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At least 1,369 records · Page 76Linked to original sources
PubMed1982

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↗
PubMed1985

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↗
PubMed1994

An autoantibody to human plasma prekallikrein blocks activation of the contact system.

A patient without a history of bleeding or thromboembolism presented with an activated partial thromboplastin time (aPTT) of 55.1 s (normal 24-38 s). Incubation of the patient plasma with an equal volume of normal plasma failed to correct the aPTT, suggesting the presence of an inhibitor. The MRVVT (modified Russell Viper venom time) was normal, and the anti-cardiolipin antibody titres were not elevated, indicating that the presence of a lupus anticoagulant was unlikely. Plasma prekallikrein (PK) measured by a coagulant assay (2 U/dl) was very low, but PK was in the low normal range (approximately 65%) when measured by an enzymatic assay (amidolytic) or by an antigenic assay (ELISA). The purified patient IgG reacted with purified PK, the heavy chain, and the 28 kD fragment of the heavy chain, indicating that it contained an autoantibody to PK. The purified IgG did not directly inhibit the amidolytic activity of kallikrein, but it did inhibit the activation of PK to kallikrein by activated factor XII. Activation of the contact system by dextran sulphate, as reflected by the cleavage of HK on a Western blot, was inhibited when the patient IgG was added to pooled normal plasma. The antibody appears to be oligoclonal with IgG1 being most abundant, followed by IgG4. This report appears to be the first of a spontaneously occurring antibody to prekallikrein.

Autoantibodies↗
PubMed1987

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↗
PubMed1987

Studies on the effect of serine protease inhibitors on activated contact factors. Application in amidolytic assays for factor XIIa, plasma kallikrein and factor XIa.

Amidolytic assays have been developed to determine factor XIIa, factor XIa and plasma kallikrein in mixtures containing variable amounts of each enzyme. The commercially available chromogenic p-nitroanilide substrates Pro-Phe-Arg-NH-Np (S2302 or chromozym PK), Glp-Pro-Arg-NH-Np (S2366), Ile-Glu-(piperidyl)-Gly-Arg-NH-Np (S2337), and Ile-Glu-Gly-Arg-NH-Np (S2222) were tested for their suitability as substrates in these assays. The kinetic parameters for the conversion of S2302, S2222, S2337 and S2366 by beta factor XIIa, factor XIa and plasma kallikrein indicate that each active enzyme exhibits considerable activity towards a number of these substrates. This precludes direct quantification of the individual enzymes when large amounts of other activated contact factors are present. Several serine protease inhibitors have been tested for their ability to inhibit those contact factors selectively that may interfere with the factor tested for. Soybean trypsin inhibitor very efficiently inhibited kallikrein, inhibited factor XIa at moderate concentrations, but did not affect the amidolytic activity of factor XIIa. Therefore, this inhibitor can be used to abolish a kallikrein and factor XIa contribution in a factor XIIa assay. We also report the rate constants of inhibition of contact activation factors by three different chloromethyl ketones. D-Phe-Pro-Arg-CH2Cl was moderately active against contact factors (k = 2.2 X 10(3) M-1 s-1 at pH 8.3) but showed no differences in specifity. D-Phe-Phe-Arg-CH2Cl was a very efficient inhibitor of plasma kallikrein (k = 1.2 X 10(5) M-1 s-1 at pH 8.3) whereas it slowly inhibited factor XIIa (k = 1.4 X 10(3) M-1 s-1) and factor XIa (k = 0.11 X 10(3) M-1 s-1). Also Dns-Glu-Gly-Arg-CH2Cl was more reactive towards kallikrein (k = 1.6 X 10(4) M-1 s-1) than towards factor XIIa (k = 4.6 X 10(2) M-1 s-1) and factor XIa (k = 0.6 X 10(2) M-1 s-1). Since Phe-Phe-Arg-CH2Cl is highly specific for plasma kallikrein it can be used in a factor XIa assay selectively to inhibit kallikrein. Based on the catalytic efficiencies of chromogenic substrate conversion and the inhibition characteristics of serine protease inhibitors and chloromethyl ketones we were able to develop quantitative assays for factor XIIa, factor XIa and kallikrein in mixtures of contact activation factors.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Periodic painful purpura: fact or factitious?

A 60-year-old woman with multiple psychosocial issues presented with a history of spontaneous painful bruising on her left upper arm. Extensive investigations did not reveal any abnormality apart from an elevated activated partial thromboplastin time as a result of factor XII deficiency. An autoerythrocyte sensitization test reproduced the tender bruises on her back. Our patient reported relief of pain with promethazine injections. She was subsequently referred to the psychiatric team for ongoing assessment and management. Having an awareness of this rare condition will assist in the prevention of unnecessary investigation of such cases and will allow the early referral of patients for appropriate psychological counselling.

Diagnosis, Differential↗
PubMed2005

Stroke and pulmonary thromboembolism after a long flight.

In the economy class syndrome (ECS) the patient presents a deep venous thrombosis (DVT) with or without pulmonary thromboembolism (PTE) during or after a long trip as a result of prolonged immobilization. Economy class stroke syndrome is an infrequent ECS variant in which ischemic stroke is associated with a patent foramen ovale (PFO). Few cases have been published in the literature to date. We present a patient who suffered a PTE and an ischemic stroke immediately after a transoceanic flight. A 36-year-old woman with no significant medical or familial history flew economy class from Lima, Peru, to Madrid, Spain. On disembarkation she presented sudden dyspnea and a depressed level of consciousness, global aphasia, and right hemiparesis. A pulmonary scintigraphy showed a PTE and a cranial MRI revealed an ischemic infarct in the left middle cerebral artery territory. We simultaneously performed a transesophageal echocardiography and a transcranial Doppler and observed a massive right-to-left shunt through a PFO. The patient was a heterozygous carrier of the C46T mutation of coagulation factor XII. The appearance of a stroke following a long trip is suggestive of paradoxical embolism through a PFO, mainly if it is associated with a DVT and/or a PTE. The cause of the initial event, the DVT, could be a prothrombotic state.

Adult↗
PubMed1995

Effect of nafamostat mesilate on bradykinin generation and hemodynamics during LDL apheresis.

Dextran-sulfate (DS) cellulose used for low-density lipoprotein (LDL) apheresis seems to be a weak activator of the contact phase of the intrinsic coagulation pathway because the surface of this substance has negative charges. Heparin, a commonly used anticoagulant, has no effect on this process whereas the process is inhibited by a newly developed anticoagulant, nafamostat mesilate (NM). The effects on bradykinin generation were compared between heparin and NM. Five patients with severe hypercholesterolemia were treated with LDL apheresis using either heparin or NM on a different day. During apheresis with heparin, factor XII, high molecular weight kininogen, and prekallikrein were markedly decreased by passing through the DS column. A distinct generation of bradykinin was observed by passing plasma through the DS column, and this led to the rise of bradykinin levels from 12 +/- 5 (mean +/- SE) to 72 +/- 14 pg/ml after treatment of 1,000 ml of plasma. NM suppressed almost completely the rise of bradykinin levels. Although blood pressure was apt to decrease during apheresis with heparin, there was no significant difference in blood pressure between heparin and NM. Since an angiotensin-converting enzyme inhibitor may lead to a marked rise in blood levels of bradykinin by suppressing its degradation, the use of NM is recommended for apheresis in patients taking this drug.

Adolescent↗
PubMed1989

Thrombin and bradykinin enhance prostaglandin production in human peripheral blood monocytes.

Thrombin and bradykinin stimulate production of prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1 alpha (the stable breakdown product of prostacyclin) in isolated human peripheral blood monocytes in a dose- and time-dependent manner. Since PGE2 and prostacyclin can affect the activity of immunocompetent cells and bone resorbing osteoclasts, our finding indicates that thrombin and bradykinin, both of which are formed in inflammatory processes as a consequence of activation of the Hageman factor (coagulation factor XII), may have important roles in the modulation of the inflammatory response and the loss of alveolar bone in periodontitis.

Arachidonic Acids↗
PubMed1982

Dextran-induced lowering of plasminogen proactivator and functionally active high molecular weight kininogen in the rat.

Incubation of plasminogen-free rat citrated plasma with acetone (23% v/v) yielded enzyme preparations with high levels of plasminogen activator (PGA) and kininogenase (kallikrein), but with a low concentration of high molecular weight kininogen (HMWK) active as cofactor for kaolin-induced activation of factor XII. When benzamidine (4.0 mM) was present during acetone activation, a high yield of functionally active HMWK was obtained. Gel chromatography separated PGA into one high molecular weight fraction (HMW-PGA) without kininogenase and BAEe esterase activity, and one fraction (LMW-PGA) eluting together with plasma kallikrein. Injection of dextran (100 mg/kg intravenously) reduced the amount of LMW-PGA to 40%, without altering the concentration of HMW-PGA, and with only a small reduction of the kininogenase activity.

Animals↗
PubMed1982

The initial phase of the dextran-induced anaphylactoid reaction in the rat: a comparison of inhibitors of the blood pressure fall.

The histamine H2-receptor antagonist cimetidine (25-100 mg/kg) caused a partial inhibition of the pronounced blood pressure fall induced by dextran (Macrodex, 40-100 mg/kg) in the rat. The inhibition by cimetidine could not be distinguished from the inhibition achieved by the serotonin D-receptor antagonist bromolysergic acid diethylamide (BOL, 1-4 mg/kg). Doses of cimetidine and BOL that gave submaximum inhibitory effects separately, showed approximately additive effects when combined. The combined effect of these drugs never exceeded the maximum effects of the drugs separately, whereas injection of tranexamic acid (AMCHA, 100-300 mg/kg) together with cimetidine or BOL, increased the total inhibition. Previous works showed that dextran injected intravenously into rats reduced the level of plasminogen (PG) and plasminogen proactivator (pro-PGA) in plasma (Briseid et al. 1979; Berstad 1980a; Berstad & Briseid 1982). High doses of AMCHA (200 mg/kg) did not inhibit these effects, but significantly increased the lowering caused by dextran of the capacity of high molecular weight kininogen (HMWK) to function as a cofactor in the activation of factor XII. BOL (1-4 mg/kg, Berstad 1981) and cimetidine (50-100 mg/kg) also reduced the cofactor capacity of HMWK in the doses that were required to provide a manifest inhibition of the dextran-induced blood pressure fall. It is suggested that the early phase of the state of shock induced by dextran in the rat can be counteracted at different sites, correlated with histamine and serotonin receptors on the one hand, and with an effect antagonized by AMCHA, on the other. The lowest effective doses of cimetidine and BOL were rather high, suggesting a less specific mechanism for their effects than inhibition at selective receptor sites.

Anaphylaxis↗
PubMed1985

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

Plasma kallikrein purified from acetone-activated, plasminogen-free rat plasma yielded in polyacrylamide gel electrophoresis protein bands corresponding to Mr values of 143,000 (main band) and 135,000 (lighter band). After SDS treatment without reduction the protein pattern had changed to two strong bands corresponding to Mr values of 87,000 and 78,000. Gel electrophoresis of kallikrein purified from plasma of rats pretreated with clinical dextran (200 mg/kg intravenously) produced main bands corresponding to Mr values of 120,000-130,000 and 78,000-80,000 for native samples and SDS-treated samples respectively (Johansen & Briseid 1983). Both kinds of kallikrein reduced the capacity of human high molecular weight kininogen to function as a cofactor in the surface-mediated activation of factor XII in a crude plasma preparation. The preparation obtained from plasma of dextran-treated rats was significantly more potent than was the normal kallikrein preparation, both as regards the effect against HMrK, and as an activator of plasminogen.

Aminocaproic Acid↗
PubMed1999

Human homozygous type I plasminogen deficiency and ligneous conjunctivitis.

On the basis of a questionnaire sent to the ophthalmology departments of hospitals throughout Germany, 10 patients with ligneous conjunctivitis or pseudomembranous disease, ranging in age from 1 to 71 years were identified. All 10 patients had severely reduced plasminogen levels. Genetic analysis revealed homozygous type I plasminogen deficiency (which had not previously been described in humans) in 7 patients and compound heterozygous plasminogen deficiency in 1 patient. Clear differentiation was not possible in 2 patients. Most of the parents had heterozygous plasminogen deficiency. None of the patients had experienced any episodes of thrombosis. Additionally, the following observations were made: 1) Levels of polymorphonuclear (PMN)-elastase protein were markedly elevated in 6 of 6 patients and 10 of 11 parents tested, and levels were higher in homozygotes than in heterozygotes. 2) Hereditary factor XII deficiency was found in 3 of 6 patients tested. 3) C1-inhibitor was elevated in 2 of 4 patients, prekallikrein was elevated in 1 of 4 patients, and plasminogen activator inhibitor type 1 was elevated in 1 of 4 patients. Infusions of lys-plasminogen concentrate induced pronounced fibrinolytic activity as indicated by high levels of D-dimer, increases in plasmin-antiplasmin complex and decreases in polymorphonuclear elastase. C1-inhibitor, prekallikrein and PAI-1 normalized after repeated infusions of lys-plasminogen. In contrast to dysplasminogenemia, severe type I plasminogen deficiency might be seen as a problem of extravascular space, in particular of the mucous membranes, possibly triggered by mechanically induced or inflammatory lesions of the vessels supplying the tissue.

Adolescent↗
PubMed1989

Effect of heparin on the inhibition of the contact system enzymes.

1. One can accurately predict the contribution of each inhibitor to the total inactivation of an enzyme in plasma once its pseudo-first-order reaction rate constant and concentration are known. 2. Because the mechanism of augmentation of the inactivation rate of an enzyme by ATIII occurs via formation of an ATIII-heparin complex, the degree of potentiation can be predicted by knowing the binding capacity (sites per mole) of the heparin preparation and the concentration of heparin in the reaction (to calculate the concentration of the ATIII-heparin complex). 3. The augmentation by heparin of the inactivation rate of a particular enzyme by ATIII is dependent upon the presence of other enzymes with higher kassoc, since these would strongly compete for the ATIII-heparin complex. 4. In a plasma environment, using therapeutic levels of heparin, there is no augmentation of the inactivation rate of any of the contact enzymes.

Antithrombin III↗
PubMed2001

Staphylococcus aureus induces release of bradykinin in human plasma.

Staphylococcus aureus is a prominent human pathogen. Here we report that intact S. aureus bacteria activate the contact system in human plasma in vitro, resulting in a massive release of the potent proinflammatory and vasoactive peptide bradykinin. In contrast, no such effect was recorded with Streptococcus pneumoniae. In the activation of the contact system, blood coagulation factor XII and plasma kallikrein play central roles, and a specific inhibitor of these serine proteinases inhibited the release of bradykinin by S. aureus in human plasma. Furthermore, fragments of the cofactor H-kininogen of the contact system efficiently blocked bradykinin release. The results suggest that activation of the contact system at the surface of S. aureus and the subsequent release of bradykinin could contribute to the hypovolemic hypotension seen in patients with severe S. aureus sepsis. The data also suggest that the contact system could be used as a target in the treatment of S. aureus infections.

Bradykinin↗