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)

399 out of 474 inpatients with unstable angina were monitored for 48 h and 97 of these were found to be refractory to conventional antianginal treatments and entered a randomised double-blind study. With the initial protocol heparin infusion or bolus were compared with aspirin; with a modified protocol, heparin infusion, the best of these three treatments, was compared with alteplase. Patients were monitored for 3 days after starting treatment and then observed clinically for 4 more days. On the first days of treatment heparin infusion significantly decreased the frequency of angina (by 84-94%), episodes of silent ischaemia (by 71-77%), and the overall duration of ischaemia (by 81-86%). Heparin bolus and aspirin were not effective. Alteplase caused small (non-significant) reductions on the first day only. Only minor bleeding complications occurred.
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PMID:Effect of heparin, aspirin, or alteplase in reduction of myocardial ischaemia in refractory unstable angina. 196 13

The effect of purified human activated protein C (APC) on fibrinolysis was studied by using in vitro clot lysis techniques. Clots were formed from citrated blood or plasma (supplemented with 125I-labeled fibrinogen) by adding thrombin and Ca(2+)-ions; lysis of the clots was achieved by the addition of tissue-type plasminogen activator before clot formation. The gradual release of labeled fibrin degradation products from the clot into the supernatant was taken as a measure for the lysis rate. It was demonstrated that the acceleration of clot lysis by APC added before clot formation depends on the presence of Protein S, Ca(2+)-ions and phospholipids. These observations suggest a role of APC as anticoagulant in clot lysis, since the cofactors for the expression of its anticoagulant and profibrinolytic effect are very similar. Indeed, we could demonstrate that the profibrinolytic effect of APC in vitro is associated with reduction of thrombin generation through the coagulation cascade by inactivation of factor VIIIa and factor Va. For instance, APC did not accelerate the lysis of factor X deficient blood clots. More generally, thrombin generation was associated with retarded fibrinolysis in vitro. Consequently anticoagulants such as APC or Heparin are profibrinolytic, whereas pro-coagulants such as phospholipids (in cell-free plasma) inhibit fibrinolysis through the generation of thrombin. Thrombin thus plays a crucial role as a link between coagulation and fibrinolysis. As thrombin is able to inhibit the lysis of blood and plasma clots, and not of purified fibrin clots, we hypothesize that thrombin inhibits lysis through an as yet unidentified mediator in plasma.
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PMID:Protein C and fibrinolysis: a link between coagulation and fibrinolysis. 210 14

Two in vitro models of coronary thrombolysis in man, i.e. dislodgement of thrombi formed from non-anticoagulated human blood, either by (i) shear-stress or (ii) interaction of platelets with type I collagen fibre, were studied. Heparinization (1 U/ml) of blood prior to thrombus formation by (i) strongly inhibited spontaneous dislodgement (P less than 0.0001). Heparin (1 U/ml), when added with streptokinase (SK) or tissue-type plasminogen activator (rt-PA) prior to thrombus formation, considerably delayed thrombolysis. Furthermore, thrombolysis occurred much earlier when thrombi were perfused with SK or rt-PA in native than in heparinized blood. Heparin inhibited binding of 125I-rt-PA (17%, P less than 0.02) and plasminogen (88%, P less than 0.0005) to platelets activated by ADP in citrated platelet-rich plasma. We conclude that heparin interferes with the fibrinolytic system at the surface of activated platelets. Our findings suggest that heparin administration prior to thrombolytic therapy for acute myocardial infarction should be questioned.
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PMID:Heparin inhibits spontaneous thrombolysis and the thrombolytic effect of both streptokinase and tissue-type plasminogen activator. An in vitro study of the dislodgement of platelet-rich thrombi formed from native blood. 210 72

Heparin stimulates the activity of tissue plasminogen activator (t-PA) and binds to t-PA. To study this interaction, a complex between t-PA and N-acetylated heparin was formed and then linked to Sepharose. This procedure selectively links the t-PA to the column because the acetylated heparin has no free amino groups. The procedure also protects the heparin-binding site(s) on the enzyme during coupling to the matrix. The t-PA column separates heparin into two fractions, one with low affinity for t-PA and one with high affinity. Both fractions of heparin effectively accelerate inactivation of thrombin by antithrombin III. However, the fractions differ in their ability to stimulate t-PA: the low-affinity heparin has no effect on the activity of t-PA, whereas the high-affinity heparin enhances this activity. These heparin fractions will be useful in characterizing the biochemical basis and physiological consequences of the heparin--t-PA interaction.
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PMID:Fractionation of heparin by chromatography on a tissue plasminogen activator-Sepharose column. 210 84

The severity of the infarct-related residual coronary stenosis after spontaneous or therapeutic thrombolysis was quantitatively assessed in 91 patients with an acute myocardial infarction who were allocated to treatment in the acute stage with either a thrombolytic agent (100 mg of recombinant tissue-type plasminogen activator given over 3 h, 49 patients) or a placebo (42 patients). Heparin and aspirin were given to both groups until angiography was performed. Digital subtracted images of the infarct-related coronary vessel were obtained 10 to 14 days after hospital admission and were subsequently analyzed with the use of a computer-assisted coronary stenosis measurement system. Neither treatment group differed significantly in age, gender or location of the culprit coronary lesion. Median values (90% range) in the thrombolysis and control groups were, respectively, 1.95 (0.9 to 5.3) mm versus 1.7 (0.9 to 3.4) mm for stenosis length; 1.4 (0.8 to 2.7) mm versus 1.4 (0.9 to 1.8) mm for minimal luminal diameter; 57% (36% to 75%) versus 58% (44% to 71%) for diameter obstruction; 82% (59% to 95%) versus 82% (68% to 92%) for geometric area obstruction; and 78% (58% to 91%) versus 79% (66% to 90%) for densitometric area obstruction. The difference between the two groups was not statistically significant for any of these measurements. Thus, in this study no significant differences in anatomy or severity of residual coronary stenosis could be demonstrated at 10 to 14 days after an acute myocardial infarction in patients with a recanalized infarct-related vessel, whether or not thrombolytic therapy was given on admission. These results indicate that with effective antithrombotic treatment, gradual endogenous fibrinolysis or more rapid lysis induced by the infusion of a thrombolytic agent results in a similar infarct-related coronary lesion at the time of hospital discharge.
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PMID:Angiographic assessment of the infarct-related residual coronary stenosis after spontaneous or therapeutic thrombolysis. 212 5

The regulation of tissue-plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) synthesis was studied in cultured human mesothelial cells derived from omentum (HOMC). Heparin (100 U/ml) as well as pentosan polysulfate (300 micrograms/ml) stimulated tPA synthesis by HOMC 2.9-4.5-fold. Heparin-induced tPA production was dose- and time-dependent and was inhibited by cycloheximide. tPA production by HOMC was also stimulated by phorbol 12-myristate 13-acetate (2.6-fold), fibrin clots (1.9-fold), or batroxobin (1.9-fold). Heparin and pentosan polysulfate did not stimulate PAI-1 production by HOMC, while phorbol 12-myristate 13-acetate (100 nM) increased the concentration of PAI-1 in the conditioned medium by 2.6-fold over 24 h. The interaction of heparin with HOMC was studied by direct binding experiments. Dose-dependent specific binding of biotinylated heparin to HOMC was saturable at about 10 micrograms/ml, the KD was estimated to about 0.15 microM. Biotinylated heparin bound rapidly to HOMC and reached a plateau within 60 min. Unlabeled heparin as well as pentosan polysulfate inhibited binding of biotinylated heparin in a dose-dependent fashion. These data demonstrate that heparin interacts with HOMC, and increases the fibrinolytic capacity in these cells by selectively increasing the production of tPA.
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PMID:Heparin stimulates fibrinolysis in mesothelial cells by selective induction of tissue-plasminogen activator but not plasminogen activator inhibitor-1 synthesis. 212 72

The following problems are considered: Thrombosis: Safe diagnosis with phlebographic verification is recommended. Heparin has been an established treatment with the great advantage that it does not enter the fetal blood stream. In selected cases surgery or thrombolytic therapy has to be considered. Owing to the high risk of recurrence, prophylactic treatment with Heparin is required throughout pregnancy. Coumarol derivatives traverse the placental membrane to the foetus and have to be avoided because of a risk for teratogenetic injury and intracranial hemorrhage in the foetus. During the puerperium, warfarin might be given because its concentration in breastmilk is low. However, administration of vitamin K1 is recommended to prematures. Attention should be given to the side-effects of Heparin i.e. thrombocytopenia and osteoporosis. The possibility of antithrombin III deficiency should not be overlooked. In such cases it is also risk of thrombosis in the newborn. Premature separation of placenta: In most cases of abruptio placenta immediate delivery by caesarean section is necessary. In cases with partial separation of placenta and immature foetus, treatment with the fibrinolytic inhibitor tranexamic acid (Cyklokapron) has proved useful to prolong pregnancy with maturation of the foetus. Thrombocytopenia: Severe hemorrhage seldom occurs above a level of 50 x 10(9)/l. Treatment with Prednisolon has proved to be of great value. The risk of the child having thrombocytopenia is about 50%. Intraventricular bleedings: Such bleedings mainly occur in prematures. Preliminary results have shown decreased concentrations of specific plasminogen activator inhibitors.
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PMID:[Thrombotic and hemostatic problems in pregnancy and labor and their significance for the fetus and newborn infant]. 218 68

Coronary thrombolysis revolutionized the treatment of acute myocardial infarction. Most of the experience was obtained with intravenous use of streptokinase and tissue-type plasminogen activator, the latter being superior to streptokinase in regard to coronary recanalization. Numerous other promising thrombolytic agents are being investigated. Both streptokinase and tissue-type plasminogen activator decreased mortality in large trials; comparison studies in terms of efficacy are presently being performed (GISSI 2). Aspirin is an important adjunct to thrombolytic therapy; it decreased mortality by itself (ISIS 2). Heparin is conventionally used together with thrombolysis. Its efficacy is under study (GISSI 2). Intracranial hemorrhage is the most devastating complication of thrombolysis. With the present dosage regimens, the incidence is approximately 0.5%. Percutaneous transluminal coronary angioplasty in conjunction with thrombolysis accomplished frequent and persistent recanalization of the infarct artery with low mortality, including high risk patients. The TIMI IIB study demonstrated that the results of a "conservative strategy" with aggressive management of recurrent ischemic events were comparable to those of an "invasive strategy." Subgroup analysis should, however, be awaited. High risk patients with low ejection fraction or with shock benefit by early mechanical coronary recanalization. The role of thrombolysis in the "late" stage of transmural myocardial infarction or in the acute ischemic syndrome (unstable angina/non-Q-wave myocardial infarction) is unclear and presently under investigation.
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PMID:Reperfusion therapy in acute myocardial infarction: present status and controversy. 219 Jul 22

We studied blood coagulation and fibrinolysis in 19 patients during surgery with cardiopulmonary bypass (CPB). CPB was performed with a rotating pump and a membrane oxygenator. Heparinization was achieved with heparin 3 mg.kg-1 and the ACT value was kept above 400 seconds throughout the CPB. Heparin was neutralized by protamine at a ratio of 1:1-1.5 of the total amount of heparin. Blood was collected four times from an indwelling arterial line. We obtained the first sample immediately after induction of anesthesia, the second sample before heparinization, the third sample before protamine administration, and the fourth sample at the end of the operation. FPA, FPB beta 15-42, alpha 2PI-Pl-C, D-dimer, and the t-PA activity were measured. A statistically significant elevation of FPA was observed during the operation. FPB beta 15-42, alpha 2PI-Pl-C, and the D-dimer rose significantly immediately after the beginning of the CPB and these elevations continued until the end of the operation. The t-PA activity was elevated significantly only during the CPB. In conclusion, the t-PA is released from the endothelial cells during CPB by some undetermined mechanism (primary fibrinolysis). Then, plasmin is generated by the t-PA and this dissolves the fibrin clots formed by thrombin before the beginning of the CPB (secondary fibrinolysis). Enhanced fibrinolytic activity before and after the CPB is physiological secondary fibrinolysis.
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PMID:[Increased fibrinolytic activity during surgery with cardiopulmonary bypass]. 238 94

We have examined the cellular mechanisms by which heparin potentiates the ability of 3T3-adipocytes to stimulate the formation of new blood vessels. Both anticoagulant and non-anticoagulant heparin species enhanced the angiogenic activity of adipocyte-secreted products in the chick chorioallantoic membrane assay, indicating that the angiotropic effect of this glycosaminoglycan is independent of its effect on the coagulation cascade. Heparin alone was unable to produce a neovascular response. The ability of heparin to modulate three endothelial functions in vitro thought to be related to angiogenesis were examined: protease activity, motility, and mitogenesis. Heparin caused a 100% increase in the adipocyte-induced stimulation of endothelial cell plasminogen activator activity and motility, but had no effect on proliferation. The enhancement of plasminogen activator and chemoattractant activities had a similar ED50 (1-2 micrograms/ml) and optimum dose (10-30 micrograms/ml). When we examined the direct effect of heparin on the activity of two distinct plasminogen activator enzymes--urokinase and tissue-type--a dual action of heparin was observed: tissue-type enzyme activity was stimulated 100% by heparin at 10 micrograms/ml, whereas urokinase activity was inhibited by 77% at this dose. These data suggest that heparin potentiates angiogenesis in vivo by stimulating endothelial cell plasminogen activator, motility, or both. Our results further suggest that for adipocyte-induced blood vessel formation, in contrast to other angiogenesis systems, heparin does not appear to affect the mitogenic activity.
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PMID:Heparin potentiation of 3T3-adipocyte stimulated angiogenesis: mechanisms of action on endothelial cells. 242 84


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