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PubMed1986

Mechanism of activation of coagulation factor XI by factor XIIa studied with monoclonal antibodies.

The interaction of Factor XIIa with Factor XI was investigated using two monoclonal antibodies, one (3Cl) directed against the heavy chain of Factor XIa and the other (5F4) against its light chain. 3C1 either as intact IgG or as Fab' fragment, enhanced the rate of Factor XIa generation in the fluid phase but inhibited it in the presence of kaolin and high molecular weight (HMW) kininogen. In contrast, the Fab' fragments of 5F4 inhibited only the fluid phase activation and had no effect on the surface-mediated activation. 3C1 was found to block the binding of Factor XI to HMW kininogen, whereas 5F4 did not. We conclude: a domain on the heavy chain region of Factor XI is essential for binding to HMW kininogen and for optimal surface-mediated activation by Factor XIIa; and binding of 3C1 to Factor XI changes its conformation rendering it a more favorable substrate for Factor XIIa in the fluid phase.

Antibodies, Monoclonal↗
PubMed1989

The fibrinolytic system during short-term treatment with tenoxicam.

The effect of 20 mg tenoxicam once daily for 7 days on various components of the fibrinolytic system was studied in 10 healthy volunteers. Plasma plasminogen, antithrombin 3, and prekallikrein decreased significantly while plasma plasminogen activator inhibitor increased significantly. The medication did not affect fibrin plate lysis area or the plasma level of plasminogen activator, alpha-2-antiplasmin, alpha-2-macroglobulin, C1 inactivator or Factor XII. It is suggested that these changes may be caused by interference with hepatic enzyme systems. The reduction in plasma prekallikrein may indicate that tenoxicam exerts its anti-inflammatory effect by more than one mechanism.

Adult↗
PubMed1989

Kaolin-induced writhing response in mice: activation of the plasma kallikrein-kinin system by kaolin.

A mechanism of writhing reaction induced by kaolin, a known activator of factor XII, was studied. Kaolin induced a distinct writhing response, when injected intraperitoneally into mice (2.5 mg/mouse). The response disappeared in 15 min, but it was reproduced by intraperitoneal injection of captopril, 20 micrograms, into mice who had received the injection of kaolin 60 min before. This later response as well as the early one was not produced when mice were pretreated with bromelain (10 mg/kg, intravenously), 30 min before the kaolin administration. Therefore we determined if bromelain, a known depleter of plasma prekallikrein and a high molecular weight (HMW) kininogen, depletes those in mice. Plasma was collected from mice with or without pretreatment of bromelain, and kinin release of these plasma samples was examined by action of kaolin. The bromelain-treated mouse plasma released kinin amount of less than detection limit when activated with kaolin, whereas normal plasma released about 300 ng/ml of kinin of bradykinin equivalent as assessed by rat uterus contraction. Furthermore, activation of prekallikrein by kaolin was observed in mouse plasma as amidase activity to produce fluorescence from the synthetic substrate. It was completely diminished in the presence of soybean trypsin inhibitor. These results suggest that bromelain could deplete the HMW-kininogen in mouse plasma in the same way as in rat plasma. Furthermore, it is assumed that the kinin released from HMW-kininogen by kaolin could be responsible for inducing the writhing response.

Animals↗
PubMed1990

Enhancement of clot formation of human plasma by beta-glucans.

Effects of (1----3)-beta-D-glucans on clot formation of human plasma were examined. Gel forming 6 branched (1----3)-beta-D-glucans, SSG, branched at every other main chain glucosyl unit, grifolan (GRN) and schizophyllan, branched at one third of main chain glucosyl unit, enhanced clot formation of human plasma. GRN derivatives also increased the contents of clot, but less effectively than GRN. This effect was dependent on dose, molecular weight (greater than 20K), side chain (branching), and ultrastructure (single chain conformer) of the beta-glucans. It may be important for the mechanism of (1----3)-beta-D-glucan induced enhancement of plasma clotting to activate factor XII, to bind with fibrinogen, and to increase the local concentration of the clotting system by steric exclusion.

Antibiotics, Antineoplastic↗
PubMed1992

Pulmonary sequelae of intraparenchymal bismuth subgallate.

Bismuth subgallate (BSG) is a heavy metal compound which is effective in lowering the incidence of hemorrhage after adenotonsillectomy and has been demonstrated to activate Factor XII. In a minority of children, the paste has been suctioned from the cuffless oral endotracheal tube after adenotonsillectomy. No pulmonary sequelae have been noted in these patients. To assess the effect of BSG aspiration, 75 rats were divided into groups receiving either intratracheal BSG or saline. Early and late parenchymal effects were documented at 5 and 30 days following administration. Although there were no differences in the general well-being, activity level, or weight in these rats, acute pneumonia followed by a histiocytic, foreign-body response was noted in a significant number of rats in the BSG group. Although no clinical pulmonary sequelae of BSG use have been noted in our patients, this information should alert clinicians to the risks of BSG use in the pulmonary-compromised patient, and encourage them to either employ all methods of preventing aspiration in such patients when using BSG, or to use another hemostatic modality for the utmost safety.

Animals↗
PubMed2001

Increase of bradykinin in plasma of patients undergoing cardiopulmonary bypass: the importance of lung exclusion.

STUDY OBJECTIVES: Hemodynamic complications including hypotensive episodes are frequently associated with cardiopulmonary bypass (CPB) and can be attributed to a generalized inflammatory response in which bradykinin may be a mediator. The purpose of this study was to determine the plasma levels of bradykinin-(1-9)nonapeptide in patients during CPB and the physiologic elimination of bradykinin by the lungs. DESIGN: Prospective, observational study. SETTING: University hospital, cardiac surgery unit. PATIENTS AND METHODS: Intra-arterial BP was monitored and serial blood samples were obtained from 27 patients undergoing CPB for cardiac surgery. We measured plasma bradykinin and parameters of coagulation, fibrinolysis, complement, contact system, and the cytokine tumor necrosis factor (TNF). RESULTS: Mean arterial pressure fell progressively until the end of CPB (- 18 mm Hg, p = 0.001) but returned to baseline by the end of surgery. The venous bradykinin level, normal in basal conditions (median, 1.90 fmol/mL), was increased (p = 0.001) from 15 min after the beginning of CPB (5.71 fmol/mL) to the end of the operation (7.07 fmol/mL), with a peak at the end of CPB (9.81 fmol/mL; p = 0.0001); it was normal at recovery 24 h later (2.81 fmol/mL). Bradykinin plasma levels fell 60% across the lung when the pulmonary circulation was fully restored while the patients were still receiving CPB. Activated-factor XII, thrombin-antithrombin complexes, prothrombin fragment F1 + 2, plasmin-antiplasmin complexes, C(3)a, and TNF increased significantly after the beginning of the surgical procedure, rising further during CPB, and remained elevated until the end of surgery, but they all returned to normal within 24 h. Changes in plasma bradykinin levels were not correlated with any of the other variables. CONCLUSIONS: During CPB, there is a progressive increase of plasma bradykinin that is at least partially due to reduced catabolism as a consequence of shunting the lungs. The increase in bradykinin may contribute to the fall in BP.

Aged↗
PubMed2001

Synthetic peptides and fluorogenic substrates related to the reactive site sequence of Kunitz-type inhibitors isolated from Bauhinia: interaction with human plasma kallikrein.

We have previously described Kunitz-type serine proteinase inhibitors purified from Bauhinia seeds. Human plasma kallikrein shows different susceptibility to those inhibitors. In this communication, we describe the interaction of human plasma kallikrein with fluorogenic and non-fluorogenic peptides based on the Bauhinia inhibitors' reactive site. The hydrolysis of the substrate based on the B. variegata inhibitor reactive site sequence, Abz-VVISALPRSVFIQ-EDDnp (Km 1.42 microM, kcat 0.06 s(-1), and kcat/Km 4.23 x 10(4) M(-1) s(-1)), is more favorable than that of Abz-VMIAALPRTMFIQ-EDDnp, related to the B. ungulata sequence (Km 0.43 microM, kcat 0.00017 s(-1), and kcat/Km 3.9 x 10(2) M(-1) s(-1)). Human plasma kallikrein does not hydrolyze the substrates Abz-RPGLPVRFESPL-EDDnp and Abz-FESPLRINIIKE-EDDnp based on the B. bauhinioides inhibitor reactive site sequence, the most effective inhibitor of the enzyme. These peptides are competitive inhibitors with Ki values in the nM range. The synthetic peptide containing 19 amino acids based on the B. bauhinioides inhibitor reactive site (RPGLPVRFESPL) is poorly cleaved by kallikrein. The given substrates are highly specific for trypsin and chymotrypsin hydrolysis. Other serine proteinases such as factor Xa, factor XII, thrombin and plasmin do not hydrolyze B. bauhinioides inhibitor related substrates.

Amino Acid Sequence↗
PubMed2006

Genetically altered animal models in the kallikrein-kinin system.

Transgenic and gene-targeting technologies allowing the generation of genetically altered animal models have greatly advanced our understanding of the function of specific genes. This is also true for the kallikrein-kinin system (KKS), in which some, but not yet all, components have been functionally characterized using such techniques. The first genetically altered animal model for a KKS component was supplied by nature, the brown Norway rat carrying an inactivating mutation in the kininogen gene. Mice deficient in tissue kallikrein, B1 and B2 receptors, some kinin-degrading enzymes, and factor XII followed, together with transgenic rat and mouse strains overexpressing tissue kallikrein, B1 and B2 receptors, and degrading enzymes. There are still no animal models with genetic alterations in plasma kallikrein, kininases I and some other degrading enzymes. The models have confirmed an important role of the KKS in cardiovascular pathology, inflammation, and pain, and have partially elucidated the distinct function of the two receptors. This created the basis for rational decisions concerning the putative use of kinin receptor agonists and antagonists in therapeutic applications. However, a more thorough analysis of the existing models and the generation of new, more sophisticated transgenic models will be necessary to clarify the still elusive issue as to where and by which mechanisms the kinins exert their actions.

Animals↗
PubMed1977

Consumptive coagulopathy as biochemical mechanism in oxygen toxicity and its enhancement by lead(II) ions.

Consumptive coagulopathy and disseminated intravascular coagulation can be observed in rats exposed to 4 ata of oxygen. These events clearly precede the death of the animal and appear to be initiated by an activation of coagulation factor XII (Hageman). The onset and the extent of consumptive coagulapathy are greatly enhanced by a single and low intravenous dose of lead acetate. Mechanisms of activation of the intrinsic coagulation system and its role in oxygen toxicity are being discussed.

Animals↗
PubMed2005

Type 2 diabetes: an atherothrombotic syndrome.

Insulin resistance is found in around 80-90% of subjects with older onset (type 2) diabetes and in approximately 25% of the general population. Insulin resistance prior to the development of frank type 2 diabetes and type 2 diabetes itself is associated with a significant increase in the risk of atherothrombotic disease, which is due in part to a disruption in the balance of factors regulating coagulation and fibrinolysis. Both insulin resistance and type 2 diabetes are associated with the development of endothelial dysfunction, and enhanced platelet aggregation and activation. Whilst the plasma levels of many clotting factors including fibrinogen, FVII, FVIII, FXII, FXIII b-subunit are elevated, the fibrinolytic system is relatively inhibited as a consequence of an increase in plasminogen activator inhibitor type-1 (PAI-1) levels. These changes favour the development of a hypercoagulable pro-thrombotic state, which may in turn enhance cardiovascular risk by increasing the likelihood of developing an occlusive thrombus within a coronary/cerebral artery, and/or contributing to the development of atherosclerotic lesions. This article reviews the current published evidence of the pro-thrombotic changes that occur in association with type 2 diabetes and insulin resistance, and the putative underlying mechanisms which lead to these changes.

Animals↗
PubMed2004

Novel human plasma proteins, IHRP (acute phase protein) and PHBP (serine protease), which bind to glycosaminoglycans.

A novel human plasma protein was found in the eluate from the dextran sulfate column, which was used for the treatment of the patients with hypercholesteremia to reduce plasma low density lipoprotein. The results of sequence analysis revealed that this protein was a homologue of heavy chains of inter-alpha-trypsin inhibitor (ITI) family, and it was termed IHRP (ITI family heavy chain related protein). IHRP was identified as an acute-phase protein in animals, and slightly increased concentrations in human plasmas were observed in the patients with inflammatory disorders. IHRP bound to actin and inhibited its polymerization, and IHRP suppressed the phagocytosis and chemotaxis of polymorphonuclear cells. These results suggest that IHRP may function as an anti-inflammatory protein. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which was also found in human plasma. It is consisted of three epidermal growth factor domains, one kringle domain and one serine protease domain from its amino terminus. The amino acid sequence of PHBP is homologous to that of hepatocyte growth factor activator. Purified 75-kDa single chain pro-form of PHBP was auto-activated (auto-cleaved) to 50-kDa heavy chain and 25-kDa light chain, both of them are bridged by a disulfied bond. PHBP digested alpha-chain and beta-chain of fibrinogen to prevent coagulation and cleaved single chain urokinase type plasminogen activator (scuPA) to the active hetero dimer form (tcuPA). The auto-activation of PHBP was accelerated in the presence of dextran sulfate or phosphatidylethanolamine as well as factor XII of the coagulation system. C1 inhibitor of the complement system was identified as the main inhibitor of PHBP in human plasma. Partial hepatectomy and administration of carbon tetrachloride or galactosamine caused the conversion of pro-PHBP to the active form in mouse but administrations of turpentine and mercury chloride did not, suggesting the hepatic injury specific activation of PHBP. These results indicate that PHBP participates not only in the fibrinolytic system but also in the degradation cascade of extracellular matrix (ECM), i.e., PHBP activates scuPA to tcuPA, tcuPA activates matrix metalloproteases (MMPs) and activated MMPs degrade ECM for the tissue remodeling after hepatic injury.

Amino Acid Sequence↗
PubMed2003

Potential pharmacological applications of the antithrombotic molecule high molecular weight kininogen.

During the past 20 years, the proteins of the "contact system", namely high molecular weight kininogen (HK), kallikrein and Factor XII have been shown to have very little direct impact on hemostasis despite their initial description as initiators of the "intrinsic system". In fact these proteins have rather anticoagulant and profibrinolytic properties. The focus of this review is to summarize the known antithrombotic properties of HK demonstrating its potential application for the novel therapeutic interventions against thromboembolic complications. In particular, HK can inhibit platelet aggregation, as (i) its domain 5 interferes with ligand binding of alphaIIbbeta3-integrins, (ii) its domain 3 blocks thrombin-dependent platelet aggregation by interfering with thrombin binding to the glycoprotein Ib-IX-V complex on platelets, (iii) bradykinin, which is derived upon cleavage of HK, blocks thrombin-induced platelet aggregation, and (iv) HK domain 2 can inhibit the function of platelet calpain. Moreover, HK may have profibrinolytic actions as it can (i) inhibit plasminogen activator inhibitor-1 function and (ii) potentiate prourokinase activation with subsequent pericellular plasmin formation. Indeed, patients lacking circulating HK are at increased risk for thrombosis, and a prothrombotic phenotype was reported for kininogen-deficient rats. All these observations render kininogen antithrombotic, rather than prothrombotic, and the ongoing research aims to develop novel kininogen-related antithrombotic therapies.

Animals↗
PubMed2006

Induction of vascular leakage and blood pressure lowering through kinin release by a serine proteinase from Aeromonas sobria.

Aeromonas sobria causes septic shock, a condition associated with high mortality. To study the mechanism of septic shock by A. sobria infection, we examined the vascular leakage (VL) activity of A. sobria serine proteinase (ASP), a serine proteinase secreted by this pathogen. Proteolytically active ASP induced VL mainly in a bradykinin (BK) B(2) receptor-, and partially in a histamine-H(1) receptor-dependent manner in guinea pig skin. The ASP VL activity peaked at 10 min to 1.8-fold of the initial activity with an increased BK B(2) receptor dependency, and attenuated almost completely within 30 min. ASP produced VL activity from human plasma apparently through kallikrein/kinin system activation, suggesting that ASP can generate kinin in humans. Consistent with the finding that a major part of the ASP-induced VL was reduced by a potent kallikrein inhibitor, soybean trypsin inhibitor that does not affect ASP enzymatic activity, ASP activated prekallikrein but not factor XII to generate kallikrein in a dose- and incubation time-dependent manner. ASP produced more VL activity directly from human low m.w. kininogen than high m.w. kininogen when both were used at their normal plasma concentrations. Intra-arterial injection of ASP into guinea pigs lowered blood pressure specifically via the BK B(2) receptor. These data suggest that ASP induces VL through prekallikrein activation and direct kinin release from kininogens, which is a previously undescribed mechanism of A. sobria virulence and could be associated with the induction of septic shock by infection with this bacterium. ASP-specific inhibitors, and kinin receptor antagonists, might prove useful for the treatment or prevention of this fatal disease.

Aeromonas↗
PubMed1999

[Hereditary or acquired angioedema caused by functional deficiency of C1 inhibitor--a still unfamiliar disease picture].

Hereditary angioneurotic oedema or hereditary angiooedema (HAE) and acquired angiooedema (AAE) are disorders of the C1-inhibitor (C1-INH) protein, caused by the lack, dysfunction or exhaustion of the C1-INH molecule. Inadequate function of C1-INH results in inappropriate control of various enzymes of the fibrinolytic, complement and kinin systems as well as of factor XII, being the initial enzyme of the kinin and contact coagulation systems. As C1-INH functional deficiency is rare and the clinical manifestation little known, even nowadays the most feared complication of the deficiency may evolve: death from acute airway obstruction. Patients deficient in C1-INH function whose clinical manifestations are misinterpreted as allergic angiooedema are most at risk for fatal laryngeal oedema. The therapy of allergic and C1-INH-related angiooedema is fundamentally different. The background for the hereditary form of inadequate C1-INH function is a gene defect. The predominant primary underlying disease of the acquired form of the deficiency (AAE) is a lymphoproliferative process.

Angioedema↗
PubMed1999

[The influence of the intra-tissue electrical phonophoresis on the hemostasis system in the treatment of acute thrombophlebitis and phlebothrombosis].

In 39 patients with an acute thrombophlebitis and phlebothrombosis there was established the hemostatic potency normalisation, the enzymic fibrinolytic activity of the blood plasm rising, the nonenzymic fibrin/fibrinogen lysis lowering, the plasminogen potential activity restoration and of the fibrinolysis intensity rising, caused by XII factor, under the influence of intratissue electrophonophoresis conduction using nicotinic acid, heparin and novocaine.

Acute Disease↗
PubMed2000

[Hypofibrinolysis and other hemostatic defects in women with antecedents of early reproductive failure].

The fibrinolytic system is involved in blood clot lysis and in other biological processes that require extracellular proteolysis such as ovulation, blastocyst implantation and trophoblastic invasion. An impaired fibrinolytic capacity is a common feature in women suffering from unexplained early recurrent pregnancy loss. We carried out a prospective study with 114 patients. Three groups were established: Group 1: women who had two or more unexplained miscarriages of < 12 weeks of gestation (n = 52). Group 2: women who had 2 or more embryo-implantation failure after embryo-transfer with good quality embryos in assisted reproduction (n = 46). Group 3: women who had 2 or more embryo-implantation failure after embryo-transfer and one early loss of a pregnancy achieved in a cycle of assisted reproduction (n = 16). Fibrinolytic pattern pre and post-occlusion test was carried out: ECLT, PAI-1i, PAI-1b, t-PAi, t-PAb. In addition other studies were performed: LAC, ACA IgG and IgM, fibrinogen, factor XII, APCR. A high prevalence of thrombophilic defects and hypofibrinolysis was observed in the three groups. The fibrinolytic pattern was similar in the three groups, although a prolonged pre occlusion ECLT was more frequent in women with primary infertility (Group 2). Isolated hypofibrinolysis was found in 50% of the patients. The remaining patients with hypofibrinolysis presented combined defects with LAC, ACA and abnormal APCR. The fibrinolytic pattern in women with or without antiphospholipid antibodies was similar, although an elevated pre occlusion PAI-1i was more common in women without antiphospholipid antibodies. High prevalence of fibrinolytic abnormalities observed in women with unexplained early recurrent pregnancy loss and in women with repeated failure implantation after embryo-transfer in assisted reproduction, suggests that hypofibrinolysis could be a parameter of early reproductive failure.

Abortion, Spontaneous↗
PubMed1975

Rheological properties of fibrin clots. Effects of fibrinogen concentration, Factor XIII deficiency, and Factor XIII inhibition.

The effect of fibrinogen concentration, Factor XIII deficiency, and Factor XIII inhibition, utilizing hydroxylamine, on the formation of clot structure in vitro was studied in human platelet-free plasma systems. Rheological and biochemical techniques were employed to relate changes in clot elasticity and viscosity to clot structure formation following recalcification of citrate anticoagulated samples. Classical theories of linear viscoelasticity for swollen crosslinked materials were shown to give an excellent estimate of the number of covalent crosslinks per fibrin monomer, which is directly attainable from rheological data. SDS gel electrophoresis was utilized to show qualitatively that decreases in maximum clot elasticity, at constant fibrinogen concentration, are directly related to a decrease in Factor XIII-mediated intermolecular crosslinking. The use of the technique to investigate both kinetic and equilibrium crosslinking (or structure formation) abnormalities in plasma systems is discussed.

Blood Coagulation↗