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PubMed1986

Description and evaluation of a new chromogenic substrate assay kit for the determination of prekallikrein in human plasma.

Because of an increasing interest in the determination of prekallikrein a kit was made for the determination of this plasma proenzyme. The kit consists of 1) a prekallikrein activator of the cephalin-ellagic acid type containing Factor XII and HMW-kininogen to ensure a total activation of the prekallikrein even in pathological plasmas, 2) a buffer which is optimal for both activation and substrate hydrolysis and 3) the chromogenic substrate S-2302. A control plasma is also included. This kit was evaluated by thirteen research groups as well as by ourselves. Both normal and patient plasmas were analyzed. Good correlations were obtained for prekallikrein levels in plasma samples between the kit method and two other methods (immunochemical and functional). As well as in deficiency states the prekallikrein level was low in pancreatitis (n = 20), cancer (n = 16), early pregnancy with gestosis (n = 15), cirrhosis (n = 9) and cases with thromboembolic disorders (n = 5). The prekallikrein level was high in late pregnancy (n = 4).

Colorimetry↗
PubMed1989

Contact phase of blood coagulation in cardiogenic pulmonary oedema (CPO) and adult respiratory distress syndrome (ARDS).

In order to assess the role of the kallikreinkinin (k-k) system in the pathogenesis of pulmonary oedema, we studied the contact phase factors of blood coagulation, as well as the haemodynamics and blood gas changes in 34 patients with pulmonary oedema, 23 of them with Adult Respiratory Distress Syndrome (ARDS) and 11 with cardiogenic pulmonary oedema (CPO). We have verified significant differences in the haemodynamic pattern and blood gases between the two groups of patients, which corroborate the previously established differences between both types of pulmonary oedema. Our results reveal k-k system activation in ARDS patients, with a significant fall in factor XII (p less than 0.05), prekallikrein (p less than 0.01), alpha-2-macroglobulin (p less than 0.01) and high molecular - weight kininogens (p less than 0.005), with a rise in C1-esterase inhibitor (p less than 0.001) in comparison with patients with CPO. All of the CPO patients had normal prekallikrein levels, whereas 15 out 23 ARDS cases (65%) had decreased prekallikrein values. Our results suggest that the k-k system activation could play a role in the pathogenesis of ARDS. Estimation of prekallikrein levels may be helpful in the differential diagnosis of ARDS.

Adult↗
PubMed1989

Release of elastase from purified human lung mast cells and basophils. Identification as a Hageman factor cleaving enzyme.

Elastase, a serine protease, is capable of inducing severe lung destruction in experimental animal models. We now report that this proteinase exists preformed in neutrophil-free sonicates of purified human lung mast cells (greater than 98% purity) and in circulating peripheral blood basophils (greater than 97% purity). The elastase levels in both cell types (41-174 ng/10(6) cells) represents approximately 3-20% of those found in human neutrophils; both cell types released their elastase following anti-IgE and ionophore A23187 challenge. The apparent molecular size of the mast cell enzyme on Sephadex G-100 gel filtration, as well as its inhibition profile, was identical to that of purified human neutrophil elastase. This mast cell elastase is identical to our previously reported mast cell-derived Hageman factor cleaving activity. Mast cell-, basophil-, and neutrophil-derived elastases cleave Hageman factor into fragments of 52,000 and 28,000 Da; cleavage by all three enzymes is inhibited by preincubation with polyclonal antibodies directed against human neutrophil elastase.

Autoradiography↗
PubMedDate not supplied

Acquired and congenital clotting syndromes.

Although Virchow postulated 100 years ago that hypercoagulability states exist, it has only been in recent years that methods of documenting hypercoagulability have been developed. These clotting tendencies can be acquired or congenital. The common causes of acquired clotting tendencies include conditions which result in tissue and cellular damage, shock, transfusion reactions, and tissue necrosis. Certain drugs and drug reactions, and certain disease states which include blood dyscrasias and cancer are also associated with clotting problems. In certain diseases such as homocystinuria, hyperlipidemia, and lupus erythematosus, abnormal clotting tendencies may also develop. Important advances in the recognition of hypercoagulability have come with the documentation that congenital clotting abnormalities exist. Moreover, these abnormalities are proving to be more common than are congenital bleeding syndromes. Patients who appear to have spontaneous clotting manifestations and are under 40 years of age should be screened for one of these abnormalities. These congenital clotting tendencies can be classified as defects in thrombosis inhibitors, dysfibrinogenemias, or defects in fibrinolysis. The first thrombotic inhibitor defect recognized was antithrombin III deficiency which was reported in 1965. Subsequently, Protein C, Protein S, and Heparin cofactor II deficiencies have been recognized as contributing to thrombotic tendencies. Dysfibrinogenemias are relatively rare and most are associated with bleeding problems; however, 11% of the abnormal fibrinogens are associated with a clotting tendency. The reason appears to be that these fibrins are resistant to fibrinolysis. The most common defects which are associated with thrombotic tendencies appear, at the present time, to be due to defects in fibrinolysis. These include hypoplasminogenemia, decreases in plasminogen activator, increases in plasminogen activator inhibitor, and Factor XII deficiency.

Blood Coagulation Disorders↗
PubMed1990

Patterns of contact phase proteins indicating neuropathy in diabetic patients.

In 42 outpatients of the diabetology division, coagulation and fibrinolysis variables were determined in order to detect typical patterns of results with which it was possible to discriminate between three groups with different diabetic complications (17: no complication, 7: angiopathy alone, 18: neuropathy with or without other complications). There was a statistically significant discriminatory function involving C1-inhibitor concentration, high molecular weight kininogen coagulant activity and fibrinogen as the most decisive variables. The neuropathy group was appropriately separated from the others with an 81% correct reclassification. Heparin cofactor II, histidine-rich glycoprotein, alpha 2-macroglobulin, pre-kallikrein and factor XII had no discriminative power.

Adult↗
PubMed1976

Haemorrhagic and inflammatory properties of collagenase from C. histolyticum.

Collagenase from Clostridium histolyticum induced haemorrhages when applied to the surface of dog lung; it exerted a similar effect on mouse lung when injected intrathoracically. Injected into rat paws, bacterial collagenase induced haemorrhage and oedema. Effects of collagenase were prevented by several procedures that inhibit collagenolytic activity (heating at various temperatures and incubation with metal-complexing agents such as EDTA, penicillamine and dithiothreitol). Protein protease inhibitors, dexamethasone and standard acidic anti-inflammatory drugs had only a slight or no effect on collagenase-induced haemorrhages; dexamethasone and acidic anti-inflammatory drugs blocked collagenase-induced oedema. Inhibition of endogenous kinin-releasing mechanisms by administration of hexadimethrine, a recognized inhibitor of the activation of clotting Factor XII, and depletion of kininogen by administration of carrageenin blocked collagenase-induced oedema. Collagenase did not increase permeability of rat skin vessels, nor did it release potential inflammatory mediators, such as bradykinin or prostaglandins, from plasma or platelets. Bacterial collagenase-induced haemorrhage presumably resulted from enzymatic destruction of membranous structures; at least a portion of the inflammatory response may be due to activation of a kinin-like system.

Animals↗
PubMed1987

Isolation and properties of a capillary injury-related protease from lung lymph.

Lung microvascular injury induced in sheep by intravenous infusion of Escherichia coli endotoxin, oleic acid, or air emboli caused the appearance in lung lymph of high levels of a protease with trypsin-like activity. The enzyme was isolated as an apparently homogeneous protein from pooled samples of active lung lymph, after an almost 9000-fold purification by affinity chromatography on columns of Reactive Blue 2-agarose, aprotinin-agarose, and p-aminobenzamidine-agarose, and chromatography on a column of Sephadex G-100. A molecular weight of about 70,000 to 75,000 was determined from mobility in polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The pH optimum was between 7.3 and 7.6. The isolated enzyme was quite labile, rapidly losing activity at both 37 and 25 degrees C. Addition of albumin to enzyme solutions protected against inactivation. Inhibition by diisopropylfluorophosphate and phenylmethanesulfonyl fluoride indicated that the enzyme belongs to the class of serine proteases. The enzyme cleaved peptide bonds on the carboxyl side of arginine residues and showed a relatively high affinity toward peptides containing several basic amino acid residues. Bonds involving the carboxyl group of lysine were cleaved at a much slower rate. The enzyme showed no plasminogen activator activity and its substrate specificity was quite different from that of several proteases of the clotting cascade. Its appearance in lymph was not influenced by lymph clotting and the isolated enzyme was not capable of correcting the clotting defect of plasmas deficient in factors XII, XI, IX, VII, and X.

Animals↗
PubMed1976

Aromatic Tris-amidines. A new class of highly active inhibitors of trypsin-like proteases.

A number of novel aromatic Tris-amidines have been synthesized and investigated for their antiproteolytic property. The basic structure of the compounds is that of mesitylene where each of the methyl groups has been substituted with a 3- or 4-amidinophenoxy moiety. The compounds displayed considerable activity against trypsin (EC 3.4.21.4) and thrombin (EC 3.4.21.5), but proved most effective against porcine pancreatic kallikrein (EC 3.4.21.8). With this enzyme a Ki value of 2.43-10(-8) M was recorded for alpha,alpha',alpha''-tris(4-amidino-2-bromophenoxy)mesitylene at pH 8.1 and 37 degrees C. The most potent thrombin inhibitor, alpha,alpha',alpha''-tris(3-amidinophenoxy)mesitylene, had a Ki value of 6.51-10(-7) M and was also a strong overall anticoagulant. The inhibitors were able to interfere with the kinin release by human plasma kallikrein at concentrations as low as 1-10(-10) M. However, despite this remarkable antikallikrein effect and the known importance of plasma kallikrein in the activation of Hageman factor (factor XII), the compounds had only little influence on the early stages of blood coagulation.

Amidines↗
PubMed1980

Purification of guinea-pig plasma prekallikrein. Activation by prekallikrein activator derived from guinea-pig skin.

Prekallikrein was purified from guinea-pig plasma. The prekallikrein appeared homogeneous as a single-chain protein on polyacrylamide gels in the presence of sodium dodecyl sulfate (SDS) and beta-mercaptoethanol. The apparent molecular weight was 82 000 by SDS-polyacrylamide gel electrophoresis, 99 000 by gel filtration on a Sephadex G-150 column and 84 500 (protein part) by amino acid analysis. The isoelectric point was approx. 9.0. The purification method yielded 3.8 mg (A280 3.800) of prekallikrein from 500 ml of plasma. Kallikrein was generated from the prekallikrein by limited proteolytic action of a prekallikrein activator which was derived from guinea-pig skin. From analysis using SDS-polyacrylamide gel electrophoresis, the kallikrein has two fragments with apparent molecular weights of 52 000 and 40 000 which are linked by disulfide bond(s). The 40 000 molecular weight fragment was shown to incorporate [3H]diisopropylfluorophosphate. The kallikrein hydrolyzed the synthetic substrates containing the Phe-Arg sequence at the COOH-terminal, and it cleaved carbobenzyloxy-Phe-Arg-4-methylcoumaryl-7-amide more readily than Pro-Phe-Arg-methylcoumaryl-7-amide. The Km for the kallikrein with carbobenzyloxy-Phe-Arg-methylcoumaryl amide was 2 times 104 M. Also, the kallikrein showed negligible activities on peptide-methylcoumaryl amide-substrate for alpha-thrombin, Factor Xa or plasmin.

Amino Acids↗
PubMed1983

Survey of plant inhibitors of polymorphonuclear leukocyte elastase, pancreatic elastase, cathepsin G, cathepsin B, Hageman factor fragments, and other serine proteinases.

Various flower bulbs and vegetable and legume seeds were tested for inhibitors of polymorphonuclear leukocyte elastase, pancreatic elastase, cathepsin G, cathepsin B, trypsin, alpha-chymotrypsin, Hageman factor fragments, plasma kallikrein, and plasmin. Calla bulbs contained a 33,000 dalton polymorphonuclear leukocyte elastase inhibitor and a 4,000 dalton cathepsin G inhibitor. Seeds of some members in the Cruciferae family, such as radish and broccoli, were found to contain one or more 2,500-4,000 dalton inhibitors which inhibited cathepsin G, trypsin, Hageman factor fragments, and plasmin, but not plasma kallikrein. These seeds also contained a 1,000 dalton cathepsin B inhibitor. The above inhibitors were probably polypeptides which inhibited proteinases by making an enzyme-inhibitor complex, with the exception of the cathepsin B inhibitor. These newly found inhibitors with their characteristic profiles of inhibition should be useful in biochemical and pathophysiological studies on granulocyte proteinases and enzymes of the coagulation and fibrinolytic pathways.

Cathepsin B↗
PubMed1991

Mechanized assay of plasma prekallikrein by activation with Pseudomonas aeruginosa elastase and amidolysis of chromogenic substrate.

An automated assay of plasma prekallikrein is described. Prekallikrein was converted to kallikrein with Pseudomonas aeruginosa elastase, and the hydrolytic activity of kallikrein to H-D-Pro-Phe-Arg-paranitroanilide subsequently measured. The conversion was complete within 8 minutes and the amidolytic activity remained stable at least another 10 min at 37 degrees C. This method worked in plasma deficient in Hageman factor (blood coagulation factor XII). Using anti-prekallikrein antibody and plasma deficient in prekallikrein, the amidolytic activity generated in normal plasma was identified as due to kallikrein. With plasma samples, the coefficients of variation (CV) for multiple measurements within run (n = 10) and between run (n = 10) were as low as 5.0% and 6.6%, respectively, and the minimum measurable concentration of prekallikrein in plasma was 10% of the normal level.

Adult↗
PubMed1982

Naloxone attenuates the hypotension induced by Hageman factor.

The hypotension induced in the pentobarbital anesthesized rat by the i.v. administration of an active Hageman factor fragment (Hff) is significantly attenuated by naloxone. This effect is specific because the opiate antagonist does not modify the hypotension elicited by rat urinary kallikrein, bradykinin or nitroglycerin. These results suggest that the contact activation of endogenous Hageman factor could result in the generation of vasoactive opioid peptides derived from circulating large molecular weight precursors.

Animals↗
PubMed1988

Effects of an oral antidiabetic drug on the fibrinolytic system of blood in insulin-treated diabetic patients.

Selected variables of the fibrinolytic system were assessed in 23 men with insulin-treated diabetes with no measurable pancreatic beta-cell function. Gliclazide, a second-generation sulphonylurea drug, was administered to the patients over a period of 6 months in daily doses of 160 mg or 240 mg, and blood samples were obtained before, during, and after treatment. Determined by global assays, the drug did not significantly change plasminogen activator activities in euglobulins. Measurements of specific components of the system of fibrinolysis showed a marginal increase during administration of gliclazide of tissue-type plasminogen-activator antigen and prekallikrein activity in plasma, whereas the activities in euglobulins of the intrinsic plasminogen proactivators remained nearly the same during the study. Levels in plasma and euglobulin of C1-inactivator antigen and in plasma of factor XII antigen and t-PA inhibition capacity remained constant throughout the study. There were no changes of the increase in concentration of t-PA activity and t-PA antigen following venous occlusion. The metabolic state remained the same during the whole study. It is concluded that gliclazide induces small, but significant, non-insulin-dependent extrametabolic effects on the extrinsic (t-PA) and intrinsic (prekallikrein) system of fibrinolysis. Whether these changes are of physiological importance remains to be demonstrated.

Administration, Oral↗