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PubMed1988

Tryptase from human mast cells does not activate purified human Hageman factor.

The effect of tryptase, a neural protease released from human lung mast cell secretory granules, on purified human Hageman Factor (Factor XII) was examined. No increase in Hageman Factor enzymatic activity was detected after incubation with tryptase at 37 degrees C; activation of Hageman Factor by bovine trypsin served as a positive control. Furthermore, pre-incubation of Hageman Factor with tryptase did not diminish the subsequent activation of Hageman Factor by trypsin. Polyacrylamide gel electrophoresis was also performed to show that incubation with tryptase does not alter the molecular weight of Hageman Factor. Therefore, tryptase neither activates nor destroys human Hageman Factor.

Factor XII↗
PubMed1992

The contact activation proteins: a structure/function overview.

In recent years, extensive knowledge has been obtained on the structure/function relationships of blood coagulation proteins. In this overview, we present recent developments on the structure/function relationships of the contact activation proteins: factor XII, high molecular weight kininogen, prekallikrein, and factor XI, with the emphasis on the localization of domains on these proteins that are involved in the interaction with activators, substrates and cofactors.

Amino Acid Sequence↗
PubMed1982

Cold-induced contact surface activation of the prothrombin time in whole blood.

Studies of the prothrombin time (PT) have revealed that contact with borosilicate or commercial siliconized borosilicate markedly shortens the PT. This shortening is related to the activation of the contact phase of blood coagulation. This shortening of the PT occurs in both normal whole blood and plasma when stored in borosilicate or siliconized borosilicate tubes at 4 degree C and to a lesser degree at room temperature. Studies indicated the importance of several coagulation factors in decreasing the PT. The PT did not change in blood deficient in factor XII or in plasma deficient in Fletcher factor or high molecular weight kininogen, while blood deficient in CI esterase inhibitor (CI INH) had the most profound shortening. Shortening of the PT correlated directly with increased levels of factor VII. When purified CI INH was added to normal blood, it markedly reduced the activation of factor VII and the shortening of the PT in a dose-related manner. These studies indicate the pivotal roles of the contact phase of coagulation in initiating activation of the PT and of CI INH in inhibiting the activation of the coagulation factor(s) responsible for the cold-promoted activation of factor VII.

Blood Coagulation Factors↗
PubMed1977

Demonstration and mode of action of an inhibitor for activated Hageman factor (factor XIIa) of the intrinsic blood coagulation pathway from Schistosoma mansoni.

An anticoagulant activity from adult Schistosoma mansoni whole worm homogenate is described. The inhibitor appears to be specific for the contact activation step of the intrinsic pathway. Experiments with both human and mouse plasmas have defined the specificity of the inhibitor as follows: (1) It lengthens the partial thromboplastin time of normal plasma. (2) It has no effect on the prothombin time and Russell's viper venom time of normal plasma. (3) Preactivation of normal plasma by a contact activator such as Celite eliminates essentially all inhibitory activity. (4) The inhibitor appears to be heat stable and can be precipitated by centrifugation above 27,000 g. (5) The inhibitor has no effect on the activation of factor XII by Celite. (6) The activation of factor XI by factor XIIa, however, is inhibited by the schistosomal inhibitor. The above data are consistent with the view that S. mansoni adults possess an anticoagulant that is capable of specifically inhibiting the conversion of factor XI to factor XIa by factor XIIa.

Animals↗
PubMed1979

Prekallikrein activator and kallikrein in acetone- and kaolin-activated rat plasma.

Activation of plasminogen-free rat citrated plasma (RCPL-P) with acetone/kaolin yielded BAEe-esterase activities of 0.6--0.8 U/ml. Gel filtration demonstrated one single peak of BAEe-esterase activity (mol. wt. approximately 135000) with a kininogenase-esterase ratio (3.3) close to that known for human plasma kallikrein (2.7). Similarly activated rat citrated plasma (RCPL) revealed on gel filtration an additional esterase peak (mol. wt, approximately 47,000) with a low kininogenase-esterase ratio (0.3), and should accordingly not be used for a BAEe-esterase assay of rat plasma kallikrein. Acetone activation of RCPL-P and of RCPL yielded prekallikrein activator (PKA) activities which were about doubled by treatment with kaolin to 1.9--2.1 and 3.5--4.2 PKA-U/ml respectively. Gel filtration of acetone-activated RCPL-P or RCPL revealed two peaks of PKA activity, mol. wt. approximately 110,000 corresponding to activated factor XII (XIIa), and mol. wt. approximately 33,000 corresponding to XII fragments (XIIf). Kaolin-treatment of acetone-activated RCPL-P, but not of RCPL, caused an extensive fragmentation of XIIa to the 4--6 times more active XIIf. The lower yield of PKA-activity in acetone/kaolin-activated RCPL-P, as compared with activated RCPL, seems to be due to the absence of a factor of significance for the activation of factor XII, which is not plasmin, plasma kallikrein, or high molecular weight kininogen.

Acetone↗
PubMed2001

Contact between a polymer and whole blood: sequence of events leading to thrombin generation.

The mechanism by which thrombin is generated on a polymer surface in an extracorporeal circuit is not yet fully understood. To address this question we have developed an in vitro chamber model in which whole blood containing heparin (1 IU/mL) comes in contact with a commonly used biomaterial, polyvinyl chloride (PVC). Incubation of blood in the chamber for 60 minutes at 37 degrees C resulted in the binding of platelets to the material surface and the generation of thrombin-antithrombin complexes. Corn trypsin inhibitor, a specific inhibitor of factor XIIa, inhibited this thrombin-antithrombin complex generation in blood in contact with PVC, which is not considered an efficient activator of factor XII. The addition of the glycoprotein IIb/IIIa inhibitor Ro44-9883 abrogated platelet binding and aggregation and resulted in decreased generation of thrombin-antithrombin complexes. Thrombin-antithrombin generation was also negligible in platelet-rich plasma but could be partially restored in the presence of erythrocytes. Taken together, these data are compatible with a model in which thrombin generation is triggered by factor XII. The response to contact with PVC appears to begin with a low-grade generation of thrombin that involves both erythrocytes and leukocytes and that activates platelets, followed by the activation of a platelet-dependent amplification loop that produces most of the thrombin.

Acetates↗
PubMed1992

Kallikrein-kinin system in the plasma of snakes.

Using pharmacological preparations suitable for assay of mammalian kinins, it was shown that Bothrops jararaca (Bj) venom and other kininogenases were unable to release kinins from snake plasma. The kallikrein-kinin system presents species-specificity in birds. In order to detect such a specificity in snakes, the effects of Bj venom on snake blood pressure and the effect of incubates of snake plasma with trypsin, on snake blood pressure and snake uterus, were studied. The possibility of activating snake plasma kallikrein with ellagic acid, glass beads or kaolin was also investigated. Whereas plasma of the snakes Waglerophis merremii (Wm) and Crotalus durissus (Cd), were shown to contain factor XII, prekallikrein, kininogen, kininases and to present a low but definite activation rate of the kinin system, the plasmas of Bj, Bothrops mojeni (Bm) and Oxyrophus trigeminus (Ot), yielded only kininogen and kininases. Activation of the system was not even detected by the sensitive substrate Ac-Phe-Arg-Nan (acetyl-phenylalanyl-arginyl-4nitro-anilide), indicating that the plasma of these species does not possess either factor XII and/or prekallikrein. Snake plasma may constitute an interesting model for the study of blood clotting, fibrinolytic and complement systems.

Animals↗
PubMed1980

Contact activation of prekallikrein and of fibrinolysis by heparinoids and heparin.

Contact activation of plasma prekallikrein (PPK) assayed by a tripeptide chromogenic substrate, and surface-mediated fibrinolysis by the euglobulin test (both tests being insensitive to the anticoagulant effect of heparin and heparinoids) were studied. The following substances were tested: Dextran solutions of different molecular weight (M.W.), heparinoids such as dextran sulphate, pentosan and mannuronate sulphuric polyesters. Liquoid and Moranyl and various commercial therapeutic preparations of heparin. Most of these anionic polyesters are able to activate both PPK and fibrinolysis, dextran sulphate (500,000 M.W.) being the most active. Factor XII, PPK and HMWK are necessary for full activation. Besides dextran sulphate, other heparinoids such as Na pentosan polysulphate, or Na polyanhydromannuronic sulphuric acid, are also contact activators. This may explain some of their side effects observed in vivo. Non-sulphated dextrans used in therapy have no activating effect. Nine therapeutic commercial preparations of heparin were tested. They appear to have a slight activating effect on PPK but an uncertain effect on fibrinolysis. Such factor XII activability has until now been unnoticed, being masked by the anticoagulant activity of heparinoids and heparins on later phases of blood coagulation. It appears that heparin is unable to prevent contact activation in vivo as well as in vitro. This allows PPK assays during extracorporeal circulation in the presence of circulating heparin.

Dextrans↗
PubMedDate not supplied

Effect of nafamostat mesilate on bradykinin generation during low-density lipoprotein apheresis using a dextran sulfate cellulose column.

The dextran sulfate (DS) cellulose column usually used for low-density lipoprotein (LDL) apheresis, is an activator of the contact phase of intrinsic coagulation pathway. Hageman factor (factor XII), high-molecular-weight kininogen (HMWK) and prekallikrein (PK) form a complex on the surface of this activator, and bradykinin is released from HMWK by the action of kallikrein converted from PK. Heparin, a frequently used anticoagulant, has no effect on this process, whereas a protease inhibitor, nafamostat mesilate (FUT-175) is thought to inhibit the process. Five patients with severe hypercholesterolemia were treated with LDL apheresis using heparin or FUT-175, each on a different day. During treatment with heparin, factor XII, HMWK, and PK were markedly decreased by passing through the DS column. A distinct generation of bradykinin was observed by passing through the DS column, which led to an increase of blood bradykinin levels from 12.5 +/- 5.3(Mean +/- SEM) pg/ml to 127.3 +/- 67.1 pg/ml after 1000 ml plasma treatment. FUT-175 almost completely suppressed this bradykinin generation. Because bradykinin generated during LDL apheresis seems to have some vasodilative effect, FUT-175 might be preferred in cases with unstable hemodynamics, although this presumption remains to be demonstrated.

Adult↗
PubMed2005

Anticoagulation during extracorporeal circulation under conditions of an ongoing systemic inflammatory response syndrome: effects of heparin.

OBJECTIVE: Open-heart surgery with cardiopulmonary bypass (CPB) causes changes in haemostasis. Artificial surfaces are bioincompatible and, thus, may initiate a reaction similar to an acute inflammation. In some patients, this 'postperfusion syndrome' (PPS), which includes changes in haemostasis, is the beginning of a systemic inflammatory response syndrome (SIRS). However, it is not clear whether the changes in coagulation represent a consequence or a main cause of the inflammatory reaction. Thus, the aim of our study was to investigate the cascade of coagulation and the effects of heparin under special circumstances of an ongoing SIRS. METHODS: In a prospective evaluation using standardized operative procedures with CPB, we compared Group A (control group with normal postoperative course, n =20) with Group B (patients with postoperative SIRS, n =12). At six time points beginning before and ending two days after surgery, we measured platelet counts, leucocyte counts and plasma levels of fibrinogen, factor XII and antithrombin III (ATIII), in addition to standard coagulation tests (PTT, TT and ACT). Furthermore, we determined parameters of inflammation, such as C-reactive protein, PCT, IL-6, IL-8, IL-10 and TNF-alpha. RESULTS: In Group B (SIRS), we found a reduced anticoagulation during CPB with significantly lower values for PTT (60+/-7 versus 160+/-11 s), ACT (270+/-33 versus 532+/-44 s) TT (40+/-3 versus 150+/-15 s) compared to the control Group A. Simultaneously, we found a significant increase of factor XII in the SIRS group (191+/-16 versus 10+/-2%). There were no significant differences concerning the preoperative ATIII levels and the intraoperative dosage of heparin; the intraoperative decrease of fibrinogen, ATIII and platelets was comparable in both groups. Furthermore, we could see that significant changes of inflammatory parameters in the SIRS group (increasing levels of TNF-alpha, Il-6, IL-8 and IL-10) occurred at least 30 min after the observed reduction of anticoagulatory effect. CONCLUSIONS: With our results, it could be demonstrated that the development of inflammatory complications after CPB is correlated to a significantly reduced intraoperative effect of heparin. As this reduction of anticoagulation significantly preceded the changes of inflammatory parameters in SIRS patients, we think that a hypercoagulatory state, especially in cases of ongoing inflammation, is an additional trigger of SIRS.

Aged↗
PubMed1987

Alpha 2-macroglobulin-kallikrein potentiates contact system activity: possible effect in asthma.

Bradykinin release, an end product of contact system activation, is thought to play a significant role in the pathophysiology of asthma. We have found an increased level of native alpha 2-macroglobulin-kallikrein (alpha 2M-KK) in asthma plasmas, and have demonstrated increased levels of contact system activity in these plasmas under certain laboratory conditions. We investigated the possible role of alpha 2M-KK as a modulator of the contact system activity. Alpha 2M-KK potentiated the factor XII activation on kaolin and the kallikrein production in a dextran-sulfate-mediated assay. This potentiation presumably involves a proteolytic effect of alpha 2M-KK on high molecular weight kininogen.

Asthma↗
PubMed2002

Absence of paradoxical thrombin activation by fibrin-specific thrombolytics in acute myocardial infarction: comparison of single-bolus tenecteplase and front-loaded alteplase.

OBJECTIVES: Thrombolytic therapy in patients with acute myocardial infarction is hampered by bleeding complications and procoagulant effects favoring early reocclusion. TNK-tPA was shown in vitro to have considerable fibrin specificity. We investigated the effects of tenecteplase (TNK-tPA) and alteplase (rt-PA) on the haemostasis and fibrinolytic system. METHODS AND RESULTS: We enrolled 30 patients with AMI into the study. Twenty patients received front-loaded rt-PA up to 100 mg; 10 patients were given TNK-tPA in a single bolus up to 50 mg. All patients received aspirin and intravenous heparin. During the first 2 days, the following parameters were repetitively determined: thrombin-antithrombin III complexes (TAT), antithrombin III (ATIII), prothrombin fragment F 1 + 2 (F 1 + 2), kallikrein-like activity (KK), activated factor XII (FXIIa), plasmin alpha 2-antiplasmin complexes (PAP), fibrinogen, D-dimers (DD), tissue-type plasminogen activator (t-PA). A total of 75 healthy persons served as control group. TAT increased significantly after rt-PA but not after TNK-tPA (3 h: 38.1 +/- 29.4 versus 10.5 +/- 4.2 microg/l; p < 0.01), indicating paradoxical thrombin activation. F 1 + 2 increased transiently after rt-PA but not after TNK-tPA. Fibrinogen was significantly lower after rt-PA versus TNK-tPA (3 h: 163 +/- 27 versus 380 +/- 54 mg/dl; p < 0.05). KK activities in the rt-PA group were significantly (p < 0.01) increased over 48 h versus TNK-tPA. PAP and D-dimers were lower over the time course of 48 h in the tenecteplase group versus rt-PA. CONCLUSIONS: This study indicates that tenecteplase has higher fibrin specificity not only in vitro but also in vivo versus alteplase. TNK-tPA consecutively has no paradoxical systemic procoagulant effect due to the lower extent of activation of the kallikrein-factor XII system than alteplase.

Aged↗
PubMed1982

Murine lymphoid procoagulant activity induced by bacterial lipopolysaccharide and immune complexes is a monocyte prothrombinase.

Murine lymphoid cells respond rapidly to bacterial lipopolysaccharide or antigen-antibody complexes to initiate or accelerate the blood coagulation pathways. The monocyte or macrophage has been identified as the cellular source, although lymphocyte collaboration is required for the rapid induction of the procoagulant response. This procoagulant activity is identified in the present study as a direct prothrombin activator, i.e., a prothrombinase. Studies with plasmas deficient in single coagulation factors demonstrate that the induced murine procoagulant activity effector molecule does not require factors XII, VIII, VII, X, or V, but does require prothrombin to transform fibrinogen to fibrin. This enzyme(s) produces limited proteolysis of prothrombin to yield thrombin or thrombinlike products that are functionally capable of converting fibrinogen to fibrin. The prothrombinase is undetectable in freshly isolated Murine lymphoid cells respond rapidly to bacterial lipopolysaccharide or antigen-antibody complexes to initiate or accelerate the blood coagulation pathways. The monocyte or macrophage has been identified as the cellular source, although lymphocyte collaboration is required for the rapid induction of the procoagulant response. This procoagulant activity is identified in the present study as a direct prothrombin activator, i.e., a prothrombinase. Studies with plasmas deficient in single coagulation factors demonstrate that the induced murine procoagulant activity effector molecule does not require factors XII, VIII, VII, X, or V, but does require prothrombin to transform fibrinogen to fibrin. This enzyme(s) produces limited proteolysis of prothrombin to yield thrombin or thrombinlike products that are functionally capable of converting fibrinogen to fibrin. The prothrombinase is undetectable in freshly isolated

Animals↗
PubMed1988

[Activation of the kallikrein-kinin system by intravenous administration of ionic and non-ionic radiographic contrast media].

Conventional ionic contrast media (sodium meglumine and amidotrizoate) were injected intravenously in 22 patients (group A); the nonionic, low-osmolar contrast medium iohexol was similarly administered to 24 patients (group B). This resulted in a significant (group A: P less than 0.05; group B: P less than 0.01) reduction in prekallikrein (93 and 94%, respectively), inhibition of kallikrein (90 and 88%), beta-factor XIIa inhibition (86 and 85%), and C1 inhibition (90 and 91%). Factor XII levels remained unchanged in both groups. These results indicate that the kallikrein-kinin system is activated even during routine, complication-free radiographic procedures involving contrast-media injection. There was no difference between ionic and nonionic contrast media.

Complement C1 Inactivator Proteins↗
PubMed1983

Prekallikrein activation and high-molecular-weight kininogen consumption in hereditary angioedema.

Patients with hereditary angioedema lack C-1 inhibitor, a plasma alpha 2-glycoprotein that inhibits both the proteolytic action of C1, the activated first component of the complement system, and the activity of components of the contact phase of coagulation: kallikrein, factor XIa, and factor XIIa. Such patients have been shown to have low levels of C4 and C2, the natural substrates for C-1, but the levels were not correlated with the presence of symptoms. We studied three patients with angioedema for evidence of activation of the contact system and found that during a symptomatic period they had decreased levels of prekallikrein, a substrate for the activated forms of factor XII, and reductions in high-molecular-weight kininogen, a substrate for plasma kallikrein. These observations suggest that zymogens of the contact system are activated during attacks of hereditary angioedema and that some of the clinical manifestations may be mediated through products of this pathway, such as kinins.

Adolescent↗
PubMed1999

The levels of factor XIIa generated in human plasma on an electronegative surface are insensitive to wide variation in the concentration of FXII, prekallikrein, high molecular weight kininogen or FXI.

The contribution of the various components of the contact system in the generation of factor XIIa (FXIIa) and of kallikrein (KRN) on an electronegative surface and the release of the generated enzymes to the bulk phase was examined in mixtures of normal human plasma and plasmas congenitally deficient in these components. The incubation of normal human plasma in the presence of sulphatide vesicles (40 microM) resulted in a fast generation of amidolytic activities due to FXIIa and to KRN followed by slower first-order inactivation rates of FXIIa (k'FXIIa) and of KRN (k'KRN) due to the presence of esterase inhibitors. Variation of the levels of factor XII (FXII), over a wide range, showed little effect on levels of FXIIa and of KRN but no activities were detected in 100% FXII-deficient plasma. The variation of prekallikrein (PKRN) concentration showed little effect on the generation of FXIIa but the generation of KRN declined linearly with the decrease in the level of PKRN. No activities were detected on treatment of PKRN-deficient plasma. The variation in the concentration of high molecular weight kininogen (HK) showed effects on FXIIa and KRN that were qualitatively similar to those seen on variation of PKRN but 100% HK-deficient plasma generated considerable activities of both FXIIa and KRN. The variation in the concentration of factor XI (FXI) showed no effect on the generation of FXIIa, whereas KRN levels increased linearly with the contribution of FXI-deficient in normal plasma. The present results suggest that the contiguous binding of FXIIa, FXII, PKRN-HK and FXI-HK onto the electronegative surface induces a rapid generation of FXIIa and KRN. The bound PKRN-HK complex prevents the release of generated FXIIa and therefore further binding and activation of FXII from the bulk phase. Consequently, the turnover of FXII is independent of its levels in the bulk phase and is rather related to the concentration of contact surface. The generated KRN is also protected by HK. However, since the enzyme responsible for the activation of PKRN-HK is FXIIa, the levels of generated KRN are positively related to the concentration of substrate.

Animals↗
PubMed1986

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

Plasma kallikrein activated spontaneously during the purification of prekallikrein (I) and acetone-activated plasma kallikrein (II) were at pH 7.4 both capable of reducing the capacity of purified human high molecular weight kininogen (HMrK) to function as cofactor in the contact phase activation of factor XII in a crude plasma preparation. At pH 6.8 only I had such an effect. SDS polyacrylamide gel electrophoresis with reduction indicated that both I and II contained kallikrein as a cleaved 'three-chain molecule. I contained in addition a Mr 49,000 fraction reflecting possibly uncleaved heavy chain. The registration of reduced cofactor function of HMrK induced by plasma kallikrein is discussed in view of the assay procedure used.

Enzyme Activation↗
PubMed2001

Changes in the extrinsic and intrinsic coagulation pathways in humans after decompression following saturation diving.

We have investigated the effect of simulated saturation diving on the activation of intrinsic and extrinsic coagulation pathways. Thirty-one male divers divided into two groups were tested in decompression habitat LSH-200. The first group of 16 divers was subjected to hyperbaric exposure at pressure of 180 kPa with air as a breathing mixture, and the second group of 15 divers, exposed to a pressure of 400 kPa with a heliox breathing mixture (helium-oxygen mixture: pO2, 40 kPa; pN2, 40 kPa; pHe, 420 kPa). The concentrations of tissue factor, tissue factor pathway inhibitor, factors XII, X, VII, and I, prothrombin fragment F1 + 2, and thrombin-antithrombin complex as well as platelet count, prothrombin time, activated partial thromboplastin time, plasmin-antiplasmin complex (PAP) and D-dimers were measured. We did not detect activation of the extrinsic coagulation pathway after decompression. There was a statistically significant decrease in platelet counts and factor I, XII and X concentrations after air-diving, and a potent and statistically significant increase of PAP concentration in both groups of divers. We suggest that saturated air or heliox diving followed by decompression have little if any effect on thrombin generation. Saturated air diving, however, may induce a decrease in platelet count and factor XII concentration. The observed elevation of PAP concentrations in both groups of divers suggests possible activation of fibrinolysis. The exact effect of diving and decompression on fibrinolytic system has to be further investigated.

Adult↗