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PubMed1977

Normal plasma arginine esterase and the Hageman factor (factor XII) -prekallikrein-kininogen system in cystic fibrosis.

Previous investigators have suggested that the biological activity of plasma prekallikrein is defective in cystic fibrosis. In contrast, no such difference was demonstrable between normal and cystic fibrosis plasma. Esterolytic activity for the synthetic substrate p-toluene sulfonyl-arginine methyl ester (TAMe) evolved normally in cystic fibrosis plasma treated with chloroform and ellagic acid, a measure of generation of plasma kallikrein. Additionally, plasma prekallikrein (Fletcher factor) and high molecular weight kininogen (Fitzgerald factor), a substrate of plasma kallikrein, were normal. Thus, the concept that cystic fibrosis is associated with abnormalities in the plasma kallikrein-kinin system could not be supported.

Adolescent↗
PubMed1994

Coincidence of familial platelet glycoprotein Ib/IX deficiency (Bernard-Soulier syndrome), idiopathic autoantibody against platelet glycoprotein Ib/IX, familial appearance of antiphospholipid antibodies, and familial factor XII deficiency.

The case of an 8-year-old boy with apparently homozygous Bernard-Soulier syndrome (platelet GP Ib/IX complex deficiency) and a transient idiopathic autoantibody against GP Ib/IX is described. He had been diagnosed with chronic autoimmune thrombocytopenia (due to the detection of antiplatelet autoantibodies) before Bernard-Soulier syndrome was proven. Both parents and his brother displayed intermediate deficiency of GP Ib/IX, thus indicating a heterozygote state for Bernard-Soulier syndrome. Alloimmunization as an explanation for the appearance of GP Ib/IX antiplatelet antibodies in the propositus can be excluded. A so-called pseudo Bernard-Soulier syndrome due to selective antibodies was also excluded. Flow cytometric analysis revealed residual expression of 2% GP Ib and 13% GP IX on the propositus' platelets. It seems that the propositus showed an idiopathic autoantibody against a platelet glycoprotein in which he is genetically deficient (but which is not completely lacking). Thus, in patients with untypical behavior upon therapy of "autoimmune thrombocytopenia", other differential diagnoses should also be considered even if antiplatelet antibodies are detected. In addition, all family members displayed elevated concentrations of antiphospholipid antibodies. These findings raise the question of a genetic predisposition for the development of autoantibodies. Moreover, an F. XII deficiency was found in all family members except the mother.

Adult↗
PubMed1987

Protection by recombinant alpha 1-antitrypsin Ala357 Arg358 against arterial hypotension induced by factor XII fragment.

The specificity of serpin superfamily protease inhibitors such as alpha 1-antitrypsin or C1 inhibitor is determined by the amino acid residues of the inhibitor reactive center. To obtain an inhibitor that would be specific for the plasma kallikrein-kinin system enzymes, we have constructed an antitrypsin mutant having Arg at the reactive center P1 residue (position 358) and Ala at residue P2 (position 357). These modifications were made because C1 inhibitor, the major natural inhibitor of kallikrein and Factor XIIa, contains Arg at P1 and Ala at P2. In vitro, the novel inhibitor, alpha 1-antitrypsin Ala357 Arg358, was more efficient than C1 inhibitor for inhibiting kallikrein. Furthermore, Wistar rats pretreated with alpha 1-antitrypsin Ala357 Arg358 were partially protected from the circulatory collapse caused by the administration of beta-Factor XIIa.

Animals↗
PubMed1989

Plasminogen activators in dextran sulfate-activated euglobulin fractions: a molecular analysis of factor XII- and prekallikrein-dependent fibrinolysis.

To elucidate the mechanism by which activation of the contact system of blood coagulation leads to expression of fibrinolytic activity, we have determined the molecular characteristics of the plasminogen activators present in dextran sulfate-treated euglobulin fractions by electrophoretic-zymographic analysis and specific immunoadsorption. In addition to free and protease inhibitor-bound tissue-type plasminogen activator (t-PA), dextran sulfate precipitates of euglobulins contained the complex formed between plasma kallikrein and C1-inhibitor, an indicator of prekallikrein activation. These precipitates also contained substantial fibrinolytic activity related to urinary-type plasminogen activator (u-PA). Autoradiographic analysis was then used to evaluate the cleavage of 125I-single-chain u-PA (prourokinase) in dextran sulfate euglobulins as well as after exposure to kallikrein or beta-factor XIIa. This analysis supported the conclusion that plasma kallikrein-mediated cleavage and activation of single-chain u-PA is the mechanism operative for the development of lytic activity in euglobulin precipitates following activation of the contact system.

Blood Proteins↗
PubMed1991

Contact activation factors in plasma from pregnant women--increased level of an association between factor XII and kallikrein.

The plasma levels of FXII, prekallikrein (PK), and high- and low molecular weight kininogens (HK and LK) were studied in pregnant women in the last trimester and in non-pregnant controls. FXIIa and plasma kallikrein were assayed in acetone-treated citrated plasma (CPLa) with the tetrapeptide S-2222 as substrate, using soybean trypsin inhibitor and corn inhibitor to exclude kallikrein and FXIIa respectively. No difference in PK-level could be registered for the two kinds of plasma, but the level of FXII had increased to about 150% in the pregnancy plasma. No difference in HK-level was observed, whereas the LK-level was significantly higher in pregnancy plasma, about 250% and 160% in rocket immunoassay and bioassay respectively. In fractions from gel filtration of plasma acetone-activated in the presence of benzamidine (BPLa), kallikrein was assayed as S-2302 amidase, HK and LK were measured in rocket immunoassay, and HK and FXII were studied in PAGE immunoblot experiments. In contrast to previous results obtained upon gel filtration of CPLa, not only kallikrein and HK, but in addition also FXII now appeared together in the same fractions and as two separate peaks. One peak eluting in early fractions (gel mol. wt. 300-400 KD), and one late eluting peak of proteins adsorbed to the gel material. The first peak was notably marked in pregnancy plasma. The results provide support for the assumption of an association in plasma between the three contact activation factors studied.

Adult↗
PubMed1993

Factor XII activation and inhibition in inflammation.

Biochemical observations during clinical sepsis using functional and immunological measurements of enzymes, cofactors and inhibitors of the kallikrein-kinin system indicate that activation of these proteases occur during hypotensive gram-negative septicemia and adult respiratory distress syndrome. Using animal models of septicemia, we demonstrated that protease inhibitors or neutralizing monoclonal antibodies to proteins of the contact system inhibit or prevent the formation of kallikrein and the decrease in kininogen. In addition, the irreversible phase of hypotension can be prevented and survival prolonged. Thus, bradykinin is one of the important mediators of hypotension. In contrast, the contact system plays little role in the associated DIC. In cardiopulmonary bypass, the formation of kallikrein leads to neutrophil degranulation and release of elastase. Selective inhibitors of kallikrein not only block its activation but play a predominant role in inhibiting elastase release.

Animals↗
PubMed1991

Contact activation factors in plasma from women using oral contraceptives--increased levels of factor XII, kinin-free high molecular weight kininogen and acetone-activated kallikrein.

The plasma levels of FXII, prekallikrein (PK) and high- and low molecular weight kininogens (HK and LK) were measured in women on low estrogen dose (30-40 micrograms ethinylestradiol) oral contraceptives (OC) and in controls. FXIIa was assayed in acetone-treated citrated plasma (CPL) with PK and the tetrapeptide S-2222 as substrates, and in acetone-treated citrated plasma with benzamidine (BPL) with PK as substrate. The level of FXII was found to be about 20% higher in OC-plasma than in control plasma. Kallikrein was assayed in CPL with S-2222 as substrate and in BPL with the tripeptide S-2302 as substrate. No difference in PK-level was observed in the CPL-based method, whereas an increase in kallikrein activity of about 30% was registered in BPL. The levels of HK and LK were estimated both in rocket immunoassay and in bioassay of released kinin. No difference in HK-level could be registered in immunoassay, whereas the bioassay revealed a HK-level in OC-plasma of 40% of the control level. Immunoblot studies showed that a substantial part of HK in OC-plasma was present as kinin-free protein (mol. wt. 103 KD), assumed to possess a higher cofactor potency than that of native HK. Both in bioassay and immunoassay the level of LK was found to be 60% higher in OC-plasma than in control plasma. Considered together the observations on contact factors made in this study provide support for the assumption of an increased readiness for contact activation in plasma from women using OC.

Adult↗
PubMed2004

Role of bradykinin B2-receptor in the sympathoadrenal effects of 'new pressor protein' related to human blood coagulation factor XII fragment.

BACKGROUND: Human plasma new pressor protein (NPP) increases blood pressure, heart rate and plasma adrenal medullary catecholamines in bioassay rats - all potentiated by angiotensin-converting enzyme (ACE) inhibition. High plasma NPP activity has been found in haemodialysis patients with hypertension. OBJECTIVE: To investigate whether the bradykinin B2-receptor mediates the effects of NPP. METHODS AND RESULTS: Male Wistar bioassay rats were anaesthetized with inactin, ganglion blocked with pentolinium and injected intravenously (i.v.) with human NPP (20 microl plasma equivalent) or bradykinin (100 ng/kg). Both NPP and bradykinin increased systolic (SBP) and diastolic (DBP) blood pressures, heart rate and plasma adrenaline and noradrenaline concentrations. All these responses were potentiated by the ACE inhibitor, captopril (10 mg/kg i.v.), but not by antagonism of the angiotensin II type 1 receptor with losartan (10 mg/kg i.v.). Administration of the bradykinin B2-receptor antagonist, HOE-140 (20 microg/kg i.v.), significantly attenuated the peak NPP responses as follows: SBP from 58 +/- 3 to 40 +/- 4 mmHg (decrease of 30%; P < 0.05); DBP from 22 +/- 4 to 10 +/- 1 mmHg (decrease of 55%; P < 0.05); heart rate from 124 +/- 8 to 28 +/-6 beats/min (decrease of 77%; P < 0.05); plasma adrenaline from 14297 +/- 2477 to 3318 +/- 1105 pg/ml (decrease of 77%; P < 0.05) and noradrenaline from 505 +/- 66 to 77 +/-29 pg/ml (decrease of 85%; P < 0.05). CONCLUSIONS: The haemodynamic and sympathoadrenal effects of NPP involve substantial mediation by the bradykinin B2-receptor, in addition to other mechanisms.

Angiotensin II Type 1 Receptor Blockers↗
PubMed1999

Interaction of factor XII and high molecular weight kininogen with cytokeratin 1 and gC1qR of vascular endothelial cells and with aggregated Abeta protein of Alzheimer's disease.

High molecular weight kininogen (HK) attaches to endothelial cells at separate sites on the heavy and light chains by a process which requires 15-50 microM zinc. Previously identified binding proteins include gClqR, cytokeratin 1, and the urokinase plasminogen activator receptor (U-par), however, their relative contribution to binding are not yet clarified. We have purified the binding proteins by affinity chromatography, in the presence of zinc ion, and identified cytokeratin 1 and gC1qR by amino acid sequencing of an internal peptide and by immunoblot as heavy chain and light chain binding proteins, respectively. Antibody to cytokeratin 1 inhibited HK binding to endothelial cells by 30%, antibody to gClqR inhibited HK binding to endothelial cells by 72%, and a mixture of both inhibited binding by 86%. The binding and activation of the proteins of the kinin-forming cascade along the cell surface is zinc-dependent. Similarly, proteins of the plasma kinin-forming cascade can be activated by binding to aggregated A(beta) protein of Alzheimer's disease. Activation of the cascade using purified proteins or upon addition of Abeta to plasma requires aggregation of A(beta) and the reactions are zinc-dependent. In plasma, HK is cleaved and bradykinin is liberated. The data demonstrate that aggregated A(beta) can bind and activate proenzymes of the plasma kinin-forming cascade to release bradykinin and these reactions are dependent on zinc ion.

Amyloid beta-Peptides↗
PubMed2004

[Activated factor XII in patients with hyperglycaemia and dyslipidaemia].

BACKGROUND: Increased plasma levels of activated factor FXII (FXIIa) are associated with increased risk of atherosclerosis and coronary heart disease. There are increased levels of FXIIa in patients with dyslipidaemia and also elevated levels of FXIIa have been reported in patients with diabetes mellitus. No studies were reported whether FXIIa correlates rather with plasma glucose levels or with other metabolic markers like hypertriacylglycerolemia. METHODS: We measured plasma FXIIa levels, triacylglycerols, uric acid and glucose in a group of 158 hyperglycaemic patients with P-glucose more than 8 mmol/l and variable serum lipid parameters [cholesterol, triacylglycerols, HDL-cholesterol, LDL-cholesterol, lipoprotein (a), apolipoprotein AI, apolipoprotein B] in a group of 55 patients of lipid clinic on hypolipidaemic treatment (statins, fibrates). RESULTS AND CONCLUSION: The comparison of FXIIa with the age in the group of hyperglycaemic patients has shown that the number of patients with FXIIa more than 2.5 microg/l is growing with increasing age. Low concentration of FXIIa was observed in the youngest age group (10-30 years), where all values are within the reference ranges. We proved positive correlation between plasma FXIIa levels and age, triacylglycerols, uric acid. No correlation was found between plasma FXIIa and glucose in both groups.

Adolescent↗
PubMed1984

The contact phase of blood coagulation and renin activation in essential hypertension before and after captopril.

The contact phase of blood coagulation in a group of patients suffering from essential hypertension was studied before and after captopril administration. The baseline levels of factor XII, factor XI and plasminogen were significantly higher than in normals and correlated with baseline diastolic blood pressure levels. On the contrary, plasma prekallikrein was not significantly different from normal. These results suggest the presence of a hypercoagulable state in essential hypertension. After captopril administration, factor XII, factor XI and prekallikrein rapidly decreased, perhaps as a consequence of the drug's effect on the vascular endothelial surface. There was no correlation between the changes of active and inactive renin and the changes of prekallikrein and plasminogen levels. Our data do not support the view that factor XII-plasma kallikrein or plasmin dependent pathways are involved in the activation of inactive renin in vivo. Captopril, by provoking rapid pressure changes, appears to be able to affect the clotting system.

Adult↗
PubMed1989

[Comparative studies of measuring condition of activated partial thromboplastin time and contact factors in experimental animals].

For establishing the optimal incubation time (OIT) for measurement of the activated partial thromboplastin time (APTT) in dogs, rabbits, guinea pigs, rats and mice, we determined the shortest clotting time of the plasma from each animal species and compared them with that of human plasma. The OIT for APTT determination was 15 to 30 sec in guinea pigs, rats and mice and 5 to 10 minutes in dogs and rabbits. The mouse APTT (about 30 sec) with the OIT thus determined was similar to human APTT, and relatively longer than APTT in other animal species (10-20 sec). To elucidate the mechanism of the species differences in OIT, we examined the plasma of each animal species for the activity of the contact factors such as factor XII, factor XI, high molecular weight kininogen (HMWK) and prekallikrein (PK) and their effect on the coagulation of contact factor-deficient plasma. The total activity of contact factors was higher in dogs and guinea pigs and lower in rabbits and mice than that in humans. Species difference with the factor XII, Factor XI and HMWK was noted in clotting time but not in OIT. These results suggest that the species difference in OIT for APTT is probably due to difference in activity of the plasma contact factors and in the mode of coagulation for each contact factor.

Animals↗
PubMed1990

The inositol-phospholipid-accelerated activation of prekallikrein by activated factor XII at physiological ionic strength requires zinc ions and high-Mr kininogen.

In a system consisting of purified proteins inositol-phospholipid-accelerated activation of prekallikrein by alpha-factor XIIa was determined by measuring the appearance of kallikrein amidolytic activity towards the chromogenic substrate, H-D-Pro-Phe-Arg-NH-PhNO2 (PhNO2, 4-nitrophenyl). The activation reaction was ionic-strength dependent. In the absence of high-Mr kininogen optimal activity was recorded at I = 50 mM. Searching for conditions, which could change this optimum towards physiological values, high-Mr kininogen was added. This resulted in an inhibition of the activity, with no change in ionic strength optimum. If, however, Zn2+ were added concomitant with high-Mr kininogen, the inhibition was abolished and optimal activity recorded at physiological ionic strength. The optimal Zn2+ concentration was found to be 0.1 mM. Kinetic analysis of the reaction demonstrated that the kcat/Km was 1.2 x 10(5) M-1 s-1 in the absence and 1.1 x 10(6) M-1 s-1 in the presence of Zn2+. Zn2+ were also required for inositol-phospholipid-accelerated initiation of the contact activation in whole plasma.

Blood Coagulation↗
PubMed1994

Platelet-bound prekallikrein promotes pro-urokinase-induced clot lysis: a mechanism for targeting the factor XII dependent intrinsic pathway of fibrinolysis.

Clots formed from platelet rich plasma were found to be lysed more readily by low concentrations of pro-urokinase (pro-UK) than clots formed from platelet poor plasma. This was not a non-specific effect since the reverse occurred with tissue plasminogen activator. A mechanical explanation due to platelet-mediated clot retraction was excluded by experiments in which retraction was inhibited with cytochalasin B. Therefore, a platelet-mediated enzymatic mechanism was postulated to explain the promotion of fibrinolysis. Casein autography of isolated platelets revealed a approximately 90 kDa band of activity which comigrated with plasma prekallikrein (PK)/kallikrein, a known activator of pro-UK. Furthermore, treatment of platelets with plasma PK activator (PPA), consisting essentially of factor XIIa, induced activation of pro-UK and of chromogenic substrate for kallikrein (S-2302). This activity corresponded to approximately 40-200 pM kallikrein per 10(8) washed and gel filtered platelets per ml. The activation of pro-UK by PPA-pretreated platelets was dose-dependent and inhibited by soybean trypsin inhibitor but not by bdellin, a specific inhibitor of plasmin, nor by the corn inhibitor of factor XIIa. Kinetic analysis of pro-UK activation by kallikrein showed promotion of the reaction by platelets. The KM of the reaction was reduced by platelets by approximately 7-fold, while the kcat was essentially unchanged. In conclusion, PK was shown to be tightly associated with platelets where it can be activated by factor XIIa during clotting. The activation of pro-UK by platelet-bound kallikrein provides an explanation for the observed platelet mediated promotion of pro-UK-induced clot lysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗