Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The administration of Interleukin-2 (IL-2) causes the release or generation of other cytokines such as tumour necrosis factor (TNF) which, by disturbing the anticoagulant properties of the endothelium, may induce a procoagulant state in patients receiving this drug. We therefore evaluated the effects of IL-2 on coagulation and fibrinolysis in 14 patients receiving 12 or 18 x 10(6) IU/m2/d of IL-2 given as a 15 min infusion for 5 d. Blood samples were drawn at short intervals after the first IL-2 infusion. The parameters were analysed by way of analysis for repeated measures (F tests rather than t tests). During the first day, thrombin-antithrombin (TAT) complexes started to increase 2 h after the IL-2 infusion, reaching peak levels at 4 h (n = 14; 11.2 +/- 6.4 micrograms/l v 49.8 +/- 49.2 micrograms/l, P < 0.01). Plasma alpha 2 antiplasmin (PAP) complexes showed a similar pattern rising from a mean baseline value of 17.5 +/- 7.6 nmol/l to 66.8 +/- 47.7 nmol at 4 h (P < 0.01). In four patients the peak of PAP preceeded that of TAT. Tissue plasminogen activator (tPA) rose from a mean baseline value of 4.9 +/- 3.7 micrograms/l to 26.3 +/- 13.5 micrograms/l at 4 h (P < 0.01). Plasminogen-activator-inhibitor-1 (PAI-1) levels increased from 59 +/- 35 micrograms/l to 113 +/- 39 micrograms/l at 6 h (P < 0.01). tPA PAI-1 complexes increased from 0.15 +/- 0.07 to 0.69 +/- 0.21 nmol/l at 6 h (P < 0.01). Our study indicates that IL-2 activates the coagulation and fibrinolytic systems in vivo. The changes resemble the perturbations observed after endotoxin/TNF administration. These abnormalities may play a role in the side-effects induced by IL-2 therapy.
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PMID:Interleukin-2 induces activation of coagulation and fibrinolysis: resemblance to the changes seen during experimental endotoxaemia. 141 10

Lower rates of deep vein thrombosis have been noted following total hip replacement under epidural anesthesia in patients receiving exogenous epinephrine throughout surgery. To determine whether this is due to enhanced fibrinolysis or to circulatory effects of epinephrine, 30 patients scheduled for primary total hip replacement under epidural anesthesia were randomly assigned to receive intravenous infusions of either low dose epinephrine or phenylephrine intraoperatively. All patients received lumbar epidural anesthesia with induced hypotension and were monitored with radial artery and pulmonary artery catheters. Patients receiving low dose epinephrine infusion had maintenance of heart rate and cardiac index whereas both heart rate and cardiac index declined significantly throughout surgery in patients receiving phenylephrine (p = 0.0001 and p = 0.0001, respectively). Tissue plasminogen activator (t-PA) activity increased significantly during surgery (p < 0.005) and declined below baseline postoperatively (p < 0.005) in both groups. Low dose epinephrine was not associated with any additional augmentation of fibrinolytic activity perioperatively. There were no significant differences in changes in D-Dimer, t-PA antigen, alpha 2-plasmin inhibitor-plasmin complexes or thrombin-antithrombin III complexes perioperatively between groups receiving low dose epinephrine or phenylephrine. The reduction in deep vein thrombosis rate with low dose epinephrine is more likely mediated by a circulatory mechanism than by augmentation of fibrinolysis.
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PMID:The hemodynamic and fibrinolytic response to low dose epinephrine and phenylephrine infusions during total hip replacement under epidural anesthesia. 144 77

18 type II diabetes mellitus patients with coronary artery disease (CAD) have been studied. Tissue plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor (PAI) antigen and activity, thrombin-antithrombin III (TAT) complexes were determined in blood samples. Diabetic CAD patients showed higher TAT levels with clearly increased PAI levels whereas t-PA levels levels were similar in patients and controls. Long term defibrotide treatment induced marked changes in fibrinolytic parameters of these diabetic patients with CAD with increased t-PA activity, that could be related to an evident reduction of PAI antigen and activity. Drugs able to modulate PAI activity may be useful in clinical conditions at high risk of thrombotic vascular complications like diabetics with stable angina.
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PMID:Effects of defibrotide on fibrinolytic activity in diabetic patients with stable angina pectoris. 157 96

The changes in coagulation and fibrinolysis were studied in cases of hepatocellular carcinoma with (n = 20) and without (n = 8) transcatheter hepatic arterial embolization (TAE). The plasma levels of thrombin-antithrombin III complex (TAT) and alpha 2 plasmin inhibitor complex (PIC) were significantly elevated after TAE, concurrently with a decrease in antithrombin III and antiplasmin (alpha 2-plasmin inhibitor) levels. The elevation of TAT was most significant (2.4-fold of the pre-TAE level) on day 3, whereas that of PIC was relatively less (1.3-fold on day 3). Tissue plasminogen activator in blood was also significantly increased on day 1, but it was decreased thereafter, although plasminogen activator inhibitor (PAI) remained high for at least 7 days after TAE. In contrast, such hematological changes were not observed in patients without TAE. Thus, both coagulation and fibrinolysis were activated after TAE, but its effect on fibrinolysis was less prominent, due probably to the increased synthesis of PAI.
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PMID:Effects of transcatheter hepatic arterial embolization on coagulation and fibrinolysis in patients with hepatocellular carcinoma. 166 Feb 19

The mechanism of coagulation activation in renal cell carcinoma was investigated using immunohistochemical techniques applied to fresh frozen sections of resected primary tumors. Tissue factor antigen was detected in the endothelium of vascular channels within the tumors. Fibrinogen and factor V were distributed diffusely in the perivascular tumor connective tissue. Fibrin was readily detected in a linear pattern along the edges of nodules of viable tumor indicating that thrombin had formed from the interaction of coagulation factors demonstrated previously in renal cell carcinoma tissue. Tissue plasminogen activator was detected in the endothelium of blood vessels in the vicinity of the tumor and urokinase in areas of necrosis but neither were associated with viable tumor cells. These results indicate that thrombin is formed locally in renal cell carcinoma tissue that transforms fibrinogen to fibrin. There also appears to be a net deficit in fibrinolysis in situ in this tumor. We postulate that these conditions might contribute to stabilization and progression of renal cell carcinoma and that clinical trials of antithrombotic agents are justified in this tumor type.
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PMID:Fibrinogen-fibrin transformation in situ in renal cell carcinoma. 211 16

Tissue plasminogen activator (tPA) dissolves intravascular thrombus and restores blood flow after thromboembolic vascular occlusion. The utility of this agent for treatment of stroke in humans may be limited by post-reperfusion hemorrhagic complications. We studied tPA-mediated thrombolysis in an animal model of cerebrovascular occlusion in order to determine what factors, if any, predispose tPA-treated animals to suffer hemorrhage. Small blood clot emboli were injected into the internal carotid arteries of rabbits. Angiograms confirmed occlusion of the middle cerebral artery or internal carotid artery in 100% of subjects. tPA or saline was administered as a 30-minute infusion at various times after embolization. Hemorrhage rates were similar in all groups regardless of treatment. tPA increased the prothrombin time and the thrombin time but not the partial thromboplastin time. There was no correlation between these changes in blood coagulation and the finding of cerebral hemorrhage. We observed a significant association between stroke severity and cerebral hemorrhage. We conclude that tPA treatment successfully causes thrombolysis of cerebral emboli without causing an increase in the incidence of cerebral hemorrhage in rabbits.
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PMID:Tissue plasminogen activator-mediated thrombolysis of cerebral emboli and its effect on hemorrhagic infarction in rabbits. 249 32

Tissue plasminogen activator (TPA) converts plasminogen to plasmin within the fibrin clot, thus localizing activation of fibrinolysis. To determine the extent to which platelets promote activation of plasminogen by TPA, we studied the interaction of TPA and plasminogen with unstimulated platelets. Normal washed platelets incubated in the presence of physiologic concentrations of plasminogen (180 micrograms/mL) and TPA (20 ng/mL) failed to generate plasmin activity. In contrast, incubation of platelets with TPA concentrations achieved during thrombolytic therapy (40 to 800 ng/mL) produced a tenfold to 50-fold increase in plasmin activity. After exposure to plasminogen and 200 ng/mL of TPA for one hour, platelets failed to agglutinate in the presence of ristocetin. Incubation of platelets suspended in autologous plasma with 400 ng/mL of TPA for one hour also inhibited ristocetin-induced agglutination. Exposure of platelets to plasminogen and increasing concentrations of TPA correlated with a decrease in glycoprotein Ib (GPIb) and an increase in glycocalicin, as shown by immunoblotting. The glycoprotein IIb/IIIa (GPIIb/IIIa) complex and a 250,000-dalton protein also disappeared from washed platelets after incubation with plasminogen and 200 ng/mL of TPA for one hour. These platelets failed to aggregate in the presence of adenosine diphosphate (ADP) or gamma thrombin, although aggregation in response to calcium ionophore A23187 and arachidonic acid remained intact. However, aggregation in response to all four agonists was normal when platelets were incubated with TPA in the presence of autologous plasma. Platelets from a patient with Glanzmann's thrombasthenia also generated plasmin in the presence of TPA. Hydrolysis of GPIb and inhibition of ristocetin-induced agglutination occurred to a lesser extent with these platelets than with control platelets. We conclude that platelets provide a surface for activation of plasminogen by pharmacologic amounts of TPA. Plasmin generation leads to degradation of GPIb and decreased ristocetin-induced agglutination in normal and thrombasthenic platelets, as well as degradation of GPIIb/IIIa in normal washed platelets and inhibition of ADP and gamma thrombin-induced aggregation. These findings suggest that pharmacologic concentrations of TPA may cause platelet dysfunction due to plasmin generation on the platelet surface.
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PMID:Activation of plasminogen by tissue plasminogen activator on normal and thrombasthenic platelets: effects on surface proteins and platelet aggregation. 294 Oct 84

Tissue plasminogen activator (t-PA) and single chain urokinase-plasminogen activator (scu-PA) are relatively "fibrin-specific" thrombolytic drugs with short plasma half lives of 6-8 minutes. Most treatment regimens with these agents utilize a bolus injection followed by continuous drug infusion, usually combined with anticoagulant therapy. The purpose of this study was to establish the dose-response characteristics for scu-PA and t-PA, when given as a single intravenous bolus injection, in a dog model of arterial thrombosis. Eight groups of 6 dogs each were given one of the following doses of scu-PA (mg/kg): 0.20, 0.50, 1.00, 2.00; or t-PA: 0.05, 0.10, 0.20; or an equivalent amount of saline (control group). All doses were given as a single bolus injection 60 minutes after formation of a totally occlusive femoral artery thrombus. Thrombolysis was measured by monitoring the continuous decrement of 125I activity from a radiolabelled thrombus. Ninety minutes after drug injection, all scu-PA treated dogs showed greater thrombolysis (30%, 45%, 56%, and 67%, respectively) than the control group (15%, p less than 0.01). The 0.10 and 0.20 mg/kg t-PA treated dogs showed greater thrombolysis (35% and 49%, respectively) than the control group (15%, p less than 0.01). Both scu-PA and t-PA caused a partial and dose-dependent decrease in alpha 2-antiplasmin activity but scu-PA caused a greater depletion (72% vs. 18%, respectively, p less than 0.05) at 60 minutes after the highest dose of drug administration. Both drugs showed a longer than expected thrombolytic effect based upon the known half lives. Neither drug caused significant changes in the prothrombin time, activated partial thromboplastin time, thrombin time, hematocrit, platelet count, or fibrin degradation product concentration. Single bolus injections of scu-PA and t-PA produce safe and effective thrombolysis in this dog model of arterial thrombosis.
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PMID:Bolus dose response characteristics of single chain urokinase plasminogen activator and tissue plasminogen activator in a dog model of arterial thrombosis. 314 52

Tissue plasminogen activator (t-PA) purified from culture of human lung cells was infused over 30 min at the dose of 7.2 mg or 14.4 mg per person into human male volunteers. T-PA declined rapidly after the cessation of infusion with T1/2, alpha of about 4 min and T1/2, beta of about 40 min. The plasma fibrinogen and plasminogen did not change during and after the infusion of t-PA. The concentration of alpha 2antiplasmin (alpha 2AP) did not change but that of alpha 2AP-plasmin complex increased to about 200 nM at the infusion of 14.4 mg/person. Fragment D was hardly found at the infusion of 7.2 mg but some increase in the concentration of D was observed at the infusion of 14.4 mg. The concentration of free plasminogen activator inhibitor (PAI-1) rapidly declined and kept low up to 150 min, and returned to normal the following day. The concentration of t-PA-PAI-1 complex increased rapidly, and slowly declined after the end of the infusion of t-PA, suggesting no significant release of PAI-1 in response to increase in plasma concentration of t-PA or t-PA-PAI-1 complex. The addition of thrombin to the blood after withdrawal resulted in the significant formation of D-dimer, even at 150 min after the infusion. There was not hyperaggregability of platelets during and after the infusion of t-PA. These results suggest that the infusion of t-PA at the dose of 7.2 mg or 14.4 mg/person for 30 min resulted in high fibrinolytic potential in the blood without the breakdown of fibrinogen or increase in PAI-1.
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PMID:Changes in various parameters of fibrinolysis in persons infused with tissue plasminogen activator: special reference to plasminogen activator inhibitor. 314 66

The function of fibrinolysis is to dissolve fibrin clots. The agent of fibrinolysis is plasmin, a glycoprotein with gram molecular weight (GMW) of 90,000. Under natural conditions, plasminogen is converted to plasmin by tissue plasminogen activator (TPA). Activation occurs on the fibrin surface, thus confining proteolytic activity to the appropriate site. Tissue plasminogen activator, produced by monoclonal methods, has recently been made available for limited therapeutic use. Currently streptokinase and urokinase are widely used therapeutically to activate plasminogen. These agents cause plasmin to be formed which is free in the circulation as well as bound to fibrin, resulting in proteolysis of circulating plasminogen and clotting factors. Fibrinolytic therapy has proven to be more beneficial than anticoagulation alone for deep vein thrombi and for pulmonary emboli. During therapy, laboratory studies demonstrate reduced concentrations of plasminogen, fibrinogen, and of alpha-2 plasmin inhibitor, and prolongation of activated partial thromboplastin time and thrombin time. Laboratory findings must be correlated with the clinical course. Demonstration of circulating plasmin-antiplasmin complex may be a useful indicator of active fibrinolysis.
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PMID:Fibrinolysis--a review. 623 87


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