Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Desmopressin is a widely used hemostatic drug. It is a synthetic analogue of the natural hormone vasopressin, but, in contrast to vasopressin, it has no pressor activity. The effect is immediate, with two- to sixfold increases in the plasma concentrations of coagulation factor VIII, on Willebrand factor, and tissue plasminogen activator, and increases in platelet adhesiveness of comparable magnitude. Desmopressin is used in patients with mild hemophilia A, von Willebrand's disease, congenital platelet dysfunction, or acquired platelet dysfunction due to uremia or intake of such drugs as aspirin. It may also be used to reduce surgical blood loss in patients without known bleeding diathesis. Optimal hemostatic effect is achieved with a dosage of 0.3 micrograms/kg given intravenously. Other routes of administration are subcutaneous injection or intranasal spray. The latter proved to be efficient for home treatment of patients with bleeding disorders.
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PMID:Desmopressin (DDAVP) and hemostasis. 794 3

We attempted to determine if a hypercoagulability state exists in patients with polycythemia vera (PV) and essential thrombocythemia (ET). We studied the hematocrit level, platelet count, use of any antiaggregant drugs, thrombotic or bleeding accidents and plasma levels of antithrombin III, protein C, total protein S, free protein S, vWF:Ag (Von Willebrand's factor related antigen), thrombin-antithrombin complexes, D-dimer, fibrinolytic activity, tissue plasminogen activator, plasminogen and PAI-1 in 33 patients (19 with ET and 14 with PV). PAI-1 plasma concentration was significantly higher in, both ET and PV patients than in the control group, and were higher in those patients with previous thrombotic episodes than in asymptomatic patients or with previous bleeding episodes. Increasing age was associated to more thrombotic episodes while younger patients presented with more hemorrhagic complications. A linear correlation between platelet count and PAI-1 levels in PV patients (r = 0.44, p < 0.05) and ET patients (r = 0.30, p < 0.05) was found. Fibrinolytic activity in patients with ET was significantly decreased when compared to the control group. A hypofibrinolytic state could be an additional factor which could be used as a predictive index of the thrombotic or bleeding tendency in each patient.
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PMID:High plasma levels of plasminogen activator inhibitor 1 (PAI-1) in polycythemia vera and essential thrombocythemia are associated with thrombosis. 799 52

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

Some well-described similarities exist between tissue plasminogen activator (t-PA) and von Willebrand factor (vWf) which may suggest a link in either the synthesis or release of both proteins from endothelial cells. To investigate this relationship further immunocytochemical localization of t-PA and vWf was performed in normal tissues and in skin obtained from patients with type I and type III von Willebrand's disease (vWd). Components of the fibrinolytic system were measured at baseline and after venous occlusion in healthy controls and patients with vWd. Patients with severe vWd received intravenous vWf concentrate, followed by desmopressin (DDAVP), to study the plasma response of vWf and t-PA. By immunocytochemical staining, t-PA was demonstrated in endothelial cells of normal skin, kidney and liver and also in the skin of patients with type I and type III vWd. vWf was localized in endothelial cells of all tissues except the specimens from an individual with severe vWd. Basal plasma levels of fibrinolytic components were normal in patients with vWd. Venous occlusion resulted in a rise of fibrinolytic activity in controls and patients with type I, but not type III, vWd. No rise in plasma t-PA was observed following DDAVP in severe vWd, even though near-normalization of plasma vWf levels had been obtained by prior infusion of vWf concentrate. It is concluded that the synthesis of t-PA and vWf is probably regulated by independent processes. Constitutive and regulated release of both proteins occur through different mechanisms and the basal secretion of t-PA is intact in severe vWd.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Study of endothelial t-PA and vWf in normal subjects and in von Willebrand's disease. 807 4

Dynamic vaso-occlusive and vaso-proliferative events occur in sickle cell retinopathy. Using streptavidin peroxidase immunohistochemistry, we investigated changes in distribution and relative levels of components in the fibrinolytic system and growth factors in retina and choroid from 2 sickle cell patients: a 20 month old SS patient and a 54 year old SC patient. Antigen localization in the sickle cell patients was compared to localization from 2 non-sickle cell, non-diabetic control subjects. In the fibrinolytic system, tissue plasminogen activator (tPA) localization and immunoreactivity were comparable in all eyes, but plasminogen activator inhibitor-1 (PAI-1) immunoreactivity was elevated within the walls of retinal vessels in the sickle cell tissue. Immunoreactive fibrin was often observed within the lumen of retinal and choroidal vessels and in choroidal neo-vascularization (CNV) in sickle cell subjects. Blood vessels containing fibrin generally exhibited elevated PAI-1 immunoreactivity. Von Willebrand's factor (vWf) and basic fibroblast growth factor (bFGF) immunoreactivity in sickle cell patients were elevated in choriocapillaris and the walls of some retinal vessels. Transforming growth factor-beta 1 (TGF-beta 1) immunoreactivity was significantly lower in sickle cell choriocapillaris than in controls. In chorioretinal pigmented lesions of the SC patient, bFGF and TGF-beta 1, beta 2, and beta 3 immunoreactivity was present within migrating retinal pigment epithelial (RPE) cells. Our interpretation of the data presented in this case study is that fibrin deposition within retinal and choroidal vessels of sickle cell subjects may occur due to elevated PAI-1 activity. Moreover, vaso-occlusions of choroidal vessels may influence the expression of growth factors in choriocapillaris endothelium, which could stimulate formation of choroidal neovascularization. Finally, fibrosis and gliosis in and near chorioretinal pigmented lesions may be stimulated by RPE production of bFGF and TGF-beta's.
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PMID:Immunohistochemical insights into sickle cell retinopathy. 819 59

It is generally held that factor VIII (FVIII) does not increase in the plasma of severe von Willebrand disease (vWD) patients treated with DDAVP because they lack von Willebrand factor (vWF), which is the plasma carrier for FVIII. To test this hypothesis, FVIII plasma levels were monitored in severe vWD patients treated with DDAVP after normalization of vWF plasma levels with infusions of cryoprecipitate. Each of four severe vWD patients underwent four different treatments at intervals of at least 15 d: (1) cryoprecipitate plus DDAVP; (2) cryoprecipitate plus saline; (3) cryoprecipitate plus recombinant FVIII (rFVIII); (4) saline plus rFVIII. Cryoprecipitate increased the plasma levels of FVIII and vWF. The infusions of saline or DDAVP after cryoprecipitate did not further increase FVIII and vWF plasma levels and had no effect on the plasma levels of tissue plasminogen activator (tPA), which are raised by DDAVP in normal subjects and in patients with vWD of other types. The infusion of rFVIII further increased by 182 +/- 32 U/dl (mean +/- SEM) the plasma levels attained after cryoprecipitate, which disappeared from the circulation with a half-life of 11.95 +/- 0.86 h. In contrast, the infusion of rFVIII after saline increased by only 107 +/- 18 U/dl the plasma levels of FVIII, which disappeared from the circulation with a half-life of 2.68 +/- 0.14 h, indicating that the vWF infused with cryoprecipitate is able to bind additional FVIII. These studies indicate that DDAVP does not increase the plasma levels of FVIII in patients with severe vWD even after normalization of plasma vWF. The possibility is discussed that severe vWD patients may be insensitive to the releasing effect of DDAVP.
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PMID:Patients with severe von Willebrand disease are insensitive to the releasing effect of DDAVP: evidence that the DDAVP-induced increase in plasma factor VIII is not secondary to the increase in plasma von Willebrand factor. 819 23

Von Willebrand factor and platelet membrane glycoprotein Ib receptors interact to mediate platelet adhesion and thrombogenesis in stenosed and endothelium-injured arteries. We wished to determine whether blocking glycoprotein Ib receptors with a recombinant von Willibrand factor binding domain (VCL) increases the time required for thrombus formation after injury to the coronary arteries. We also wished to determine whether, after thrombolysis with tissue plasminogen activator (TPA), VCL delays or protects against coronary artery reocclusion. Twenty-seven dogs were treated with either saline, VCL, or aspirin before thrombosis was induced in their coronary arteries by electrical injury. The time from injury to the formation of occlusive thrombi was significantly greater with VCL (70 +/- 10 minutes) and aspirin (69 +/- 20 minutes) than with saline (18 +/- 3 minutes, P < .001 and P < .05). Thrombosis was induced in 30 other dogs that then received thrombolytic treatment in four groups. Our major finding was that coronary artery reocclusion occurred in 72 +/- 11 minutes after treatment with TPA (80 micrograms/kg + 8 micrograms.kg-1.min-1) and heparin (200 U/kg) (n = 7); in 142 +/- 24 minutes after TPA, heparin, and VCL (4 mg/kg + 2 mg.kg-1.h-1) (n = 7) (compared with TPA and heparin, P < .05); in 74 +/- 13 minutes after TPA, heparin, and aspirin (5 mg/kg) (n = 8); and in 173 +/- 8 minutes after TPA, heparin, VCL, and aspirin (n = 8) (compared with TPA and heparin, P < .001). Thus, VCL increases the length of time required for thrombus formation in coronary arteries, and, when given with TPA and heparin, delays coronary artery reocclusion more effectively than aspirin.
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PMID:Blockade of platelet membrane glycoprotein Ib receptors delays intracoronary thrombogenesis, enhances thrombolysis, and delays coronary artery reocclusion in dogs. 820 97

In a recent prospective study of allogenic bone marrow transplantation we reported that decreases in factor VII and protein C were predictive markers for high risk of veno-occlusive disease (VOD). In order to determine the relative involvement of endothelial and hepatocyte injury in the genesis of VOD, 34 consecutive patients undergoing autologous bone marrow transplantation (BMT) were studied. Conditioning was performed by chemotherapy alone or associated with total body irradiation (TBI). Protein C and factor VII, the endothelial markers Von Willebrand factor (vWF and t-PA, fibrinogen and fibronectin were measured weekly before and after BMT. Protein C and factor VII were within the normal range before BMT, decreased significantly on day 7 to 73 and 64% respectively (p < .01) and then returned to normal values. Fibrinogen increased to 7 g/l (p < .001) on day 7 but then returned to normal levels. Fibronectin was abnormally high (p < .001) before BMT and decreased thereafter, while vWF increased (p < 0.001) for three consecutive weeks. t-PA was low (p < 0.001) before conditioning but increased thereafter. These results demonstrate the presence of endothelial lesions before BMT and acute hepatic and endothelial lesions after conditioning. Although VOD was never observed in our patients, this complication could well arise from preexisting vascular lesions due to previous chemotherapy and/or from acute hepatocytic injury, which could also be of endothelial origin, after conditioning.
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PMID:Changes in protein C, factor VII and endothelial markers after autologous bone marrow transplantation: possible implications in the pathogenesis of veno-occlusive disease. 833 49

1. The effects of venous occlusion on the coagulation and fibrinolytic systems were investigated in six patients with type 1 (insulin-dependent) diabetes and 11 age- and sex-matched non-diabetic control subjects. The coagulation parameters (fibrinogen, prothrombin time, partial thromboplastin time with kaolin, von Willebrand factor antigen) did not differ between patients and control subjects either before or after 20 min of venous occlusion. No rise was observed in von Willebrand factor antigen after venous occlusion in either group. 2. In the diabetic patients, chronic activation of the fibrinolytic system was found at baseline, which was indicated by a shortened euglobulin lysis time (P < 0.01), increased tissue plasminogen activator activity (P < 0.05) and decreased plasminogen activator inhibitor type 1 antigen level (P < 0.05), when compared with control subjects. In both groups venous occlusion resulted in significant increments in all measurements, except plasminogen activator inhibitor type 1 antigen level. The post-occlusion values did not differ between the two groups, except the plasminogen activator inhibitor type 1 antigen level, which remained significantly lower in the diabetic patients. The mean increments in each parameter did not differ between the two groups. 3. Coagulation and fibrinolysis were assessed in response to acute insulin-induced hypoglycaemia. Von Willebrand factor antigen levels increased significantly in both groups, with no difference in maximal increments. Significant activation of the fibrinolytic system occurred in response to hypoglycaemia, demonstrated by shortened euglobulin lysis time and increased fibrin plate lysis, tissue plasminogen activator antigen level and tissue plasminogen activator activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coagulation and fibrinolytic systems in type I diabetes: effects of venous occlusion and insulin-induced hypoglycaemia. 838 39

Vasopressin and in particular its structural analogue dDAVP (1-deamino-8-D-arginine vasopressin) can increase plasma concentrations of Factor VIII and tissue plasminogen activator (tPA) in some species of animals and in humans. For this reason dDAVP is used therapeutically in the treatment of bleeding episodes in patients suffering from haemophilia A and Von Willebrand's disease. However, the high antidiuretic activity of dDAVP constitutes and unwanted effect in this context. In the present study, a large number of analogues of vasopressin were designed, synthesized and tested in monkeys with the aim of producing compounds in which the Factor VIII-releasing activity was selectively isolated from the vasopressor and antidiuretic actions of the peptide. The results indicate that it is possible to separate these biological activities; however, none of the analogues tested so far possessed Factor VIII potencies comparable to that of dDAVP.
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PMID:Antidiuretic activity and release of factor VIII by vasopressin analogues. 846 59


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