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PubMed1983

Plasma prekallikrein: quantitative determination by direct activation with Hageman factor fragment (beta-XIIa).

This report describes a plasma prekallikrein assay which, unlike methods that employ contact activation, is not affected by the factor XII or HMW kininogen content of the plasma analyzed. In this assay beta-XIIa, a potent fluid-phase activator of prekallikrein, is added to diluted plasma in the presence of 20% acetone (to inactivate kallikrein inhibitors) at 30 degrees C and the kallikrein generated is measured with the chromogenic substrate S-2302. Prekallikrein is fully activated under these conditions and the activity remains stable for at least 30 hr. The mean prekallikrein concentration in plasma samples from 24 healthy individuals was 1.50 +/- 0.35 (S.D.) S-2302 U/ml, corresponding to 20.3 +/- 4.7 micrograms/ml prekallikrein (the specific activity of highly purified human prekallikrein was determined to be 74 S-2302 U/mg). In contrast, the mean concentration in five plasma samples from patients deficient in HMW kininogen was 0.38 +/- 0.02 S-2302 U/ml. No activity was generated in prekallikrein-deficient plasma, and essentially normal levels (1.35 +/- 0.18 S-2302 U/ml) were measured in plasmas from three patients with factor XII deficiency. Plasma prekallikrein was also quantitated by radial immunodiffusion, which gave results similar to those obtained by functional assay with beta-XIIa. The determination of plasma prekallikrein by direct activation with beta-XIIa in the presence of acetone offers several advantages over the use of contact activators such as dextran sulfate. These advantages include complete inactivation of kallikrein inhibitors and total activation of prekallikrein (even in plasmas deficient in other contact factors) without simultaneous generation of plasmin.

Activation Analysis↗
PubMed2001

Role of contact system activation in hemodialyzer-induced thrombogenicity.

BACKGROUND: The contact system is generally believed to be the main trigger of the coagulation cascade during extracorporeal circulation. However, the extent of contact activation, its role for intradialytic thrombin generation as well as the influence of different dialyzer membranes have not been well established. METHODS: In a novel full-scale ex vivo recirculation dialysis model, we investigated the thrombogenicity of three widely used hemodialyzers (Cuprophan Renak RA15-U, Polysulfone F6HPS and AN69XT Nephral 200). The activation of the contact system was evaluated using a newly developed ELISA for factor XIIa-C1-inhibitor complexes. Additionally, we determined free FXIIa (ELISA), thrombin-antithrombin (TAT) complexes, platelet factor 4 (PF4), complement activation (C5a), granulocyte elastase and blood cell counts. The findings in blood from normal volunteers were compared with factor XII-deficient blood. RESULTS: With normal blood AN69 exhibited the highest thrombogenicity in comparison to Cuprophan and Polysulfone, as assessed by TAT generation and platelet consumption. AN69 caused a rapid increase of the FXIIa-C1-inhibitor complexes and of free FXIIa. Despite significant TAT generation with Cuprophan and Polysulfone free FXIIa remained unchanged and the FXIIa-C1-inhibitor complexes stayed below the detection limit. With factor XII-deficient blood Polysulfone exhibited the same TAT generation, whereas the thrombogenicity of AN69 was greatly reduced. CONCLUSIONS: Our data challenge the common assumption that activation of the contact system with generation of FXIIa is the main trigger for coagulation and thrombus formation in hemodialysis. Only the negatively charged AN69 membrane with enhanced thrombogenicity strongly induced contact activation.

Adult↗
PubMed1986

Recent evolutionary divergence of plasma prekallikrein and factor XI.

The evolution in mammals of the zymogens of the contact activation system of coagulation (factor XII, prekallikrein and factor XI) has been investigated. The NH2-terminal sequences of human plasma prekallikrein and the heavy and light chains of kallikrein have been determined and compared with those of bovine prekallikrein and of human and bovine factors XII and XI. The human and bovine NH2-terminal sequences of the light chains (catalytic polypeptide) show striking similarities both among themselves and with those of the catalytic polypeptide chains of other coagulation and digestive proteases, indicating a common origin. Comparison of the NH2-terminal sequences of human prekallikrein with those of the bovine prekallikrein and human bovine factors XIa and XIIa indicates a common origin of the heavy chain of kallikrein and factor XIa, different from that of either factor XIIa or other known amino acid sequences. Ancestral sequences for human and bovine prekallikrein and factor XI, deduced by genetic analysis of the minimum number of base changes indicate that the NH2-terminus of prekallikrein and factor XI have evolved at about the same rate. The estimated time for the gene duplication was about 124 million years ago, a value consistent with the age of the mammals.

Amino Acid Sequence↗
PubMed1997

Risk of coronary heart disease and activation of factor XII in middle-aged men.

Increased activity is known to be present in the extrinsic, intrinsic, and final common pathways of the hemostatic system in men at high risk of coronary heart disease (CHD), but the status of the contact system of coagulation in this condition is uncertain. Plasma levels of activated factor XII (XIIa), the initial product of contact activation, have therefore been measured by ELISA in 2464 men aged 51 to 62 years, clinically free of CHD, who were taking part in a prospective cardiovascular survey based in general medical practices. Statistically significant, independent, and positive associations of XIIa were found with serum cholesterol and triglyceride concentrations, blood pressure, body mass index, factor VII activity, plasma fibrinogen concentration, and tobacco smoking, all associated with CHD. Plasma XIIa also increased with recent alcohol intake. Men in the highest quintile of risk according to their conventional risk factors had a mean XIIa of 2.07 ng/mL (95% confidence interval 1.99-2.16), 31% higher than that of men in the lowest quintile (1.58; 95% confidence interval 1.51-1.65). Thus, the contact system of coagulation appears to be activated when CHD risk is increased. Furthermore, the independent associations of XIIa with the major conventional CHD risk factors and its broad range of values in the general population (0.1 to 12.5 ng/mL), combined with a relatively low day-to-day variability in individuals (the within-person component of its total variation being 14.7%), suggest its potential usefulness as a marker of atherosclerotic vascular damage.

Coronary Disease↗
PubMed1990

The increased rate of activation of factor XII in late pregnancy can contribute to the increased reactivity of factor VII.

The amidolytic activity of enzymes derived from factor XII (XIIa) was 3-fold higher in plasmas collected during pregnancy than from control subjects. Factor VII coagulant activity (VIIc) and XIIa increased in both kinds of plasmas on incubation on ice for 24 h (cold activation). These increases could be attributed to the decreased potency of C1 inhibitor (C1INH). However, variations in the concentration of C1INH and of factor XII could not explain the differences in VIIc and in XIIa between late pregnancy and control plasmas following cold activation under the same conditions. It is concluded that in vitro the increased amount of contact surface in the late pregnancy plasma promotes a higher rate of generation of XIIa and consequently a higher rate of activation of factor VII. The increased amount of contact surface could also be responsible for the increased concentration of XIIa in non-treated plasma from late pregnancy and could contribute in vivo to the higher reactivity of factor VII in this condition.

Amides↗
PubMed1993

Blood activation during neonatal extracorporeal life support.

Cardiopulmonary bypass for heart operations is associated with a whole body inflammatory reaction. The main factors involved in this reaction are the contact system and the complement system. The activation of the contact system is considered mainly responsible for impaired hemostasis because it affects platelet function. The activation of the complement system is considered the main cause for organ dysfunction, particularly of the lung, due to activation of leukocytes. This study in 10 neonates was undertaken to evaluate if there are effects of activation of the contact and the complement systems in neonatal extracorporeal life support comparable to those during cardiopulmonary bypass for cardiac operations. Two periods of blood activation during extracorporeal life support could be distinguished. The initial blood-material interaction at the onset of extracorporeal life support resulted in activation of both the contact and the complement systems. The contact activation was apparent by elevated factor XIIa-C1 esterase inhibitor complexes, decreased kallikrein inhibitory capacity, thrombin-antithrombin III formation, and moderate generation of fibrin(ogen) degradation products. The complement activation was characterized by elevated C3a, decreased leukocyte count, elastase release, and tumor necrosis factor-alpha production. This initial activation pattern subsided by 24 hours. A second activation period was observed 72 hours after the onset of extracorporeal life support, which was characterized only by increased clotting and fibrinolytic activity while no activation of the complement system was observed. We conclude that the initial activation pattern in extracorporeal life support is similar to that observed during cardiopulmonary bypass for cardiac operations. The contact activation that affects platelets might explain the continuous platelet consumption observed during extracorporeal life support. In this period, as in cardiopulmonary bypass, aprotinin given in the pump prime might be effective to prevent platelet consumption and impairment of hemostasis also in extracorporeal life support. The complement activation and leukocyte inflammatory reaction during the initial period are able to cause a capillary leak syndrome and might therefore explain the frequently observed temporary compromised lung function in extracorporeal life support. This reaction, as in cardiopulmonary bypass, might be reduced by the use of specific drugs or heparin coating also in extracorporeal life support. The cause of the second period of activation during extracorporeal life support requires further studies before adequate measures can be recommended.

Acute-Phase Proteins↗
PubMed2004

Prothrombotic markers in familial combined hyperlipidemia: evidence of endothelial cell activation and relation to metabolic syndrome.

BACKGROUND: Familial combined hyperlipidemia (FCHL) is characterized by a varied expression of hypertriglyceridemia and hypercholesterolemia within a family, and a high risk of premature coronary artery disease. The present study evaluated a number of potential prothrombotic markers in familial combined hyperlipidemia, and studied their relationship to the hypercholesterolemic (Fredrickson type IIa) and hypertriglyceridemic (IIb and IV) phenotypes. METHODS AND RESULTS: Selected prothrombotic markers were studied in 68 subjects: 34 hyperlipidemic subjects with familial combined hyperlipidemia and 34 controls. FCHL patients exhibited significantly higher Thrombin-Antithrombin complex (TAT), activated coagulation factor XII (F XIIa), von Willebrand Factor (vWF), Plasminogen Activator Inhibitor-1 (PAI-1) and tissue derived Plasminogen Activator (t-PA) values in comparison to controls. Within the subgroup of familial combined hyperlipidemia subjects, elevated PAI-1 activity and soluble Thrombomodulin levels were particularly associated with features of the metabolic syndrome, including hyperinsulinemia, hypertriglyceridemia and predominance of small dense low density lipoprotein (LDL). CONCLUSIONS: A general pattern of activated blood coagulation and endothelial activation is present in all hyperlipidemic subjects studied, independent of metabolic phenotype. In those familial combined hyperlipidemia subjects with features of the metabolic syndrome, impaired fibrinolysis can provide an additional cardiovascular risk factor.

Adult↗
PubMed1993

Activation of the contact system in insect-sting anaphylaxis: association with the development of angioedema and shock.

A postulated role of the contact system in anaphylactic reactions to insect stings was investigated. During prospective, in-hospital sting challenge, we collected serial blood samples from five normal volunteers and 16 patients with a history of insect-sting anaphylaxis. Activation of the contact system was assessed by measuring plasma levels of factor XIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes as well as those of cleaved high molecular weight kininogen (HK). In addition, antigenic levels of (pre)kallikrein, factor XII, and HK were measured. No significant changes in contact system parameters were observed in any of the five volunteers or the four patients who did not develop an anaphylactic reaction after sting challenge. In contrast, significant changes in contact system parameters occurred in 7 of the 12 patients with anaphylactic symptoms after challenge. Peak levels of either C1-inhibitor complex were found 5 minutes after the onset of anaphylactic symptoms. The increase in C1-inhibitor was most pronounced in the 4 patients with angioedema, 2 of which also developed shock. However, activation of HK was observed in all four patients with angioedema, the two patients with shock but no angioedema, as well as in 1 of the remaining 6 patients with anaphylactic symptoms other than angioedema or shock. Thus, activation products of the contact system may be involved in the pathogenesis of angioedema and shock in insect-sting anaphylaxis.

Adult↗
PubMed1976

Activation and consumption of Hageman factor in the anaphylactic shock of the rat.

In the early stages of anaphylactic shock of rats pretreated with Bordetella pertussis vaccine, a prompt and parallel activation of the factor XIIa-dependent intrinsic coagulation, kinin generation, and fibrinolytic acticity was observed. The coagulation studies, the similarity of anaphylactic results with those produced by a single injection of ellagic acid, and the effective inhibition of the anaphylactic and the ellagic acid-induced activation of these pathways by lysozyme all suggest that factor XII itself becomes activated in rat anaphylaxis. As the reaction proceeded, considerable anticoagulant activities emerged, but the bradykinin and the plasminogen activator levels even further increased. During the first 10 min of anaphylactic shock, factor XII was partly consumed and this was prevented by epsilon-aminocaproic acid infusion. The results show that in pathological conditions such as anaphylaxis there is an intimate in vivo interaction among the three factor XIIa-dependent pathways.

Aminocaproates↗
PubMed2006

Specific types of activated Factor XII increase following thrombolytic therapy with tenecteplase.

BACKGROUND: Activated Factor XII (XIIa) is believed to participate in a number of pathophysiological processes including inflammation, thrombosis and fibrinolysis. Increasing XIIa levels following thrombolytic therapy have previously been reported. In contrast to other thrombolytics, tenecteplase (TNK-tpa) does not show paradoxical thrombin activation, indicating a lower procoagulant effect of this fibrin-selective thrombolytic agent. Recent research has demonstrated that in-vivo XIIa exists in a number of different types, and the aim of this study was to investigate plasma variations of different types of XIIa following thrombolytic treatment with TNK-tpa. METHODS: Citrated blood samples were obtained from 34 patients admitted with acute ST-elevation myocardial infarction (STEMI) treated with TNK-tpa. Samples were taken immediately prior to treatment, 30-90 min after and 4 days post-treatment. XIIa measurements were performed using 2 ELISA assays designed to preferentially measure different types of XIIa; XIIaA and XIIaR. Both assays utilised a monoclonal antibody 2/215, which is highly specific for XIIa, as the solid phase capture antibody. The assay for XIIaA used a conjugate based on a polyclonal antibody against the entire XIIa molecule, whilst the assay for XIIaR incorporated a reagent to release otherwise unavailable XIIa and used a conjugate based on a monoclonal antibody against beta-XIIa. RESULTS: Changes in plasma XIIaA concentration as a result of therapy were more evident than changes in XIIaR concentration. XIIaA showed a significant increase from 67.1 (49.0-84.4) pM to 97.8 (75.5-133.1) pM [median and 25 and 75% percentiles] in the 30-90 min sample (P < 0.001), returning to pre-intervention levels 61.5 (47.5-81.0) pM by day 4. In contrast, no significant change in XIIaR concentration was observed following thrombolytic therapy with TNK-tpa. CONCLUSION: In patients admitted with STEMI, thrombolytic therapy with TNK-tpa resulted in a significant short-lasting increase in specific types of XIIa (namely XIIaA), whereas other types of XIIa (XIIaR) were largely unaffected by this intervention.

Aged↗
PubMed2002

Plasma markers of hypercoagulability in patients with serious infections and risk of septic shock.

Hyperthrombinogenesis due to bacterial septicemia may aggravate the risk of irreversible septic shock. In 22 patients with septicemia complicating urinary or alimentary infections, daily assessment of hemostasis was performed throughout 1 week. Standard screening of hemostasis revealed significantly increased mean values of prothrombin time, fibrinogen, and fibrinogen degradation product (FDP) concentration. However, platelet counts, activated partial thromboplastin times (APTT), thrombin times, ethanol gelation tests, and antithrombin activity remained within the normal range. By contrast, except for insignificant changes in protein C activity and activated factor VII content, specific markers of plasma hypercoagulability, that is, thrombin-antithrombin (TAT) complexes, prothrombin activating factor F 1+2, activated factor XII (XIIa), and dimer D were all markedly increased. Pathologic levels of TAT and Xlla were found in 82% and 73% of all plasma samples, respectively. The augmentation of TAT correlated with prolongation of thrombin time and increases in F 1+2 levels. The increase in XIIa correlated with thrombocytopenia, prolongation of APTT, exhaustion of antithrombin, and accumulation of F 1+2 and FDP in the plasma. Moreover, a significant increase in XIIa, stronger positivity of the ethanol gelation test, a greater increase in FDP, and a more pronounced decrease in protein C activity were observed in 8 patients with fatal septic shock. This study suggests the usefulness of TAT and XIIa measurements in the early recognition of plasma hypercoagulation in serious infections.

Adult↗
PubMed2002

C1 inhibitor infusion modifies platelet activity in hereditary angioedema patients.

CONTEXT: C1 inhibitor (C1-INH) is an alpha2-globulin that blocks esterolytic activity of the first component of the classic complement cascade. The alpha-granules of normal human platelets also contain C1-INH, which is expressed on the platelet surface during platelet secretion in healthy patients, but it is clearly reduced in patients with hereditary angioedema (HAE). OBJECTIVE: To evaluate the effects of in vivo C1-INH concentrate infusion on platelet responsiveness and coagulation system activity in patients with HAE. DESIGN: Assessment of the platelet activity and plasma levels of C1-INH, activated factor XII (XIIa), and prothrombin fragment F1.2 (F1.2) before and after infusion of 15 U/kg of C1-INH concentrate. PATIENTS: In 6 patients (4 men and 2 women), HAE was diagnosed according to the accepted clinical and laboratory criteria. MEASUREMENTS: Platelet aggregation (final concentrations: adenosine diphosphate, 0.5, 1.25, and 2.5 microM; collagen, 5 microg/mL), C1-INH antigen (radial immunodiffusion), C1-INH activity (chromogenic substrates), and XIIa and F1.2 (enzyme-linked immunosorbent assay). RESULTS: After C1-INH infusion, we observed a prompt increase of C1-INH level and a slow return toward its plasma preinfusion values within 4 to 7 days, a significant decrease of both adenosine diphosphate- and collagen-induced platelet aggregation versus preinfusion values (maximum after 1-2 days; P <.001), and a rapid decrease of high basal values of XIIa and F1.2 in 30 and 120 minutes, respectively. CONCLUSIONS: These data show a role of C1-INH in the control of platelet activity and that its deficiency increases platelet aggregability and plasma levels of XIIa and F1.2 in patients with HAE.

Adenosine Diphosphate↗
PubMed1987

Inactivation of C-1 inhibitor by proteases: demonstration by a monoclonal antibody of a neodeterminant on inactivated, non-complexed C-1 inhibitor.

Monoclonal antibodies were raised against kallikrein-C-1 inhibitor and factor XIIa-C-1 inhibitor complexes. One of the monoclonal antibodies (KII) appeared to react predominantly with C-1 inhibitor complexes in an ELISA. However, the apparent binding of KII to C-1 inhibitor complexes was probably due to the presence of proteolytically inactivated C-1 inhibitor in the complex mixture used for the coating:KII did not bind either kallikrein-C-1 inhibitor or factor XIIa-C-1 inhibitor complexes generated in plasma by dextran sulphate. SDS-PAGE analysis of C-1 inhibitor incubated with proteases revealed that KII-reactive C-1 inhibitor has a lower molecular weight than native C-1 inhibitor. We propose that the determinant that reacts with KII is exposed after cleavage of C-1 inhibitor in its reactive site. The monoclonal antibody KII will enable us to study the inactivation of C-1 inhibitor in human inflammatory disease.

Antibodies, Monoclonal↗
PubMed1996

Gemfibrozil reduces thrombin generation in patients with combined hyperlipidaemia, without influencing plasma fibrinogen, fibrin gel structure or coagulation factor VII.

A double-blind, placebo-controlled, cross-over study was conducted in 21 men with combined hyperlipoproteinaemia to examine if lipid-lowering treatment with gemfibrozil (10-12 weeks) affects blood coagulation and fibrin gel structure at rest or during mental stress. Gemfibrozil lowered plasma triglycerides by 57 +/- 4%, whereas high density lipoprotein (HDL) cholesterol increased by 22 +/- 5%. Gemfibrozil lowered the triglyceride content of low density lipoprotein (LDL). Gemfibrozil reduced the plasma concentrations of thrombin-antithrombin complex (TAT) and prothrombin fragment F1 + 2 (F1 + 2), both at rest and during mental stress. However, there were no effects of gemfibrozil treatment on the plasma concentrations of fibrinogen, factor VII antigen, activated factor VII (VIIa) or activated factor XII (XIIa), or on fibrin gel structure. Acute mental stress per se did not influence coagulation factors, reaction products or fibrin gel structure, or their responses to the study drug. Thus, gemfibrozil reduced thrombin generation in men with combined hyperlipoproteinaemia, without influencing the plasma levels of fibrinogen, VIIa and XIIa, or fibrin gel structure. Attenuation of thrombin generation may contribute to the primary-preventive effects of gemfibrozil on coronary heart disease.

Adult↗
PubMed1997

Initiation of contact system activation in plasma is dependent on factor XII autoactivation and not on enhanced susceptibility of factor XII for kallikrein cleavage.

Various mechanisms have been hypothesized to explain the initiation of contact system activation in plasma. We investigated the capability of dextran sulphate (DS) of different molecular weights to initiate contact system activation in normal human plasma, and compared this with their capability to support factor XII autoactivation and to enhance factor XII susceptibility for cleavage by kallikrein. Dextran sulphate of Mr 500,000 (DS500) and 50,000 (DS50) was able to initiate contact system activation in plasma (determined by measuring the amount of factor XIIa-C1-inhibitor, kallikrein-C1-inhibitor and factor XIa-C1-inhibitor complexes generated) as well as to support factor XII autoactivation and to enhance factor XII susceptibility for cleavage by kallikrein (as measured with amidolytic assays using purified proteins). In contrast, dextran sulphate of Mr 15,000 (DS15) and 5000 (DS5) neither induced contact system activation in plasma, nor supported autoactivation of factor XII, although both of these DS species enhanced the rate of activation of factor XII by kallikrein in the purified system. Based on these properties (i.e. binding of factor XII without inducing autoactivation), DS15 and DS5 were predicted to be inhibitors of contact system activation induced in plasma by DS500, which indeed was observed. We conclude that enhanced factor XII susceptibility for kallikrein activation and factor XII autoactivation are distinct phenomena, the latter being necessary to support activation of the contact system in plasma.

Dextran Sulfate↗
PubMed1997

Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor.

Hepatocyte growth factor (HGF) activator is a serine protease that is produced and secreted by the liver and circulates in the blood as an inactive zymogen. In response to tissue injury, the HGF activator zymogen is converted to the active form by limited proteolysis. The activated HGF activator converts an inactive single chain precursor of HGF to a biologically active heterodimer in injured tissue. The activated HGF may be involved in the regeneration of the injured tissue. In this study, we purified an inhibitor of HGF activator from the conditioned medium of a human MKN45 stomach carcinoma cell line and molecularly cloned its cDNA. The sequence of the cDNA revealed that the inhibitor has two well defined Kunitz domains, suggesting that the inhibitor is a member of the Kunitz family of serine protease inhibitors. The sequence also showed that the primary translation product of the inhibitor has a hydrophobic sequence at the COOH-terminal region. Inhibitory activity toward HGF activator was detected in the membrane fraction as well as in the conditioned medium of MKN45 cells. These results suggest that the inhibitor may be produced as a membrane-associated form and secreted by the producing cells as a proteolytically truncated form.

Amino Acid Sequence↗