95% sensitive to inhibition by STI. With regard to substrate specificity, inhibition characteristics, and gel chromatographic behaviour, it was indistinguishable from plasma kallikrein (EC 3.4.21.34, formerly 3.4.21.8). The chloroform and ellagic acid treatment of plasma resulted in a disappearance of prokallikrein simultaneous with the appearance of the arginine esterase. By these criteria, the arginine esterase activity was attributable entirely to plasma kallikrein either in its free form (methylamine-treated plasma) or bound to alpha 2M (buffer-treated plasma). Comparisons of STI-sensitive and STI-resistant arginine esterase activities of plasma samples from cystic fibrosis patients, obligate heterozyotes or other groups showed no significant differences in levels of activity, kinetics of activation or gel chromatographic behaviour. We conclude that cystic fibrosis is unrelated to any abnormality in plasma arginine esterase activity, contrary to some previous reports.

Carboxylic Ester Hydrolases↗
PubMed1999

Platelet glycoprotein Ib: a zinc-dependent binding protein for the heavy chain of high-molecular-weight kininogen.

Domains 3 and 5 of high-molecular-weight kininogen (HK) have been shown to bind to platelets in a zinc-dependent reaction. However, the platelet-binding proteins responsible for this interaction have not been identified. We have focused on the platelet-binding site for the heavy chain (domain 3), which we approached using a domain 3-derived peptide ligand and isolated binding proteins by affinity chromatography. The domain 3-derived peptide, thrombin, HK, factor XII, as well as antibody to glycocalicin (the N-terminal portion of the alpha chain of GPIb) recognized a protein at 74 kD. We also isolated the thrombin receptor (PAR 1) at 45 kD, however, none of the above-mentioned ligands bound to this protein. Isolation of platelet membrane proteins using a monoclonal anti-glycocalicin antibody column revealed the same HK binding protein at 74 kD, which was reactive with anti-GPIb and represents a GPIb fragment. By photoaffinity labeling, HK interacted with membrane GPIb, which was then isolated in native form (135 kD) along with gC1qR, a ligand for the HK light chain. Finally, (125)I-HK binding to platelets was significantly inhibited by the anti-GPIb antibody. These results suggest that the GPIb alpha chain, a known thrombin binding protein, is also one of the zinc-dependent platelet membrane binding sites for HK domain 3.

Antibodies↗
PubMed1974

Immunochemical studies of plasma kallikrein.

A monospecific antibody against human plasma kallikrein has been prepared in rabbits with kallikrein further purified to remove gamma globulins. The antisera produced contained antikallikrein and also anti-IgG, in spite of only 8% contamination of kallikrein preparation with IgG. The latter antibody was removed by adsorption of antisera with either Fletcher factor-deficient plasma or with purified IgG. Both kallikrein and prekallikrein (in plasma) cross-react with the antibody with no apparent difference between the precipitation arcs developed during immunoelectrophoresis and no significant difference in reactivity when quantified by radial immunodiffusion. Kallikrein antibody partially inhibits the esterolytic and fully inhibits the proteolytic activity of kallikrein. In addition, the antibody inhibits the activation of prekallikrein, as measured by esterase or kinin release. The magnitude of the inhibition is related to the molecular weight of the activator used. Thus, for the four activators tested, the greatest inhibition is observed with kaolin and factor XII(A), while large activator and the low molecular weight prekallikrein activators are less inhibited. With the kallikrein antibody, the incubation of kallikrein with either plasma or partially purified C1 esterase inactivator results in a new precipitin arc, as detected by immunoelectrophoresis. This finding provides physical evidence for the interaction of the enzyme and inhibitor. No new arc could be demonstrated between kallikrein and alpha(2)-macroglobulin, or alpha(1)-antitrypsin, although the concentration of free kallikrein antigen decreases after interaction with the former inhibitor. By radial immunodiffusion, plasma from healthy individuals contained 103+/-13 mug/ml prekallikrein antigen. Although in mild liver disease, functional and immunologic kallikrein are proportionally depressed, the levels of prekallikrein antigen in plasma samples from patients with severe liver disease remains 40% of normal, while the functional kallikrein activity was about 8%. These observations suggest that the livers of these patients have synthesized a proenzyme that cannot be converted to active kallikrein.

Animals↗
PubMed2000

Plasma contact system, kallikrein-kinin system and antiphospholipid-protein antibodies in thrombosis and pregnancy.

Coagulation factor XII, prekallikrein and high molecular weight kininogen are known as plasma contact proteins in the intrinsic pathway of blood coagulation. Deficiencies of these proteins are not associated with clinical bleeding despite marked prolongation of in vitro surface-activated coagulation time. Paradoxically, studies suggest that these proteins have anticoagulant and profibrinolytic activities. In fact, association between deficiencies of these proteins as well as recurrent thrombosis has been reported. Also deficiencies of these proteins and antiphospholipid antibodies are frequent haemostasis-related abnormalities found in unexplained recurrent aborters. Recently, evidence has accumulated for the presence of the kallikrein-kinin system or plasma contact system in the fetoplacental unit. This suggests that the plasma contact system may also have an important role in pregnancy. Several studies have reported the presence of autoantibodies to the contact proteins in patients with SLE, thrombosis and recurrent pregnancy loss. These autoantibodies are often in association with antiphospholipid antibodies and lupus anticoagulants. Contact proteins may be added to the list of proteins to which autoantibodies are produced in patients assigned to antiphospholipid antibody syndrome.

Abortion, Spontaneous↗
PubMed1984

Reduced cofactor function of human high molecular weight kininogen induced by human plasma kallikrein.

Most reports in the literature state that human plasma kallikrein does not destroy the capacity of human high molecular weight kininogen (HMrK) to function as a cofactor in the contact phase activation of factor XII. In the present work preparations of highly purified human plasma kallikrein that showed high plasminogen activator (PGA) activities rapidly reduced the cofactor function of human HMrK. Gel electrophoresis with SDS without reduction showed that all kallikrein preparations tested contained two protein bands, one major band with a Mr of about 83,000, and one weak band with a Mr of 80,000. The main band is probably identical with kallikrein I, which Levison & Tomalin (1982b), using Ac-Pro-Phe-Arg-OMe-HCl as substrate, found to be ten times more active (in terms of kcat/Km) than kallikrein II with Mr 3000 daltons lower. The rate of HMrK destruction in our experiments varied with the kallikrein preparation used, but assays of their hydrolytic activities against benzoyl arginine ethylester (BAEe) or the plasma kallikrein selective tripeptide substrate H-D-Pro-Phe-Arg-pNA (S-2302) did not discriminate between enzyme preparations with different HMrK-destroying capacities. Assay of PGA activities demonstrated a correlation between the level of PGA measured, and the HMrK-destroying capacity.

Carboxylic Ester Hydrolases↗
PubMed1981

Effect of surfaces on fluid-phase prekallikrein activation.

The activation of prekallikrein by factor XII fragments (XIIf), during incubation in plastic tubes was previously noted to be increased by high molecular weight (HMW) kininogen as well as other plasma proteins. In this report, we investigated the mechanism responsible for this increase. Although we confirmed that HMW kininogen, bovine serum albumin, fibrinogen, cold insoluble globulin, and mixed phospholipids apparently increased prekallikrein activation, we found that the product of prekallikrein activation (kallikrein) lost substantial activity in less than 0.5 min after exposure to a variety of fresh surfaces. This loss was partially prevented by the presence of various proteins and phospholipids. Similar protection against inactivation of XIIf, the enzyme in this reaction, was also found. In contrast, no loss of the substrate, prekallikrein, was observed during incubation. The loss of kallikrein activity was found to be proportional to the surface area of the incubation vessel as well as the concentration of kallikrein. Further loss of kallikrein activity could also be prevented by pretreating the vessel with kallikrein. We therefore conclude that various substances apparently affect prekallikrein activation in a purified system by preventing the enzyme and product in the reaction mixture from losing activity due to adsorption to a surface.

Adsorption↗
PubMed1986

Behaviour of the contact phase of blood coagulation in the adult respiratory distress syndrome (ARDS).

In order to assess the role of the kallikrein-kinin (K-K) system in the pathogenesis of the adult respiratory distress syndrome (ARDS) we have prospectively determined coagulation contact phase, blood gas and hemodynamic parameters in patients with ARDS at 0, 36 and 72 h from diagnosis. Compared to normal values, significantly lower mean levels of factor XII (71.4 +/- 9.8%, p less than 0.0005), prekallikrein (PPK) (52 +/- 5.7%, p less than 0.0005), high molecular weight kininogen (HMWK) (73 +/- 2%, p less than 0.0005) and alpha 2-macroglobulin (alpha 2-M) (51 +/- 7.1%, p less than 0.0005) were found in ARDS patients. The functional kallikrein inhibitory activity (KKI) and C1-esterase inhibitor antigenic (CIINH) were significantly higher in these patients (113.2 +/- 5, p less than 0.005 and 124.7 +/- 7.6, p less than 0.0005 respectively) compared with normal values during the entire study period. The KKI/CIINH ratio decreased significantly in our ARDS patients at 0, 36 and 72 h (p less than 0.025; p less than 0.05 and p less than 0.005 respectively). We found a significant correlation between PPK levels and oxygenation index (r = 0.69, p less than 0.001), PPK and the static thoracic compliance values (r = 0.64, p less than 0.001). There was also a significant correlation between PPK levels and Qs/Qt (r = -0.89, p less than 0.001). ARDS patients that survived presented a stability in the PPK values in successive tests. Nevertheless non-survivors showed a progressive decrease in PPK levels during the follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗