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)

Factor VIII/von Willebrand factor (FVIII/vWF) is a glycoprotein with a molecular weight greater than one-million daltons. Two activities are associated with this large molecule: FVIII procoagulant activity and vWF activity. Incubation of FVIII/vWF with proteolytic enzymes causes rapid inactivation of the FVIII procoagulant activity but has little effect on the vWF activity or antigenicity. In an attempt to gain insight into the structural features required for these two activities, antisera were raised in rabbits to normal, thrombin-inactivated, and plasmin-inactivated FVIII/vWF. All of these proteolytically modified forms of FVIII/vWF cross-reacted with each of the rabbit antisera; each blocked the ability of a human inhibitor to inactivate native active FVIII/vWF. Each of the antisera was a potent inhibitor of vWF activity and inactivated vWF activity at the same titer. The antisera were much less potent inhibitors of FVIII activity than of vWF activity. Antibodies to thrombin-inactivated FVIII/vWF or normal FVIII/vWF had about the same ability to inactivate FVIII procoagulant activity. Surprisingly, those to plasmin-inactivated FVIII/vWF still retained about 50% of this inhibitory capacity. A comparison of the three types of antigens by polyacrylamide gel electrophoresis in sodium dodecyl sulfate-6 M urea demonstrated that the structure of thrombin-inactivated FVIII/vWF was indistinguishable from that of normal FVIII/vWF, while plasmin-inactivated FVII/vWF was completely cleaved to lower molecular weight fragments. Some of the reported variations in the ability of rabbit antibodies to inhibit procoagulant activity may be due to partial degradation of the starting antigen. The retention by FVIII/vWF protein of its immunologic properties even after extensive proteolytic degradation suggests that under nondenaturing conditions, the conformation of the native and degraded molecules are very similar.
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PMID:Immunologic studies of native and modified human factor VIII/von Willebrand factor. 8 37

Thrombospondin (TSP), an adhesive integrin-binding protein of plasma and platelets, was detected in preretinal traction membranes from patients with idiopathic (8/8) and traumatic (7/8) proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR) (6/8). TSP immunoreactivity was compared to the pattern of von Willebrand factor, plasma transglutaminase (blood coagulation factor XIII), fibronectin, and mononuclear phagocytes, using double-label immunofluorescence microscopy. TSP was partially colocalised with the endothelial cell marker, von Willebrand factor, in PDR. The codistribution of catalytic factor XIII and two cross-linking substrates, fibronectin and TSP, suggests a functional role of the enzyme in the extracellular matrix build-up in PVR and PDR. No significant TSP synthesis by mononuclear phagocytes was observed. Western blotting indicated a plasmin-mediated intravitreal breakdown of presumably plasmatic TSP in PVR and PDR.
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PMID:Thrombospondin: a new attachment protein in preretinal traction membranes. 135 87

Binding of the adhesive ligand fibrinogen and the monoclonal antibody PAC1 to platelet glycoprotein (GP) IIb-IIIa is dependent on cell activation and inhibited by Arg-Gly-Asp (RGD)-containing peptides. Previously, we identified a sequence in a hypervariable region of PAC1 (mu-CDR3) that mimics the activity of the antibody. Here we examine whether monoclonal antibodies to this idiotypic determinant in PAC1 can mimic GP IIb-IIIa by binding to fibrinogen. Mice were immunized with a peptide derived from the mu-CDR3 of PAC1. Four antibodies were obtained that recognized fibrinogen as well as a recombinant form of the variable region of PAC1. However, they did not bind to other RGD-containing proteins, including von Willebrand factor, fibronectin, and vitronectin. Several studies suggested that these anti-PAC1 peptide antibodies were specific for GP IIb-IIIa recognition sites in fibrinogen. Three such sites have been proposed: two RGD-containing regions in the A alpha chain, and the COOH terminus of the gamma chain (gamma 400-411). Two of the antibodies inhibited fibrinogen binding to activated platelets, and all four antibodies bound to the fibrinogen A alpha chain on immunoblots. Antibody binding to immobilized fibrinogen was partially inhibited by monoclonal antibodies specific for the two A alpha chain RGD regions. However, the anti-PAC1 peptide antibodies also bound to plasmin-derived fibrinogen fragments X and D100, which contain gamma 400-411 but lack one or both A alpha RGD regions. This binding was inhibited by an antibody specific for gamma 400-411. When fragment D100 was converted to D80, which lacks gamma 400-411, antibody binding was reduced significantly (p less than 0.01). Electron microscopy of fibrinogen-antibody complexes confirmed that each antibody could bind to sites on the A alpha and gamma chains. These studies demonstrate that certain anti-PAC1 peptide antibodies mimic GP IIb-IIIa by binding to platelet recognition sites in fibrinogen. Furthermore, they suggest that the gamma 400-411 region of fibrinogen may exist in a conformation similar to that of an A alpha RGD region of the molecule.
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PMID:Anti-idiotypic antibodies against an antibody to the platelet glycoprotein (GP) IIb-IIIa complex mimic GP IIb-IIIa by recognizing fibrinogen. 137 Aug 32

Plasma levels of von Willebrand factor (vWf) are frequently elevated in patients with disseminated intravascular coagulation (DIC). To investigate the qualitative abnormalities of vWf and the possibility of its ex vivo modification in DIC, we analysed the multimeric composition of vWf in citrated plasma from 15 patients with DIC in the presence or absence of serine protease inhibitors (aprotinin and soybean trypsin inhibitor) and/or cysteine protease inhibitors (leupeptin, N-ethylmaleimide and EDTA). The proportion of large vWf multimers in plasma prepared in the presence of cysteine protease inhibitors was higher than those without such inhibitors. The addition of serine protease inhibitors during the preparation of plasma had no effect on the relative amounts of large multimers. The relative proportion of large multimers in plasma prepared without inhibitors and the difference between plasmas prepared with and without cysteine protease inhibitors correlated with plasma plasmin-alpha 2-plasmin inhibitor complex values, but not with other plasma or serum markers of DIC (platelet count, fibrinogen, FDP, D-dimer or thrombin-antithrombin III complex). We conclude that ex vivo proteolysis of plasma vWf occurs frequently in patients with DIC and cysteine protease inhibitors can protect this degradation.
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PMID:Enhanced ex vivo proteolysis of plasma von Willebrand factor in disseminated intravascular coagulation. 145 Mar 24

In 20 patients with acute myocardial infarction (AMI) treated with streptokinase (SK, n = 7), recombinant single-chain tissue plasminogen activator (rt-PA, n = 7) or urokinase (UK, n = 6), the behavior of plasma von Willebrand factor (vWF) was studied before and 1.5, 3, 24, 48, and 72 hours after beginning thrombolytic therapy. vWF antigen (vWF:Ag) was high in plasma, especially after SK. The ristocetin cofactor (RiCof) activity of vWF, high before therapy, tended to decrease soon after therapy. This pattern of vWF changes was paralleled by the early loss of higher molecular weight multimers. By immunoblotting of immunopurified and reduced vWF and monoclonal antibody epitope mapping, we found that vWF was degraded after thrombolysis, especially after SK, as indicated by the higher values of two plasmin-generated fragments of 176 and 145 Kd. There were more plasmin-generated fragments in the five patients who had bleeding complications than in the remaining 15 who did not. In conclusion, quantitative and qualitative changes of vWF compatible with proteolytic degradation of the protein occur during thrombolytic therapy. Such degradation, roughly proportional to the degree of the general lytic state induced by each agent, might be a cofactor of the bleeding complications occurring in treated patients.
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PMID:Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction. 153 Aug 13

In non-insulin-dependent diabetes mellitus (NIDDM) patients, microalbuminuria predicts early mortality, predominantly from cardiovascular disease. Increased free radical activity and abnormalities in hemostasis have been implicated in the development of vascular disease. Therefore, we measured markers of free radical activity (nonperoxide-conjugated diene isomer of linoleic acid [PL-9,11-LA'] and lipid peroxides expressed as malondialdehyde [MDA]) along with the hemostatic variables: fibrinogen, von Willebrand factor (vWf), plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (t-PA), and plasmin activity (B beta 15-42) in 24 NIDDM patients (12 patients with microalbuminuria and 12 without microalbuminuria) and in 12 age-matched control subjects. There were no differences in linoleic acid (PL-9,12-LA) concentrations between the three groups. PL-9,11-LA' was elevated in the microalbuminuric patients compared with control subjects (P less than 0.05), but there was no difference between the two diabetic groups. MDA was elevated in the microalbuminuric diabetic patients compared with those patients without microalbuminuria (P less than 0.05) and control subjects (P less than 0.001). MDA was also increased in the patients without microalbuminuria compared with control subjects (P less than 0.01). Except for B beta 15-42, all the hemostatic variables were increased (P less than 0.05) in the diabetic patients compared with control subjects. The microalbuminuric diabetic patients had further increases in vWf (P less than 0.03) and t-PA (P less than 0.03) compared with patients with microalbuminuria. Our study suggests that there is an increase in free radical activity and abnormalities in hemostatic variables favoring a hypercoagulable state in NIDDM, especially in those with microalbuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria. 162 64

The pathophysiology of peripheral circulatory disturbance in patients presenting with vibration syndrome was studied from the viewpoint of blood coagulation. Plasma levels of fibronectin (FN), vitronectin (VN), thrombin-antithrombin III complex (TAT), and alpha 2-plasmin inhibitor-plasmin complex (PIC) were measured in 23 subjects who showed no evidence of vibration-induced white finger [VWF(-) group] and in 24 patients who presented with VWF [VWF(+) group]. In the VWF(-) group, plasma FN concentrations were elevated but plasma TAT and PIC levels were within the normal ranges. In the VWF(+) group, plasma FN concentrations were normal but plasma TAT and PIC levels were significantly elevated. In both groups, plasma VN concentrations were similar to those in normal controls. For purposes of comparison, 32 patients presenting with diabetes mellitus were also studied. They were divided into 2 groups, 13 subjects who showed no evidence of angiopathy [complication(-) group] and 19 patients who presented with angiopathy [complication(+) group]. In the complication(+) group, plasma TAT and PIC concentrations were significantly elevated, as in the VWF(+) group. These results suggest that in vibration syndrome, vibration, cold stimulus, or other factors first injure the vascular endothelium, resulting in a rise in plasma FN, and that in the VWF(+) group, augmentation of coagulation and fibrinolysis induces a state of compensated disseminated intravascular coagulation (DIC).
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PMID:Activation of blood coagulation and fibrinolysis in vibration syndrome. 172 Jul 65

We studied the relationship between vascular complications and coagulation and fibrinolysis parameters in 75 subjects with collagen diseases. Thirty normal healthy persons served as controls. We found that patients with collagen diseases were in a state of a hypercoagulation and hyperfibrinolysis. In SLE (systemic lupus erythematosus) in particular, coagulation and fibrinolysis parameters appeared to be indices of vascular complications. Increases in the levels of thrombin-antithrombin III complex (TAT) and alpha 2-plasmin inhibitor-plasmin (PIP) were particularly associated with proteinuria, while increases in fibrinopeptide A (FPA) levels were associated with Raynaud's phenomenon. Administration of glucocorticoid seemed to improve the hypercoagulation and hyperfibrinolytic states of patients with collagen diseases. Analysis of the multimeric structure of von Willebrand factor (vWF) revealed a tendency for large and intermediate multimers (LIM) of plasma vWF to increase in SLE patients with accompanying vascular complications, whereas such increases were not observed in SLE patients without any vascular complications. Therefore, analysis of the multimeric structure of vWF appeared to be a useful indicator of vascular complications in collagen diseases.
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PMID:Plasma coagulation and fibrinolysis parameters in patients with collagen diseases, and analysis of the multimeric structure of von Willebrand factor (vWF). 175 53

Thrombospondin (TSP), a platelet-derived protein of the integrin-binding family with adhesive and mitogenic properties was localized in surgically obtained epiretinal traction membranes from patients with traumatic (7/8) and idiopathic (8/8) proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR) (6/8). Using double-label immunofluorescence techniques, we demonstrated co-localization of TSP with the endothelial cell marker, von Willebrand factor, in PDR; however, only a minority of labeled macrophages showed simultaneous staining for TSP. Therefore, macrophages are probably not a major source of TSP in PVR. We demonstrated co-distribution of blood coagulation factor XIII and two of its cross-linking substrates, fibronectin and TSP, in epiretinal membranes, as well as the detection of plasmin and presumably plasmin-induced TSP breakdown products in physiologic and pathologic vitreous. These results suggest that the coagulation system has a functional role in proliferative retinal disorders and imply that the application of inhibitors of the coagulation cascade like heparin may be a potential therapeutic approach.
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PMID:[Thrombospondin and its importance in proliferative retinal diseases]. 178 16

We demonstrate that unstimulated platelets attach to immobilized fibrinogen in a selective process mediated by the membrane glycoprotein (GP) complex IIb-IIIa (alpha IIb beta 3). The initial attachment, independent of platelet activation, is followed by spreading and irreversible adhesion even in the presence of activation inhibitors. Using fibrinogen fragments derived from plasmin digestion, we found that unstimulated platelets do not attach to immobilized fragment E, which contains an Arg-Gly-Asp sequence at A alpha 95-97, and adhere to fragments X and D, both containing the gamma 400-411 dodecapeptide adhesion sequence, less efficiently than to intact fibrinogen. Thus, the carboxyl terminus of the A alpha chain, missing in the "early" fragment X used in these studies, appears to be involved in the interaction of fibrinogen with unstimulated platelets. In contrast, activated platelets adhere to immobilized fibrinogen and fragments X, D, and E in a time-dependent and equivalent manner. Although activated platelets adhere to immobilized vitronectin, fibronectin, and von Willebrand factor through GP IIb-IIIa, unstimulated platelets fail to adhere to vitronectin and have only a limited capacity to adhere to fibronectin and von Willebrand factor. These results demonstrate that GP IIb-IIIa on unstimulated platelets displays a recognition specificity for attachment to immobilized adhesive proteins that is distinct from that seen following platelet activation. Thus, unstimulated platelets selectively interact with fibrinogen, and the initial attachment is followed by spreading and irreversible adhesion in the absence of exogenous agonists. This process may be regulated by plasmin cleavage of the fibrinogen A alpha chain and may play an important role during normal hemostasis and during the pathological development of thrombotic vascular occlusions.
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PMID:Selective recognition of adhesive sites in surface-bound fibrinogen by glycoprotein IIb-IIIa on nonactivated platelets. 204 Jun 30


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