Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used a canine model of embolic pulmonary hypertension induced by intravenous (i.v.) injection of autologous thrombi to evaluate whether the novel recombinant plasminogen activator (r-PA) BM 06.022 reversed pulmonary hypertension. The effects of BM 06.022 after bolus injection were compared with those of vehicle, alteplase, urokinase, and anistreplase in 6 dogs per group. Thirty minutes after initiation of treatment, the decrease in pulmonary artery pressure (PAP) caused by a bolus of 200 kU/kg (0.35 mg/kg) BM 06.022 was greater (p < 0.05) than that caused by a 2-h infusion of 1.33 mg/kg alteplase or of 40,000 U/kg urokinase and that caused by a bolus of 0.4 U/kg anistreplase but not that caused by a 15-min infusion of 1 mg/kg alteplase. At 3 h, all thrombolytic agents had reduced PAP equally. The greatest measured plasma concentration of BM 06.022 was higher (p < 0.05) than that of 2-h infused alteplase (4,498 +/- 716 vs. 519 +/- 119 IU/ml). We conclude that because of its bolus-pharmacokinetics, BM 06.022 more rapidly reversed thromboembolic pulmonary hypertension than did 2-h infusion of alteplase or urokinase or a bolus of anistreplase.
J Cardiovasc Pharmacol 1993 Mar
PMID:Rapid reversal of canine thromboembolic pulmonary hypertension by bolus injection of the novel recombinant plasminogen activator BM 06.022. 768 8

Direct inhibition of thrombin with agents such as hirudin and argatroban reduces reocclusion rates during experimental coronary thrombolysis. We compared the adjunctive potential of the tripeptide thrombin inhibitor D-methyl-phenylalanyl-prolyl-arginal (LY294468) during thrombolysis with tissue-type plasminogen activator (t-PA) with the less specific tripeptide thrombin inhibitor Boc-D-phenylalanyl-prolyl-arginal (LY178207) and the standard anticoagulant heparin. The left circumflex coronary artery (LCX) was isolated proximal to the first main branch, and coronary blood flow (CBF) was measured in 26 anesthetized dogs. Thrombogenesis was initiated by electrolytic injury of the intimal surface of the artery, producing an occlusive thrombus. Thrombolytic/adjunctive therapy was started 1 h later in the following groups: (a) t-PA alone (0.9 mg/kg, 1-h infusion), (b) t-PA + LY294468 (0.5 or 1 mg/kg/h, 2-h infusion), (c) t-PA + LY178207 (0.5 or 1 mg/kg/h, 2-h infusion), and (d) t-PA + heparin (80 U/kg bolus + 30 U/kg/h, 2-h infusion). LY294468 provided antireocclusive efficacy (time to reocclusion = > 200 min as compared with 65 min for t-PA alone; six of nine patent vessels vs. zero of six, respectively, at the end of the experiment), with no bleeding liability during t-PA-induced thrombolysis. Heparin and LY178207 were ineffective adjunctive agents. Heparin, however, significantly increased template bleeding times. LY294468 was effective as an adjunctive agent during thrombolysis and may represent a safer (less bleeding) and more effective adjunctive agent than heparin.
J Cardiovasc Pharmacol 1993 Apr
PMID:Reversible tripeptide thrombin inhibitors as adjunctive agents to coronary thrombolysis: a comparison with heparin in a canine model of coronary artery thrombosis. 768 4

The fibrinolytic system comprises an inactive pro-enzyme, plasminogen, that is converted by plasminogen activators to the active enzyme, plasmin, that degrades fibrin. Two immunologically distinct plasminogen activators have been identified: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Plasminogen activation is regulated by specific molecular interactions between its main components, as well as by controlled synthesis and release of plasminogen activator inhibitors, primarily from endothelial cells. The observed association between abnormal fibrinolysis and a tendency toward bleeding or thrombosis demonstrates the (patho)physiological importance of the fibrinolytic system. Transgenic animals are a suitable experimental model to examine the in vivo impact of fibrinolytic components in thrombosis and thrombolysis. Inactivation, by homologous recombination, of the tissue-type plasminogen activator genes in mice impairs thrombolysis in a significant manner whereas inactivation of the plasminogen activator-1 gene enhances the rate of spontaneous lysis. Despite their widespread use all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion and bleeding complications. Therefore, the quest for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrin-selectivity continues. Several lines of research toward improvement of thrombolytic agents are being explored, including the construction of mutants and variants of plasminogen activators, chimeric plasminogen activators, conjugates of plasminogen activators with monoclonal antibodies, or plasminogen activators from animal or bacterial origin.
Cardiovasc Drugs Ther 1994 Dec
PMID:Novel thrombolytic agents. 774 58

It was the aim of this study to investigate possible effects of biomaterials used to produce vascular grafts on the fibrinolytic system of endothelial cells. Therefore growth conditions for human umbilical vein endothelial cells on polytetrafluoroethylene and on polyurethane were optimized. Tissue culture polystyrene was used as a control material. We could demonstrate that precoating of the materials with fibronectin significantly increased the growth rate of human umbilical vein endothelial cells on these materials. Furthermore, we showed that human umbilical vein endothelial cells grown on polytetrafluoroethylene or polyurethane released more plasminogen activator inhibitor-1 and tissue type-plasminogen activator into the conditioned media than did human umbilical vein endothelial cells grown on tissue culture polystyrene. Human umbilical vein endothelial cells cultured on polytetrafluoroethylene also deposited more plasminogen activator inhibitor-1 into the extracellular matrix than did control cells grown on tissue culture polystyrene. Our results give evidence that human umbilical vein endothelial cells grown on two biomaterials used to construct vascular grafts, namely polytetrafluoroethylene and polyurethane, produce tissue-type plasminogen activator as well as plasminogen activator inhibitor-1, two major components of the fibrinolytic system also expressed by endothelial cells in vivo. In conclusion, our data suggest that endothelial cells grown on vascular grafts show functional integrity concerning their fibrinolytic system, which in turn might contribute to reduce the thrombogenic properties of the graft material.
J Thorac Cardiovasc Surg 1995 Jun
PMID:Growth and fibrinolytic parameters of human umbilical vein endothelial cells seeded onto cardiovascular grafts. 777 69

This study reports the results and complications of local thrombolytic therapy of 50 recently occluded grafts. These occurred in 41 patients with acute severe but still reversible ischemia. The majority were infra-inguinal synthetic grafts. Thrombolysis was induced with urokinase (n = 1), streptokinase (n = 11) or alteplase (n = 38) via an intra-arterial catheter. Complete angiographical lysis was obtained in 36 grafts (72%) and partial lysis in 6 (12%). The highest lysis rate was obtained with alteplase (32/36; 89%). Complementary endovascular and/or surgical intervention was needed in 17 patients to correct an underlying stenosis and/or to save the limb. Fifteen complications occurred (30%) of which distal embolization (n = 4) and bleeding (n = 8 of which 3 fatal) were the most frequent. Six of the bleeding episodes occurred in patients on chronic aspirin intake. The late results were poor. At six months, the primary patency of successfully lysed grafts dropped to 19% and the limb salvage rate to 64%. Thrombolytic therapy is far from the ideal management of thrombosed grafts: maintenance of restored patency is the challenge.
J Cardiovasc Surg (Torino) 1994 Jun
PMID:Local thrombolysis for occluded arterial grafts: is the yield worth the effort? 804 Jan 65

The clotting and fibrinolytic systems are activated by tissue factor and by tissue-type plasminogen activator in the pericardial cavity, where the thrombogenicity is greater than that of the surface of modern extracorporeal circuits. This local activation may have consequences for the systemic activation processes during cardiopulmonary bypass. To test this hypothesis, we investigated blood activation by interrupting the blood suction from the pericardial cavity during cardiopulmonary bypass in clinical coronary artery bypass operations. In blood collected in the pericardial cavity, thrombin-antithrombin III complex (p < 0.01), tissue-type plasminogen activator antigen (p < 0.05), fibrinogen degradation products (p < 0.01), and fibrin degradation products (p < 0.01) were significantly higher than in the systemic blood. Plasma heparin was significantly consumed in the pericardial cavity (p < 0.01). Once the pericardial blood was returned to the systemic circulation after resumed suction during cardiopulmonary bypass, thrombin-antithrombin III complex (p < 0.05), fibrinogen degradation products (p < 0.05), and fibrin degradation product (p < 0.05) concentrations increased significantly in the systemic blood. The effects of pericardial tissue on activation of clotting and fibrinolysis were also studied in vitro. When human plasma was incubated for 5 minutes with rabbit pericardium at reduced heparin concentrations, we found significant generation of thrombin (p < 0.05) and plasmin (p < 0.05). If the thrombin inhibitor hirudin was added, plasmin generation was also inhibited (p < 0.05). The results of the clinical and experimental study are in agreement with our hypothesis that tissue factor and tissue-type plasminogen activator accelerate the activation of clotting and sequentially of fibrinolysis under conditions of low heparin concentrations in the pericardial cavity and that this local activation contributes highly to the systemic activation, affecting hemostasis during cardiopulmonary bypass. Topical use of heparin in the pericardial cavity therefore seems indicated to reduce blood activation during cardiopulmonary bypass.
J Thorac Cardiovasc Surg 1993 Nov
PMID:Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. 823 Dec 4

Reduced hemostasis and bleeding tendency after cardiopulmonary bypass results from platelet dysfunction induced by the bypass procedure. The causes of this acquired platelet dysfunction are still subject to discussion, although, recently, greater emphasis has been placed on an overstimulated fibrinolytic system as a probable cause. In the first part of this study we assessed the effects of postoperative retransfusion of shed blood on blood loss to patients undergoing cardiopulmonary bypass. We observed that increasing concentrations of fibrinogen degradation products and tissue-type plasminogen activator stimulating activity in shed blood correlated significantly with a higher postoperative bleeding tendency (p < 0.05 for both). We further noted that retransfusion of shed blood increased the total postoperative blood loss by 43% (925 versus 1320 ml, p < 0.05). On the basis of these clinical observations, we hypothesized that the increased bleeding tendency was caused by fibrinolysis. In the second part of this study we collected evidence in support of this hypothesis by an in vitro study, in which we introduced similar (pro)fibrinolytic activity to platelet-rich plasma and measured the influence of this treatment on platelet function indicated by ristocetin agglutination. Tissue-type plasminogen activator and fibrin monomers (tissue-type plasminogen activator stimulator) together induced severe platelet damage, resulting in a decreased ristocetin agglutination response. Therefore, we propose a fibrinolysis-related mechanism for platelet dysfunction during cardiopulmonary bypass, dependent on fibrinolytic factors such as fibrin monomers, D-dimers, and tissue-type plasminogen activator.
J Thorac Cardiovasc Surg 1993 Dec
PMID:Tissue-type plasminogen activator and fibrin monomers synergistically cause platelet dysfunction during retransfusion of shed blood after cardiopulmonary bypass. 824 33

The presence of pericardial adhesions at resternotomy not only increases the operation time but also increases the risk of serious damage to the heart, great vessels, and extracardiac grafts. The reported prevalence of damage is 2% to 6%. The fibrinolytic activity of pericardial tissue may be a crucial factor in determining the extent of adhesion formation following primary operation. Ten patients undergoing cardiac operations were studied to assess the plasminogen activating activity of homogenates of pericardial tissue samples. Samples were taken at three times during the operation and the plasminogen activating activity was measured by means of a standard fibrin plate technique. Tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and plasminogen activator inhibitor-2 were also measured by means of enzyme-linked immunosorbent assays. Compared with its initial levels (median 2.06 IU/cm2, range 1.28 to 6.48 IU/cm2), the plasminogen activating activity of pericardial biopsy tissue was significantly reduced at 75 minutes (median 0.64 IU/cm2, range 0.12 to 2.44 IU/cm2, p < 0.01) and at 135 minutes (median 1.45 IU/cm2, range 0.12 to 4.39 IU/cm2, p < 0.05). The major plasminogen activator present was tissue-type plasminogen activator. Compared with its initial levels (median 2.34 ng/ml, range 1.03 to 6.42 ng/ml), subsequent tissue-type plasminogen activator values were also significantly reduced at 75 minutes (median 0.83 ng/ml, range 0.75 to 5.13 ng/ml, p < 0.005) and at 135 minutes (median 1.24 ng/ml, range 0.75 to 6.67 ng/ml, p < 0.05). Low levels of urokinase-type plasminogen activator were found in 5 of 10 patients. However, neither plasminogen activator inhibitor-1 nor plasminogen activator inhibitor-2 was detected. Examination with a light microscope showed both increasing pericardial mesothelial damage and increasing features of acute inflammatory changes with time. This study shows that plasminogen activating activity is present in pericardial tissue and that tissue-type plasminogen activator is the major plasminogen activator. The observed inflammatory changes and concomitant damage to the pericardial mesothelium, and the significant reductions in pericardial tissue-type plasminogen activator and plasminogen activating activity seen during cardiac operations, may be important factors contributing to the early development of pericardial adhesions.
J Thorac Cardiovasc Surg 1993 Aug
PMID:Changes in pericardial morphology and fibrinolytic activity during cardiopulmonary bypass. 834 Oct 74

Valve thrombosis is one of the most serious complications after prosthetic valve replacement. We report the use of tissue-type plasminogen activator (t-PA) in the treatment of a patient with thrombosed aortic and mitral valves. Thrombolysis resulted in immediate hemodynamic improvement and resolution of congestive heart failure, thereby avoiding surgical intervention. Based on our experience, thrombolysis with t-PA is an effective alternative in the treatment of thrombosed prosthetic valves.
J Cardiovasc Surg (Torino) 1993 Jun
PMID:Tissue-type plasminogen activator (t-PA) lysis of aortic and mitral valve thrombosis. 834 79

To study a possible hypercoagulability in vascular disease, in 22 patients with essential hypertension and in 13 patients with obliterative arteriopathies of the lower limbs we measured the levels of plasma thrombomodulin (TM), plasma and urine beta-thromboglobulin (beta-TG), plasma D-dimer (DD) and plasminogen activator-inhibitor (PAI-1) and compared to the values obtained from 10 healthy volunteers. The values observed in hypertensive patients show only PAI-1 levels significantly higher. All the parameters were found to be significantly increased in vasculopathic patients. These data confirm that in vasculopathic patients endothelium damage, platelet activation, impaired fibrinolytic potential and increase of fibrin turnover, occur. On the other hand, in the hypertensive patients, at first stages of the disease, we have found only an increase of PAI-1 plasma levels documenting impaired fibrinolytic potential.
J Cardiovasc Surg (Torino) 1995 Oct
PMID:Hemostatic disorders associated with arterial hypertension and peripheral arterial disease. 852 67


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