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PubMed1992

Inhibition of prekallikrein activation in human plasma by components of bovine plasma.

Contact of plasma with a negatively charged surface activates prekallikrein and factor XII reciprocally. Activation of prekallikrein by several activators was impaired in bovine plasma when compared to that in human plasma. The activated partial thromboplastin time of bovine plasma, induced by several activators, was significantly longer than that of human plasma. Cleavage of [125I]factor XII was optimum at 10 min in human plasma but took up to 60 min in bovine plasma. Addition of bovine plasma to human plasma caused significant inhibition of dextran sulfate-induced prekallikrein activation, indicating that the impaired rate of contact activation in bovine plasma is due to the presence of inhibitors. The inhibitory effect was greater at lower concentrations of dextran sulfate but could not be abolished by increasing the concentration. The inhibitory activity eluted in two peaks at low and medium salt concentrations on carboxymethyl ion-exchange chromatography of bovine plasma.

Animals↗
PubMed1999

Activation of the plasma kallikrein/kinin system on endothelial cell membranes.

For more than three decades, it has been known that the plasma kallikrein/kinin system becomes activated when exposed to artificial, negatively charged surfaces. The existence of an encompassing in vivo, negatively charged surface capable of activation of the plasma kallikrein/kinin system has, however, never been convincingly demonstrated. In this report, we describe current knowledge on how the proteins of the plasma kallikrein/kinin system assemble to become activated on cell membranes. On endothelial cells, the activation of the plasma kallikrein/kinin system is not initiated by factor XII autoactivation as seen on artificial surfaces. On endothelial cells, prekallikrein is activated by an antipain sensitive protease. Prekallikrein activation is dependent on the presence of high molecular weight kininogen and an optimal free Zn2+ concentration. Kallikrein generated on the surface of endothelial cell is capable of activating factor XII. Further, kallikrein formed on endothelial cell membranes is capable of cleaving its receptor and native substrate, high molecular weight kininogen, liberating bradykinin and the HK PK complex from the endothelial cell surface. Endothelial cell-associated kallikrein also is capable of kinetically favorable pro-urokinase and, subsequent, plasminogen activation.

Animals↗
PubMed1983

Dextran sulfate-dependent fibrinolysis in whole human plasma.

This study shows that Flu-beta-Ala can reduce the ability of human plasma to inhibit plasmin. This observation was utilized to develop a method for generating detectable fibrinolytic activity in whole human plasma as assessed on a radiolabeled fibrin plate. Plasma was pretreated with Flu-beta-Ala to remove inhibitors of fibrinolysis: then dextran sulfate was added and the mixture was further incubated at 4 degrees C. When normal plasma was treated in this manner, the rate of generation of fibrinolytic activity after 0.75 hr incubation with radiolabeled fibrin was equivalent to that of 35 ng/ml plasmin. The plasminogen dependence of this activity was tested by pretreating plasma with antibodies against plasminogen. The generation of fibrinolytic activity was totally blocked by this treatment, indicating that the observed fibrinolytic activity was plasminogen-dependent. When plasmas deficient in prekallikrein, factor XII, or high-molecular-weight kininogen were treated with Flu-beta-Ala and dextran sulfate, the initial rate of fibrinolytic activity was less than normal. But after 3 hr incubation with radiolabeled fibrin, the rate of fibrinolytic activity in these deficient plasmas approached that of normal plasma. Thus this dextran sulfate-dependent fibrinolytic activity is dependent on factor XII, prekallikrein, and high-molecular-weight kininogen, but the requirement is not absolute.

Dextran Sulfate↗
PubMed1976

Activation of the coagulation system in polycythemia vera.

Thrombosis is one of the major complications of polycythemia vera. Seventeen patients with polycythemia vera in good hematologic control were evaluated for abnormalities of the coagulation system. Activation of the intrinsic coagulation cascade was suggested by low levels of factor XII, prekallikrein, and kallikrein inhibitors in 12 of 17 patients. The group also demonstrated a significant increase in soluble fibrin complexes using plasma gel filtration on 4% agarose. Fibrin degradation products were normal and antithrombin III levels were slightly elevated. It appears that patients with polycythemia vera have chronic activation of the coagulation system, probably initiated by activation of factor XII. No correlation between the degree of coagulation abnormalities and thromboembolic complications was evident in this group of patients.

Antithrombins↗
PubMed1992

Influence of 4 different membrane oxygenators on inflammation-like processes during extracorporeal circulation with pulsatile and non-pulsatile flow.

The influence of four different membrane oxygenators (HF 4000, BOS-CM 50, CML 2, Maxima) on leucocyte count, concentrations of PMN-elastase, clotting factor XII, AT-III, C1-INH, alpha 2-antiplasmin and C3a was registered before, during and after CPB with pulsatile and nonpulsatile flow in 80 male patients aged between 36 and 67 years. With all systems tested, there was a drop in the concentrations of clotting factor XII, AT-III, C1-INH and alpha 2-antiplasmin in the early extracorporeal circulation (ECC) phase, exceeding the average hematocrit reduction accounted for by dilution. This drop was the least distinct with CML 2 systems, both with pulsatile and nonpulsatile perfusion, indicating system-inherent influences. Leucocyte cound and PMN-elastase concentration rose significantly during ECC irrespective of oxygenator tested of flow type applied. The rise in leucocyte count even continued for about 4 h after ECC. During the first 40 min of ECC, these changes were paralleled by a significant rise in C3a concentration, suggesting complement activation as a main cause for PMN activation. However, there is reason to suppose involvement of further mechanisms operating in PMN activation, since the elevated C3a-concentrations began to fall off while leucocyte count and PMN-elastase concentrations were still increasing.

Acute-Phase Proteins↗
PubMed1990

Procoagulant activity of collagen. Effect of difference in type and structure of collagen.

Procoagulant activities of different types and structures of collagen were examined. Collagens used were types I (including its methylated and succinylated forms), II, III, IV and V. Each collagen was coated on an inner surface of a glass tube. The change of fluidity during coagulation of blood in the tube was measured by means of a new rheological technique. For monomeric collagen, the procoagulant activity of the succinylated form (negatively charged) was higher than that of the methylated form (positively charged). The procoagulant activity of type IV (dry) was lower than that of other types of collagen. For fibrillar collagens, the initiation of coagulation for type V (non-banded) was fairly delayed compared to those for types I, II and III (banded). An increase in water content in both monomeric and fibrillar forms promoted procoagulant activity. For most of the collagen forms, the addition of factor XII inhibitor (Polybrene) to blood brought about a remarkable delay of the initiation of coagulation, suggesting that the activation of factor XII on the collagen surface is one of main factors governing procoagulant activity. In addition, our data suggest that large numbers of adherent platelets to the collagen surface promote activation of the intrinsic coagulation system.

Adult↗
PubMed1994

Coagulation profile in persons with long-standing spinal cord injury.

Acute spinal cord injury (SCI) is associated with a marked propensity to thromboembolism and a variety of coagulation abnormalities. However, data on blood coagulation profiles in patients with uncomplicated long-standing SCI are limited. These data were studied here. Eight men with uncomplicated chronic SCI and nine able-bodied normal men were studied. Plasma activities and/or antigen concentrations of high molecular weight kininogen (HMWK) and of factors XII, XI, IX, VIII, VII, X, V, II and XIII as well as von Willebrand factor (vWF), fibrinogen and fibronectin were measured by appropriate functional and or immunological assays. The SCI group exhibited normal values for factors XII, IX, VIII, vWF, VII, X and V as well as HMWK, vWF and fibronectin concentration. However, they showed slight reductions in plasma factor XI activity, factor XIII antigen concentration and modest increases in fibrinogen and factor II concentrations. No correlation was found between the parameters studied and either the duration or the level of injury. In conclusion, in contrast to acute SCI, the coagulation profile in uncomplicated chronic SCI is noted to be largely normal with only a few minor alterations of questionable clinical significance.

Adult↗
PubMed2001

Activation of the kinin-forming cascade on the surface of endothelial cells.

Activation of the plasma kallikrein-kinin forming cascade takes place upon incubation with human umbilical vein endothelial cells. The mechanism by which initiation occurs is uncertain. Zinc-dependent binding of plasma proteins to gC1qR, cytokeratin 1, and perhaps u-PAR is requisite for activation to take place. We demonstrate here that during a 2 hour incubation time plasma deficient in either factor XII or high molecular weight kininogen (HK) fails to activate, as compared to normal plasma, but with more prolonged incubation, factor XII-deficient plasma gradually activates while HK-deficient plasma does not. Our data support both factor XII-dependent (rapid) and factor XII-independent (slow) mechanisms; the latter may require a cell-derived protease to activate prekallikrein and the presence of zinc ions and HK.

Antibodies, Blocking↗
PubMed1976

Evidence that colagen releases human platelet constituents by two different mechanisms.

Collagen is believed to be involved in the initial events in haemostasis and has been shown by others to cause platelet aggregation and release, and also to initiate the intrinsic pathway of coagulation. The present experiments provide evidence whihc suggests how these many effects of collagen may be involved in haemostasis. It is shown here that collagen releases platelet constituents by two different pathways. Collagen causes platelets washed free of loosely adsorbed coagulation factors to release constituents. This activity, is therefore, independent of the intrinsic pathway of coagulation, and is not inhibited by heparin or hirudin. Collagen also releases platelet constituents by an alternative pathway which is inhibited by heparin and hirudin and is independent of factor XII, but is dependent on factor XI, subsequent factors in the intrinsic pathway of coagulation and calcium. These results suggest that collagen-induced release of platelet constituents is in part due to a direct effect on the platelet, and , in part, to an indirect effect involving coagulation factors and mediated by thrombin. The present results suggest that irreversible aggregation by collagen is also mediated by thrombin. The possible significance of this dual action of collagen in the haemostatic process is shown in Fig 7.

Blood Platelets↗
PubMed1986

The IgE-dependent release of a Hageman factor cleaving factor from human lung.

Passively sensitized human lung fragments were shown to release a protease by an IgE-dependent mechanism which can cleave human Hageman factor (Coagulation Factor XII). This enzyme, lung Hageman factor cleaving factor, was partially purified by ion exchange chromatography and gel filtration and was shown to be a serine protease with an apparent molecular weight of 12,000-13,000. This protease appears to be unrelated to any known activator of Hageman factor by molecular weight and inhibition profile and was shown to be distinct from an IgE-dependent prekallikrein activator, as well as the kininogenase activity defined as basophil kallikrein of anaphylaxis. Although it appears marginally capable of activating Hageman factor, it rapidly cleaves and inactivates the activated form so that the net effect is a loss of activatable Hageman factor. The result suggests that diminished levels of Hageman factor that may be seen associated with IgE-dependent reactions can be due to digestion and depletion rather than activation, and other criteria for activation of the contact system must be employed.

Antigens↗
PubMed1994

Isolation and characterization of Streptoverticillium anticoagulant (SAC), a novel protein inhibitor of blood coagulation produced by Streptoverticillium cinnamoneum subsp. cinnamoneum.

Three Streptoverticillium anticoagulants, SAC I, II, and III, which strongly inhibit human intrinsic blood coagulation, were each isolated in a homogeneous form from a culture fluid of Streptoverticillium cinnamoneum subsp. cinnamoneum IFO 12852. SAC I, II, and III are simple proteins with molecular weights of around 12,000, and with isoelectric points of 9.7, 9.7, and 9.9, respectively. Their amino acid compositions are similar and each SAC possesses two disulfide bonds. The COOH-terminal residue of each of these proteins is phenylalanine. Together with the similarity of their protein chemical properties, the results of NH2-terminal amino acid sequence analysis of these SAC proteins strongly suggested that the deletion of Ser-Leu and Ser-Leu-Tyr from the NH2-terminus of SAC I (Ser-Leu-Tyr-Ala-Pro-...) results in the generation of SAC II and III, respectively. The amount of each SAC necessary to double the partial thromboplastin time was around 5 micrograms/ml. SAC I inhibited activated human factor XII and human plasma kallikrein. It also inhibited, but to a lesser extent, activated factor X. The inhibition constants (Ki) of SAC I toward activated factor XII and plasma kallikrein were 5.3 x 10(-8) and 7.2 x 10(-9) M, respectively. The SACs also inhibited some microbial serine proteases such as subtilisin Carlsberg and, to a lesser extent, mammalian serine proteases including bovine trypsin and alpha-chymotrypsin. Of these three inhibitors, only SAC I inhibited metalloproteases such as thermolysin in addition to these serine proteases.

Amino Acid Sequence↗
PubMed1993

Contact factor mediated fibrinolysis is increased by the combined oral contraceptive pill.

OBJECTIVE: To study the fibrinolytic pathways and their relationship with the contact system in women using combined oral contraceptives (COCs). DESIGN: Serial plasma samples were collected from 18 women before treatment with COCs containing 30 micrograms oestrogen during treatment cycles 3 and 6, and 2 weeks after stopping treatment. Fibrinolysis was measured before and after dextran sulphate mediated contact activation using fibrin plates. RESULTS: Fibrinolysis increased significantly during cycles 3 and 6 (from 77% to 100% and 113%, respectively, P < 0.01) and showed a further increase after dextran sulphate activation (from 134% to 158% and 167%, respectively, P < 0.01). Tissue-plasminogen activator, urokinase-plasminogen activator and plasminogen activator inhibitor did not change significantly. There were significant elevations of Factor XII (from 0.92 u/ml to 1.43 u/ml, P < 0.01) and prekallikrein (0.94 u/ml to 1.10 u/ml, P < 0.05) in cycle 3, which both remained high at cycle 6 (P < 0.01) and decreased after stopping the COC. Alpha-2-macroglobulin and C1-esterase inhibitor showed no significant change, but alpha-1-antitrypsin increased from 0.85 u/ml to 1.11 u/ml by cycle 3 (P < 0.01), and returned to near normal levels after stopping the COC. CONCLUSIONS: The increase in fibrinolysis may be due to increased levels of Factor XII and prekallikrein without a corresponding increase in their natural inhibitors (C1-esterase inhibitor and alpha-2-macroglobulin). A parallel increase in the intrinsic pathway of coagulation may be limited by elevated alpha-1-antitrypsin at the level of activated Factor XI. The increase in fibrinolysis caused by oral contraceptives may balance any potential thrombotic risk due to increased fibrinogen or vitamin K dependent coagulation factors.

Adolescent↗
PubMed2003

Deviations in coagulation activation due to treatment with different haemodialysis membranes.

Despite systemic heparinization, extracorporeal circulation will induce activation of blood coagulation. Thrombogenicity is associated with biocompatibility of dialysis membranes. Investigation of procoagulatory and fibrinolytic activity is performed prior to and during treatment with haemodialysis. In this study fluctuations of plasma coagulation factor XII, thrombin antithrombin complexes, prothrombin fragment 1 + 2 and thrombus precursor protein were monitored in 10 subjects during treatment with haemodialysis. Subjects were treated with both polysulphone high-flux dialyser membranes (F-60) and low-flux poly-methyl-methacrylate (PMMA) membranes. Immediately after start of treatment, blood in contact with artificial membrane surfaces resulted in a marked decrease in factor XII activity amounting to a mean reduction of 80% in the case of PMMA and a reduction of 40% in the case of F-60. In due course, a steady, on-going generation of thrombin antithrombin complexes was observed in several subjects, especially after treatment with F-60 membranes, amounting to increases exceeding 100% of initial values. Establishment of fibrinogen, prothrombin fragment 1 + 2 and thrombus precursor protein plasma concentrations yielded enhanced results for PMMA compared with the results for treatment with F-60 dialysis membranes. In order to prevent activation of clotting during several stages of haemodialysis, supplementation of anticoagulant can be established on the basis of analytical results of coagulation parameters.

Adult↗
PubMed1997

Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study.

The prevalence of haemostasis abnormalities was evaluated in 500 consecutive women with unexplained primary recurrent miscarriages. Two matched reference groups with no antecedent of miscarriage were studied: 100 healthy mothers and 50 childless women. In the prospective part of the study, we found 9.4% of the patients (95% C.I.: 6.8-12%) with an isolated factor XII deficiency, 7.4% of the patients (5.0-9.8%) with primary antiphopholipid antibodies, 47% of the patients (42.6-51.4%) with an insufficient response to the venous occlusion test and an isolated hypofibrinolysis was found in 42.6% (38.2-47%) of the patients (reference groups: respectively 0/150, 3/150, 2/150, p < 10(-3)). Willebrand disease, fibrinogen, deficiency, antithrombin, protein C or protein S deficiencies were not more frequent in recurrent aborters than in members of the reference groups. In the retrospective part of the study, cases of plasma resistance to activated protein C were not abnormally frequent. Patients had higher Willebrand factor antigen (vWF), tissue-type plasminogen activator antigen (t-PA), plasminogen activator inhibitor activity (PAI) and D-dimers (D-Di) than the reference women. Values of vWF, t-PA, PAI and D-Di were altogether correlated but were not related to C-reactive protein concentrations. Among patients, those with an antiphospholipid syndrome and those with an insufficient response to the venous occlusion test had higher vWF, t-PA, PAI and D-Di values than the patients with none of the haemostasis-related abnormalities. Thus, factor XII deficiency and hypofibrinolysis (mainly high PAI) are the most frequent haemostasis-related abnormalities found in unexplained primary recurrent aborters. In patients with antiphospholipid antibodies or hypofibrinolysis, there is a non-inflammatory ongoing chronic elevation of markers of endothelial stimulation associated with coagulation activation. This should allow to define subgroups of patients for future therapeutic trials.

Abortion, Habitual↗
PubMedDate not supplied

Improved outcome for seriously ill open heart surgery patients: focus on reoperation and endocarditis.

Although routine cardiac surgical procedures are now performed with low rates of mortality and relatively low rates of morbidity, certain categories of patients continue to present a major challenge. Patients who have reoperations and those with active infective endocarditis represent high-risk categories. The pathophysiologic mechanisms involved in such patients include impaired left ventricular function and low cardiac output, sepsis, endotoxemia, and gut permeability, and impaired hemostasis. Although these mechanisms are distinct, they do interrelate. Low cardiac output and imperfect systemic perfusion during and after cardiopulmonary bypass are known to induce splanchnic ischemia with altered permeability of the gut mucosal barrier to gut contents, including endotoxin. The systemic inflammatory response, triggered by contact activation of factor XII, produces functional disturbance in vital organs, notably the brain and lung. In addition, factor XII activation induces disordered hemostasis, which is related to increased fibrinolysis and a possible disturbance in platelet function. Measures to modify these mechanisms and improve outcome in high-risk patients include pulsatile perfusion during cardiopulmonary bypass and aprotinin therapy to modify the inflammatory response and prevent the disorder in hemostasis. Clinical experience with high-dose aprotinin therapy in patients who have reoperations and active endocarditis has demonstrated a very high level of efficacy in reducing blood loss and blood/blood product transfusion requirements. The potential role of aprotinin in stabilizing the microcirculation and modifying the systemic inflammatory response requires further study and may prove to be a major contribution to improved outcome in high-risk patients.

Aprotinin↗
PubMed1998

Hypercoagulable states in patients with retinal venous occlusion.

BACKGROUND AND PURPOSE: The pathogenesis of thrombus formation in the retinal vein resulting in retinal vein occlusion is not well understood. This study was carried out to ascertain the role of hypercoagulable states in patients with retinal vein occlusion. METHODS: Fifty seven consecutive patients with acute retinal vein occlusion (mean age 48 +/- 11.5 years) were investigated for possible hypercoagulable states. Levels of antithrombin III (AT III), protein C (PC), Protein S (PS), factor XII, and fibrinogen as well as the presence of antiphospholipid antibodies (APAs) were investigated. The APAs and fibrinogen results obtained in these patients were compared to those of healthy controls. RESULTS: We detected APAs in 15 out of 57 patients compared to 3 out of 74 controls (p = 0.0002). Fibrinogen levels were significantly higher in patients compared with the controls (p < 0.001). Deficiencies in the naturally occurring anticoagulant proteins including AT III (4 out of 54 patients tested), PC (8 out of 42 patients tested), and PS (12 out of 56 patients tested) were detected. Seven patients out of 32 patients tested had reduced levels of factor XII. Subgroup analysis of the thrombophilic differences between patients who aged 45 years or less and older patients and patients with major trunk vein occlusion and patients with branch vein occlusion revealed no significant differences. CONCLUSION: Hypercoagulable states are common in patients with retinal vein occlusion and may contribute to the etiology of the disease.

Adult↗
PubMed1987

Plasma prekallikrein activity in patients with total hip arthroplasty.

The behaviour of the contact system was studied in 40 patients with total hip arthroplasty, by measuring plasma prekallikrein, spontaneous kallikrein activity and factor XII. In the literature it had been shown that patients with complications from this operation had decreased prekallikrein and increased kallikrein activity (M. Nakahara. Acta orthop scand 1982; 53:591-6). In the present study, comprising patients with and without pain and proven loosening of the hip prosthesis, these findings could only partially be confirmed. Patients with a loosened prosthesis had significantly lower prekallikrein (mean 0.78 +/- 0.28 U/ml; p less than 0.01) than patients without problems, but no detectable kallikrein activity in plasma. Patients with pain but no loosening had normal prekallikrein (1.04 +/- 0.26 U/ml) and also no demonstrable kallikrein activity. Factor XII was normal in all patient groups. It is concluded that decreased prekallikrein is limited to patients with a loosened hip prosthesis, with or without pain.

Aged↗
PubMed1993

Decreased contact factor mediated fibrinolysis in cirrhosis.

We studied extrinsic and intrinsic fibrinolysis in 20 patients with cirrhosis (nine mild/moderate, group 1; 11 severe, group 2) and 19 normal controls to define the role of intrinsic (contact factor medaited) fibrinolysis in cirrhosis. Global plasma fibrinolytic activity (fibrin plate lysis) was similar in all groups. Dextran sulphate activated contact factor mediated fibrinolysis was decreased in group 2 (median 95.2%) compared with group 1 (121.0%) and controls (131.7%). Tissue plasminogen activator antigen (t-PA Ag) levels were increased in group 2 (28.2 ng/ml) compared both with group 1 (8.5 ng/ml) and controls (5.9 ng/ml). Plasma t-PA activity was raised in group 2 (5.50 IU/ml) and group 1 (5.25 IU/ml) versus controls (0.82 IU/ml). Plasminogen activator inhibitor-1 (PAI-1 Ag) levels were raised in group 2 (28.0 IU/ml) versus controls (8.5 IU/ml) but PAI activity was similar in all groups. Factor XII activity was decreased in group 2 (48.76 u/dl), but not group 1, versus controls (89.1 u/dl). Prekallikrein activity was decreased both in group 2 (27.27 u/dl) and group 1 (33.01 u/dl) versus controls (108.59 u/dl) and was lower in group 2 than group 1. C1-esterase inhibitor chromogenic activity was decreased in group 1 (102.30 u/dl) and group 2 (58.76 u/dl) versus controls (116.24 u/dl). The normal global fibrinolytic activity despite increased t-PA activity may be due to a concomitant increase in PAI. The decreased intrinsic fibrinolysis in severe cirrhosis, unaccompanied by a rise in C1-esterase inhibitor, may be explained by the decreased factor XII and prekallikrein activity. These changes are probably due to reduced liver cell mass.

Adult↗