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)

An antithrombotic action of the protein C (PC) activator from the venom of Agkistrodon blomhoffi ussuriensis on the model of platelet-dependent thrombosis in the arteriovenous shunt in rats was under investigation. Administration of the PC activator to rats resulted in a dose-dependent prolongation of the thrombus formation time, in a decrease in PC and factor V levels in blood and in APTT prolongation. There were no changes in the tissue-type plasminogen activator level and in the ADP- or epinephrine-induced platelet aggregation, but platelet adhesion to glass decreased. The possible mechanism of the antithrombotic action of the PC activator appeared to be the factor V inactivation mediated by protein C activation and the decrease in platelet adhesion.
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PMID:[The antithrombotic action of a protein C activator from the venom of Agkistrodon blomhoffi ussuriensis in thrombus formation in an extracorporeal shunt in rats]. 820 48

In 12 healthy young men, strenuous cycling exercise in the supine position, caused platelet aggregability to decrease and the ADP threshold to rise from 7.0 microM resting, to 9.5 exercising (P < 0.01). At the same time, fibrinolytic activity increased markedly: euglobulin clot lysis time shortened from 178 to 68 min, PAI-1 fell from 8.91 to 5.16 IU ml-1, and t-PA rose from 0.56 to 3.95 IU ml-1, all three values were significant to P < 0.01. When the erect posture was assumed after lying at ease for 1 h after exercise, it did not increase platelet activity as expected, but caused a modest increase of fibrinolytic activity. These results suggest that supine exercise will not affect the haemostatic system adversely.
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PMID:Effect of supine exercise on platelet aggregation and fibrinolytic activity. 820 49

The experiments reported here were carried out to define in greater detail actin's stimulation of plasmin generation by t-PA. Actin did not alter t-PA's hydrolysis of a synthetic substrate, and thus is unlikely to have a direct effect upon t-PA's proteolytic activity. When studied in a single-stage assay, actin accelerated t-PA-mediated plasmin generation from both Glu-plasminogen and Lys-plasminogen, indicating the central role of ternary complex formation. Although actin does not appear to bind two-chain urokinase (tcu-PA), it stimulates tcu-PA's cleavage of Glu-plasminogen. This finding suggests that actin alters the conformation of Glu-plasminogen to an open form. The failure of actin to increased plasmin generation by tcu-PA acting on Lys-plasminogen, which is in an open configuration, is consistent with this interpretation. Immunoglobin G, which shares with actin the property of binding to Glu-plasminogen after nicking by plasmin, did not stimulate tcu-PA's cleavage of Glu-plasminogen, indicating the uniqueness of actin's effects and suggesting interactions between actin and plasminogen at multiple binding sites. Unlike fibrin and heparin, whose stimulation of t-PA is related to polymer length actin is able to stimulate t-PA when presented in either a monomeric or polymeric form. Denaturation of actin by exposure to urea and guanidine increased its ability to stimulate plasmin generation by t-PA. Because actin's structure is maintained by a noncovalently bound adenine nucleotide (ATP or ADP), exposure to ATP/ADPases found in plasma and on cell membranes might also result in its denaturation. Actin treated with an enzyme functionally similar to such ecto-ATP/ADPases, potato apyrase, was more potent than native actin in stimulating plasmin generation by t-PA. The effects of apyrase were blocked by the addition of the plasma actin-binding proteins, gelsolin and the vitamin D-binding protein (DBP). Thus, denaturation of actin may occur in under physiologic conditions, with potential biological consequences. Actin thus appears to be unique with regard to its interactions with the fibrinolytic system and plasma actin-binding proteins may serve to protect the host from the effects of denatured actin.
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PMID:Actin stimulates plasmin generation by tissue and urokinase-type plasminogen activators. 823 51

Inhibition of the platelet glycoprotein (GP) IIb/IIIa receptor with the murine monoclonal antibody 7E3 abolishes ex vivo platelet aggregation, reduces thrombogenicity, and sustains arterial recanalization with recombinant tissue-type plasminogen activator (rt-PA). A chimeric murine/human Fab fragment of 7E3 (c7E3-Fab) has a markedly reduced immunogenicity, but its potency as an adjunct for thrombolysis with rt-PA has not been evaluated. The effects of a single intravenous bolus injection of aspirin (17 mg/kg) or c7E3-Fab (0.45 mg/kg) on thrombolysis and reocclusion induced with rt-PA were studied in groups of six baboons with femoral arterial thrombosis and superimposed high-grade stenosis. This dose of c7E3-Fab blocked 96 +/- 1% of the platelet GPIIb/IIIa receptors and abolished ADP-induced platelet aggregation. Bolus intravenous injections of rt-PA (0.25 mg/kg) were repeated at 15-minute intervals until reperfusion occurred (maximum of four injections). In the aspirin group, reperfusion was obtained within 51 +/- 16 minutes (mean +/- SD) but was rapidly followed by reocclusion within 6 +/- 9 minutes and by cyclic reflow and reocclusion. In the c7E3-Fab group, reperfusion was obtained within 25 +/- 8 minutes (P < .01 versus aspirin group) and was associated with a delayed reocclusion of 63 +/- 63 minutes (P < .05 versus aspirin group). Template bleeding times remained unchanged in the aspirin/rt-PA group but were markedly prolonged (to > 30 minutes) in the c7E3-Fab/rt-PA group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A chimeric murine/human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissue-type plasminogen activator in baboons. 824 Nov 5

Brief stress such as dynamic work protects against thrombosis by enhancing blood fluidity. The effect of isometric work on blood fluidity, however, is not known. The aim of the present study therefore was to test the effect of isometric work on heart rate (HR), blood pressure (BP), platelet function and fibrinolytic activity. Twelve healthy male volunteers were tested before and after isometric work. Isometric work resulted in an increase in HR from 62.4 to 110.0 beats/min and in systolic BP from 118.3 to 134.5 mmHg (p < 0.01). No significant change occurred in platelet release estimated as plasma levels of B-TG and PF-4, or platelet aggregation induced by ADP. Fibrinolytic activity increased, as evidenced by a decrease in ECLT from 136.7 + 10.5 to 72.3 + 9.8 min) (p < 0.01) and an increase in t-PA of 400%. No significant change was observed in PAI. The present data suggest that isometric work increases fibrinolytic activity significantly, but leaves platelet function unchanged.
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PMID:The impact of static work on fibrinolysis and platelet function. 830 86

1. Administration of bovine thrombin (100 u kg-1) into the carotid artery of rabbits induces a sustained accumulation of 111 Indium-labelled platelets within the cranial vasculature over the subsequent 3 h. 2. Intracarotid (i.c.) administration of defibrotide (64 mg kg-1 bolus plus 64 mg kg-1 h-1 for 1 h) prior to i.c. thrombin (100 u kg-1) significantly reduces the ability of thrombin to induce cranial thromboembolism in rabbits. 3. Intravenous (i.v.) administration of thrombin (20 u kg-1) in rabbits induces a reversible accumulation of radiolabelled platelets into the thoracic circulation which is significantly reduced by i.v. administration of defibrotide (64 mg kg-1 bolus plus 64 mg kg-1 h-1 for 1 h) prior to i.v. thrombin. In contrast, platelet accumulation in response to adenosine diphosphate (ADP; 20 micrograms kg-1, i.v.) or platelet activating factor (PAF; 50 ng kg-1, i.v.) is not significantly affected by this treatment. 4. Intravenous administration of the nitric oxide (NO)-synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 mg kg-1) potentiates platelet accumulation induced by low dose thrombin (10 u kg-1, i.v.) within the pulmonary vasculature of rabbits. The potentiated response is significantly abrogated following pretreatment with defibrotide (64 mg kg-1 bolus plus 64 mg kg-1 h-1 for 1 h, i.v.). 5. Intravenous injection of human thrombin (1250 u kg-1) to mice induces death within the majority of animals which is significantly reduced by pretreatment with defibrotide (150-175 mg kg-1, i.v.). In contrast, death induced by i.v. collagen (1.25 mg kg-1) plus adrenaline (75 microg kg-1) is not significantly affected by defibrotide pretreatment.6. The inhibitory effect of defibrotide in mice is abolished following concomitant treatment with the inhibitor of fribrinolysis, tranexamic acid (100 mg kg-1, i.v.), but is unaffected following treatment with the cyclo-oxygenase inhibitor, aspirin (300 mg kg-1, i.p.).7. The protective effect of defibrotide against thrombin-induced thromboembolism in the mouse is potentiated by recombinant tissue-plasminogen activator (rt-PA; 1 mg kg-1, i.v.) or unfractionated heparin (10 u kg-1, i.v.) administration.8. The results suggest that defibrotide may possess antithrombotic activity on thrombin-induced thromboembolism which, at least in the mouse, may be partially mediated via induction of the fibrinolytic pathway.
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PMID:The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits. 830 2

Protein C (PC) is an anticoagulant protein which, being activated by thrombin, degrades factors V/Va and VIII/VIIIa and releases a tissue-type plasminogen activator. Some Agkistrodon snake venoms contain PC activators which, in experiments, exert an anticoagulant action. An antithrombotic effect of the PC activator from the venom of A. blomhoffi ussuriensis on the model of thrombus formation in the arterio-venous shunt in rats was under investigation. Administration of the PC activator resulted in a dose-dependent prolongation of the thrombus formation time and a decrease in plasma PC activity, which were accompanied by a decrease in factor V activity and APTT prolongation. No reliable changes in the t-PA level, ADP- and epinephrine-induced platelet aggregation were observed. Platelet adhesion to glass beads diminished. We assume that the antithrombotic effect of the PC activator from the A. blomhoffi venom in the platelet-dependent thrombosis model is caused by PC activation and subsequent factor V inactivation as well as by platelet adhesiveness reduction.
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PMID:Protein C activator from the venom of Agkistrodon blomhoffi ussuriensis retards thrombus formation in the arterio-venous shunt in rats. 837 94

Infusion of the thrombolytic agents streptokinase (SK, 666 units/kg per minute for 60 minutes) and tissue-type plasminogen activator (t-PA, 10 micrograms/kg per minute for 15 minutes) in rabbits induced a significant hypotension and decrease in platelet count that were completely prevented by treatment with platelet-activating factor (PAF) receptor antagonists SDZ 63-675 and WEB 2170. PAF synthesis by vascular tissue was suggested by its extraction from blood-free heart and aorta of rabbits treated in vivo with SK or t-PA but not of control rabbits. In contrast, PAF was not detected in peripheral blood. Ex vivo studies on platelet aggregation response to ADP and PAF performed on platelet-rich plasma obtained before and after SK and t-PA infusion demonstrated an early hyperaggregable phase, abrogated by PAF receptor antagonists and followed by reduced sensitivity of platelets to PAF. The ED50 values for the aggregation of washed rabbit platelets induced by PAF but not thrombin were significantly increased at 60 and 120 minutes after SK and t-PA infusion, suggesting a specific desensitization of platelets to PAF. In contrast to PAF receptor antagonists, aspirin did not significantly modify the hypotension and the platelet hyperaggregability induced by SK or t-PA or the platelet hypoaggregability induced by t-PA. Thrombocytopenia induced by t-PA, but not by SK, was partially prevented by aspirin. The effect of SK, t-PA, and plasmin on the aggregation of washed platelets from untreated rabbits and from humans was also studied. Whereas SK and t-PA were inactive, plasmin induced dose-dependent platelet aggregation that was inhibited by platelet pretreatment with PAF receptor antagonists. In conclusion, the effect of PAF receptor antagonists observed in the present experimental model suggests that the hypotension and activation of platelets induced by SK and t-PA infusion are mediated by PAF.
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PMID:Role of platelet-activating factor in hypotension and platelet activation induced by infusion of thrombolytic agents in rabbits. 838 25

Fibrin(ogen) (FGN) is important for hemostasis and wound healing and is cleared from sites of injury primarily by the plasminogen activator system. However, there is emerging evidence in plasminogen activator-deficient transgenic mice that nonplasmin pathways may be important in fibrin(ogen)olysis, as well. Given the proximity of FGN and monocytes within the occlusive thrombus at sites of vascular injury, we considered the possibility that monocytes may play an ancillary role in the degradation and clearance of fibrin. We found that monocytes possess an alternative fibrinolytic pathway that uses the integrin Mac-1, which directly binds and internalizes FGN, resulting in its lysosomal degradation. At 4 degrees C, FGN binds to U937 monocytoid cells in a specific and saturable manner with a kd of 1.8 mumol/L. Binding requires adenosine diphosphate stimulation and is calcium-dependent. At 37 degrees C, FGN and fibrin monomer (FM) are internalized and degraded at rates of 0.37 +/- 0.13 and 0.55 +/- 0.03 microgram/10(6) cells/h by U937 cells, 1.38 +/- 0.02 and 1.20 +/- 0.30 microgram/10(6) cells/h by THP-1 cells, and 2.10 +/- 0.20 and 2.52 +/- 0.18 micrograms/10(6) cells/h by human peripheral blood mononuclear cells, respectively. The serine protease inhibitors, PPACK and aprotinin, and the specific elastase inhibitor, AAPVCK, do not significantly inhibit degradation. However, degradation is inhibited by chloroquine, suggesting that a lysosomal pathway is involved. Factor X, a competitive ligand with FGN for the Mac-1 receptor, also blocks degradation, as does a monoclonal antibody to the alpha-subunit of Mac-1. Autoradiography of radioiodinated, internalized FGN shows that FGN proteolysis by the pathway produces a unique degradation pattern distinct from that observed with plasmin. In a fibrin clot lysis assay, Mac-1-mediated fibrinolysis contributed significantly to total fibrinolysis. In summary, FGN is internalized and degraded by activated human monocytoid cells via Mac-1 in the absence of plasmin, thereby providing an alternative fibrinolytic pathway. Thus, in addition to the function of cell adhesion, integrins may also act as receptors that mediate the internalization and degradation of bound ligands.
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PMID:Fibrin(ogen) is internalized and degraded by activated human monocytoid cells via Mac-1 (CD11b/CD18): a nonplasmin fibrinolytic pathway. 840 Feb 91

1. A randomised double-blind placebo-controlled study was performed to investigate the effects of isosorbide dinitrate (ISDN; 20 mg orally) on various aspects of platelet function and fibrinolysis in vivo in 12 healthy volunteers. 2. Measurements were performed at rest (before and after tablet ingestion) and during platelet activation by adrenaline (0.4 nmol kg-1 min-1; 30 min infusion). 3. At rest, ISDN did not alter plasma concentrations of beta-thromboglobulin (beta TG). EC50 values for ADP induced aggregation in vitro (Born aggregometry) or ex vivo filtragometry readings. Adrenaline markedly increased platelet aggregability in vivo as measured by filtragometry and elevated levels of beta TG in plasma. ISDN treatment did not affect these responses in the group as a whole. 4. Individuals responding to ISDN with more pronounced vasodilatation at rest showed a lesser increase in aggregability during the ensuing adrenaline infusion (r = -0.66, P = 0.02) despite higher adrenaline levels during ISDN. In individuals showing a significant decrease in systolic blood pressure (n = 8) ISDN tended to attenuate the adrenaline induced increase in platelet aggregability (filtragometry; P = 0.08), despite higher plasma adrenaline and noradrenaline levels after ISDN ingestion. 5. Plasma concentrations of ISDN and its active metabolites isosorbide-5-mononitrate and isosorbide-2-mononitrate were not correlated to haemodynamic or platelet variables. 6. Fibrinolytic activity (t-PA antigen and activity, PAI-1 antigen and activity) increased similarly during the adrenaline infusion following ISDN and placebo. 7. It is concluded that ISDN may affect platelet aggregation responses to adrenaline in vivo, but only in individuals showing significant haemodynamic responses to ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of an oral dose of isosorbide dinitrate on platelet function and fibrinolysis in healthy volunteers. 844 32


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