Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to clarify the effect of hemodialysis (HD) on the fibrinolytic system, fibrinolytic activity was evaluated in 27 patients undergoing regular hemodialysis treatment (RDT) using new parameters including plasma alpha 2-plasmin inhibitor (alpha 2 PI), alpha 2-plasmin inhibitor-plasmin complex (alpha 2 PIC), cross-linked fibrin degradation products (XL-FDP), tissue plasminogen activator (t-PA) activity, t-PA antigen and plasminogen activator inhibitor-1 (PAI-1) antigen. Predialysis baseline levels of plasminogen and alpha 2PI activity in RDT patients were significantly lower and those of alpha 2PIC were significantly higher than normal control values. During a single HD session, alpha 2PIC exhibited a continuous, significant increase reaching about 180% of initial values by the end of HD. alpha 2PI activity was significantly decreased at the end of the HD, though there were no significant changes in plasminogen activity during HD. Predialysis baseline levels of XL-FDP in RDT patients were significantly higher than normal control values. No significant changes in XL-FDP were observed during HD. Both t-PA activity and t-PA antigen significantly increased during HD, and PAI-1 antigen significantly decreased during HD. Von Willebrand factor (vWF) antigen in plasma, which is regarded as reflecting a release reaction by vascular endothelial cells to certain stimuli, also significantly increased during HD. However, neither vWF antigen nor t-PA antigen was increased by heparin administration alone. The changes in alpha 2PI and alpha 2PIC levels suggest that fibrinolytic activity is slightly higher in RDT patients and is even higher during HD.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced fibrinolytic activity during the course of hemodialysis. 138 98

A small but consistent proportion of the von Willebrand factor (vWF) in normal plasma is composed of 189, 176, and 140 kD fragments cleaved from the 225 kD subunit. A monoclonal antibody map of vWF, based on the reactivity of individual antibodies with cyanogen bromide and tryptic fragments of known carboxy and/or amino termini, showed that in normal and IIA von Willebrand disease (vWD) plasmas the 140 kD fragment was derived from the amino-terminal region, whereas the 176 kD fragment was derived from the carboxy-terminal region of the subunit. In type IIA vWD, however, the fragments comprised a greater proportion of circulating vWF. In contrast, plasmin cleaved a 176 kD fragment from the amino terminus and a 145 kD fragment from the carboxy terminus of the subunit. Species similar to these plasmin-cleaved fragments were demonstrated in plasmas from four patients treated with fibrinolytic agents, but not in IIA vWD.
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PMID:Epitope mapping of the von Willebrand factor subunit distinguishes fragments present in normal and type IIA von Willebrand disease from those generated by plasmin. 243 8

Some properties of a monoclonal antibody generated against the fibrinogen component of a factor VIII preparation were investigated. The antibody bound with equal affinity in solid phase radioimmunoassays to fibrinogens isolated from both normal patients and patients with von Willebrand disease. It reacted in a sensitive immunoassay of plasma fibrinogen. The specificity of the antibody was confined to the parent molecule with no significant inhibition of fibrinogen binding by the fibrinogen degradation products (FDPs) X, Y, D, or E. The antibody had no significant effect on the activated partial thromboplastin time and prothrombin time of normal plasma. However, it prolonged the thrombin time as determined by the Clauss chronometric fibrinogen method. During fibrinogen lysis by plasmin immunoreactivity of fibrinogen to the antibody was lost at the same rate as the clottable fibrinogen content determined by the Clauss assay. The lack of reactivity of the antibody with FDPs makes it a suitable reagent for investigating plasmin activity as well as studying fibrinogen and fibrin. These findings suggest that the epitope of the antibody lies within the polar protruberance of the carboxy terminal end of the A alpha chain of fibrinogen and is destroyed by plasmin cleavage.
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PMID:Some studies with a monoclonal antibody directed against human fibrinogen. 257 30

Factor VIII coagulant protein (VIII:C) functions as a critical cofactor with factor IXa, calcium ions, and phospholipid during the activation of factor X. In the course of this reaction, the activity of VIII:C is first increased and then is destroyed by one or more serine proteases that are part of the coagulation sequence. In this study, we have investigated the influence of platelets on the inactivation of VIII:C by plasmin. Platelets were separated from plasma proteins in the presence of granule release inhibitors and were incubated with plasmin and isolated VIII:C or the complex of purified VIII:C/von Willebrand factor (vWF); VIII:C activity and antigen levels were assessed over time. In the presence of platelets, the isolated VIII:C showed an initial increase in VIII:C activity that was not present when platelets were absent, and the VIII:C/vWF showed an increase in VIII:C activity over that seen when platelets were absent. In addition, platelets stabilized VIII:C activity over a one-hour time course when compared with buffer. The VIII:C antigen did not increase and decreased slowly whether platelets were present or absent. Preincubating the platelets with ristocetin, collagen, or plasmin did not alter the results, and experiments using platelets from a patient with severe von Willebrand's disease also showed a pattern similar to that seen with normal platelets. Experiments using fixed platelets or phospholipid vesicles showed that they did not support the activation reaction or delay the inactivation reaction. These studies demonstrate that platelets modulate the activation and inactivation of VIII:C by plasmin, apparently by a mechanism that is independent of the platelet release reaction.
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PMID:Platelets modulate the proteolysis of factor VIII:C protein by plasmin. 293 96

Some patients with von Willebrand's disease do not respond to stimuli such as venous occlusion and infusion of a vasopressin analogue DDAVP. In these patients, fibrinolytic activity is not enhanced and von Willebrand's factor is not released into the blood. Skin biopsies and cryostat sections were used to study the fibrinolytic activity of skin vessels and localization of tissue plasminogen activator (t-PA) in three patients with severe form of von Willebrand's disease. On fibrin films, no fibrinolysis developed around the skin vessels of the patients; however, using specific polyclonal and monoclonal antibodies to t-PA, and peroxidase coupled specific IgG, presence of t-PA antigen was demonstrated in endothelial cells (EC) of all of them. In plasma no t-PA activity was detected either before or after venous occlusion although t-PA inhibitor activity was in a normal range. Small amounts of t-PA antigen was measured in blood by ELISA. From these results, it is concluded that in patients with severe forms of von Willebrand's disease, t-PA present in EC is not functional and can not transform plasminogen into plasmin.
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PMID:Absence of functional activity of tissue plasminogen activator in patients with severe forms of von Willebrand's disease. 311 91

To better define the role of carbohydrate in the structure and ristocetin cofactor activity of von Willebrand factor, we have removed up to 83% of total hexose by sequential treatment of the molecule with endo-beta-N-acetyl-glucosaminidase F (endo F), neuraminidase, and beta-galactosidase. Endo F alone removed 69% of total hexose and D-galactose, and 71% of sialic acid. However, there was no discernible loss of large multimers and the ristocetin cofactor activity was decreased by only 11%. The reduced von Willebrand factor subunit migrated more rapidly in polyacrylamide gels containing SDS, consistent with a 10% decrease of molecular mass. All multimers of unreduced carbohydrate-modified von Willebrand factor migrated more rapidly in SDS-agarose, but the triplet pattern of individual multimers was unchanged. This alteration in multimer migration rate did not resemble alterations found so far in von Willebrand disease variants. Further treatment of von Willebrand factor with neuraminidase and beta-galactosidase reduced the D-galactose to 15% and ristocetin cofactor activity to 57%. A similar decrease in ristocetin cofactor activity was seen if von Willebrand factor was treated only with neuraminidase and beta-galactosidase. In contrast, treating von Willebrand factor with neuraminidase and beta-galactosidase in the presence of protease inhibitors (20 mM benzamidine, 20 U/ml aprotonin, 15 micrograms/ml leupeptin) resulted in a comparable removal of carbohydrate with no change in ristocetin cofactor activity. Moreover, the multimeric structure remained intact in spite of 80% removal of D-galactose. This suggested that carbohydrate was protecting von Willebrand factor against traces of one or more protease contaminants. Evidence in support of this hypothesis was obtained by exposing von Willebrand factor to plasmin after pretreatment with neuraminidase alone or with neuraminidase and beta-galactosidase. A loss of large multimers was observed from von Willebrand factor that had been pretreated with neuraminidase, but this was even greater if pretreatment was also with beta-galactosidase. In contrast, the multimeric structure of von Willebrand factor with intact carbohydrate was not affected by plasmin under similar conditions. These studies suggest that carbohydrate protects von Willebrand factor from disaggregation occurring secondarily to proteolytic attack but does not play a direct role in maintaining its multimeric structure or ristocetin cofactor activity.
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PMID:Carbohydrate moiety of von Willebrand factor is not necessary for maintaining multimeric structure and ristocetin cofactor activity but protects from proteolytic degradation. 623 76

The aim of this study was to compare the secretory response of the vascular wall in vivo to DDAVP (i.v. 0.3 microgram/kg, 30 min) and to venous occlusion (VO, 20 min) in control healthy subjects, patients with von Willebrand's disease type I (vWd I) and patients with von Willebrand's disease type III (vWd III). In controls (n = 10) and vWd I (n = 12), DDAVP induced a 2 to 3-fold rise in plasma von Willebrand factor antigen (vWf: Ag), factor VIII coagulant activity (VIII: C) and tissue--type plasminogen activator antigen (t-PA:Ag). VO was less effective in increasing vWf: Ag and VIII:C but produced a greater rise in t-PA:Ag. Large increments (over 10-fold) were observed in plasmin-alpha 2-antiplasmin complexes following both stimuli. In vWd III (n = 10), DDAVP and VO failed to increase vWf:Ag, VIII:C and t-PA:Ag. No significant changes in plasmin-alpha 2-antiplasmin complexes were observed in this group. Moreover, the baseline t-PA:Ag values were significantly lower in vWd III (2.17 +/- 1.13 ng/ml) than in controls (4.84 +/- 1.97 ng/ml, p < 0.001). A significant increase in urokinase--type plasminogen activator antigen (u-PA:Ag) was found only in controls after VO. Neither controls nor patients with vWd showed any changes in plasma fibronectin levels following DDAVP. The low t-PA:Ag results and the abnormal fibrinolytic response to DDAVP and VO in patients with severe (type III) vWd indicate that their endothelial cell abnormality is more extensive than the defect in the synthesis or release of vWf.
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PMID:Secretory response of the vessel wall to DDAVP and venous occlusion in von Willebrand's disease. 799 99

Plasmin triggers a strong metabolic activation in human platelets, leading to shape change and granule exocytosis. However, its capacity to induce cell aggregation remains discussed and, when observed, this aggregation is preceded by a remarkable lag phase. We have thus investigated the effect of plasmin on the adhesive proteins which can be secreted by isolated platelets and mediate cell-to-cell interactions, but are also substrates for the enzyme. Immunoblot analysis of fibrinogen (Fg), thrombospondin-1 (TSP-1), fibronectin (Fn) and von Willebrand factor (vWf) was performed on extracts of platelets exposed under stirring to increasing concentrations of plasmin for up to 10 min at 37 degrees C. Under conditions leading to formation of large aggregates, Fg, Fn and TSP-1 are extensively degraded concomitantly with their secretion, and readily lost from the surface of aggregated cells. Part of the monomers in the platelet vWf are cleaved during secretion into two main fragments with Mr approximately 180,000 and approximately 145,000. However, multimer distribution analysis shows only a slight decrease in the very high molecular weight multimers, and most of the fragmented as well as intact vWf remains associated with the platelet surface when aggregation is maximal. That indeed vWf largely supports plasmin-induced aggregation is suggested by the observation that platelets from a patient with type 3 von Willebrand's disease, who totally lacks vWf, show little aggregation in response to the enzyme. Finally, plasmin-induced aggregation can be totally inhibited by antagonists of the alpha(IIb)beta3 integrin. The present study thus indicates a major role for secreted vWf in platelet aggregation induced by plasmin, through its likely interaction with the multifunctional receptor alpha(IIb)beta3.
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PMID:On the mechanism of plasmin-induced aggregation of human platelets: implication of secreted von Willebrand factor. 965 47

Pro-hemostatic therapy aims at an improvement of hemostasis, which may be achieved by amelioration of primary hemostasis, stimulation of fibrin formation or inhibition of fibrinolysis. These treatment strategies may be applied to specifically correct a defect in one of the pathways of coagulation, but have in some situations also been shown to be effective in reducing bleeding in patients without a primary defect in coagulation. Besides the transfusion of platelets in case of thrombocytopenia or severe platelet disorders, a pharmacological improvement of primary hemostasis may be achieved by the administration of desmopressin. The administration of DDAVP results in a marked increase in the plasma concentration of Von Willebrand factor (and associated coagulation factor VIII) and (also by yet unexplained additional mechanisms) a remarkable potentiation of primary hemostasis as a consequence. DDAVP is used for the prevention and treatment of bleeding in patients with von Willebrand disease or mild hemophilia A, and further in patients with an impaired function of primary hemostasis, such as in patients with uremia, liver cirrhosis or in patients with aspirin-associated bleeding. Based on the current insight that activation of coagulation in vivo predominantly proceeds by the tissue factor/factor VII(a) pathway, recombinant factor VIIa has been developed as a prohemostatic agent and has recently become available for clinical use. Indeed, in uncontrolled clinical studies this compound has been shown to exert a potent procoagulant activity and appeared to be highly effective in the prevention and treatment of bleeding, although most experience so far has been obtained in patients with severe and complicated coagulation defects. At present, a more general use of this agent for bleeding patients without an apparent coagulation defect is the subject of a number of ongoing clinical trials. Agents that exert anti-fibrinolytic activity are aprotinin and the group of lysine analogues. The pro-hemostatic effect of these agents proceeds not only by the inhibition of fibrinolysis (thereby shifting the procoagulant/anticoagulant balance towards a more procoagulant state), but also due to a protective effect on platelets, as has been demonstrated at least for aprotinin. The mechanism of this platelet-protective effect has, besides a potential prevention of plasmin-mediated loss of platelet receptors not been elucidated. Whether the pro-hemostatic effect of the anti-fibrinolytic agents will eventually result in a higher incidence of thromboembolic complications is still a matter of debate (see further), however, this has so far not been shown in straightforward clinical trials.
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PMID:Management of bleeding disorders by prohemostatic therapy. 1243 Sep 14

Pro-thrombin activatable fibrinolysis inhibitor (pro-TAFI), also called plasma procarboxypeptidase B or U, is one of the modulators of fibrinolysis in blood. Pro-TAFI is activated by thrombin/thrombomodulin complex or by plasmin to a carboxypeptidase B-like enzyme (TAFI) of 35.8 kD molecular weight. TAFI spontaneously becomes inactive as a result of a temperature-dependent conformational change in the protein (TAFIi). In this study, pro-TAFI, total TAFI antigen and TAFI-TAFIi antigen levels were measured in 32 patients with hemophilia A, 4 patients with hemophilia B, 21 patients with von Willebrand disease (VWD) and 13 healthy controls. A statistically significant decrease in pro-TAFI was found in all groups (10.72+/-4.57 mg/L (p<0.001); 8.00+/-2.35 mg/L (p<0.01) and 8.98+/-2.33 mg/L (p <0.001) for hemophilia A, hemophilia B and VWD, respectively) compared to controls (17.85+4.61 mg/L). A statistically significant increase in TAFI-TAFIi antigen was found in hemophilia A (1.05+/-1.01 mg/L) (p<0.05) and in VWD patients (0.96+/-1.01 mg/L) (p<0.05) compared to controls (0.55+/-0.36 mg/L). There was no difference in total TAFI antigen levels between any group of patients and the controls. Neither did pro-TAFI nor TAFI-TAFIi levels differ within the group of hemophilia A patients in relation to severity (mild, moderate and severe) or among the VWD patients in relation to subtype (type 1, type 2A and type 3). These findings indicate an increased conversion of pro-TAFI to TAFI and/or TAFIi in patients with bleeding disorders. As thrombin generation is seriously impaired in these patients and almost absent in hemophilia A and B and in type 3 VWD, it is possible that plasmin mediates pro-TAFI activation in these patients. Enhanced fibrinolysis via generation of plasmin has previously been reported in hemophilia and VWD. Activation of pro-TAFI by plasmin may be a feedback mechanism that counterbalances increased fibrinolysis in patients with bleeding disorders. The relationship between the TAFI activation pathway and bleeding complications associated with hemophilia A, hemophilia B and VWD requires further investigation.
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PMID:Does an enzyme other than thrombin contribute to unexpected changes in the levels of the different forms of thrombin activatable fibrinolysis inhibitor in patients with hemophilia A, hemophilia B and von Willebrand disease? 1571 93


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