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)

In septic patients capable of normal white cell responses, high plasma levels of PAI-I, t-PA antigen and t-PA-PAI-I complex were observed. The ratios of t-PA and PAI-I were such that free PA activity was almost never observed. In patients severely leucopenic prior to becoming septic the changes were significantly less marked, so presence of leucocytes enhances the fibrinolytic inhibition occurring in sepsis. The non-leucopenic septic group showed greater evidence of thrombin generation in that FPA levels were higher but fibrinogen levels were only slightly less and antithrombin levels not different from those in the leucopenic group. A greater tendency to fibrin deposition and the striking fibrinolytic inhibition noted in patients with normal white cell responses may contribute to the development of some of the complications of sepsis in which fibrin deposition participates and may explain their relative rarity in leucopenic patients. When shock supervened, levels of PAI-I were high in both leucopenic and non-leucopenic groups, indicating that a source of PAI-I outwith the leucocytes themselves contributes to the phenomena observed.
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PMID:Influence of white blood cells on the fibrinolytic response to sepsis: studies of septic patients with or without severe leucopenia. 764 91

Thrombolytic agents are widely used for the treatment of acute thromboembolic diseases, especially acute myocardial infarction (AMI). These compounds include streptokinase, anistreplase, alteplase, urokinase and, although not commercially available yet, saruplase (prourokinase). The therapeutic window of these compounds is relatively small and subtherapeutic or toxic plasma concentrations may have serious clinical implications (insufficient thrombolysis, reocclusion and bleeding). Among the factors that affect the pharmacokinetics and pharmacodynamics of thrombolytic agents, comedication is especially relevant since these drug interactions are partly predictable and sometimes preventable. Based on knowledge of the pharmacology of thrombolytic agents and general mechanisms by which pharmacokinetic drug interactions occur, interactions with alteplase and saruplase are expected. The clearance of alteplase is dependent on hepatic blood flow (HBF), and scientific evidence is emerging that saruplase is also a high-clearance compound. Each pharmacological agent that alters HBF and is given concurrently with one of these agents can change the plasma concentrations of those thrombolytics. Although there are no published data confirming drug-induced changes in the metabolism of alteplase or saruplase by this mechanism in humans, indirect supportive evidence (clinical observations and animal experiments) is available. An overview is presented of the anticipated effects of compounds that are frequently coadministered with thrombolytic agents on the pharmacokinetics of the thrombolytics with high-clearance properties. Since the clearance of these thrombolytics may be strongly affected by hypoperfusion of the liver as a result of cardiogenic haemodynamic failure, the role of circulatory changes in potential drug-drug interactions is also discussed. Pharmacodynamic drug interactions are highly relevant in the treatment of acute thrombotic lesions and are still being evaluated to further optimise treatment strategies. As most of these treatments exist as combinations of thrombolytic, antithrombin and antiplatelet compounds, beneficial effects are partly offset by bleeding complications. Changes in the pharmacokinetics and/or pharmacodynamics of thrombolytic agents may have serious consequences. It becomes imperative for the practising physician to be aware of benefits and risks of interactions with thrombolytic agents and especially of the fact that the principal way by which the pharmacokinetics of alteplase and, presumably, saruplase can be affected is by drug- and/or haemodynamic failure-induced changes of HBF.
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PMID:Drug interactions with thrombolytic agents. Current perspectives. 764 59

Junin virus, an arenaviridae, is the etiological agent of Argentine hemorrhagic fever. In addition to thrombocytopenia, patients present several alterations in both the blood coagulation and the fibrinolytic system, but diffuse intravascular coagulation could not be demonstrated. To investigate further the activation status of the two systems, levels of thrombin-antithrombin complexes (TAT), prothrombin fragment 1 + 2, protein C, total and free protein S, C4bBP, antithrombin III, t-PA, PAI-1 and D-dimer were measured. Fourteen patients with a confirmed diagnosis of Argentine hemorrhagic fever were included in the study, 2 were severe, 3 moderate and 9 mild clinical cases, but hemorrhages were slight throughout. Blood samples were collected for 6 consecutive days on admission and on remission. At admission TAT and F1 + 2 levels were increased in 13/14 patients, reaching 0.33 nM (0.06-0.87) and 2.16 nM (0.96-6.5), respectively. PC was low in 4 cases, fPS in 6 and tPS in 2, whereas C4bBP and ATIII values were within normal range. t-PA and D-dimer levels were high in 11/14 patients, reaching 20 ng/ml (2.7-106) and 1660 ng/ml (877-3780) respectively, while PAI-1 was considerably increased in the 2 severe cases and normal in the remainder. These results suggest low level though persistent process of blood coagulation and fibrinolysis activation in this viral hemorrhagic disease. We believe these abnormalities may lead to the well described bleeding manifestations in these patients.
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PMID:Early markers of blood coagulation and fibrinolysis activation in Argentine hemorrhagic fever. 766 17

Current prevention or treatment of coronary thrombosis relies on antiplatelet agents (aspirin), antithrombin agents (heparin), and plasminogen activators (t-PA). The purpose of this review is to describe novel antithrombotic agents in each of these classes and to discuss recent and future clinical trials with the new agents. Whereas aspirin is a cyclo-oxygenase inhibitor, the most promising new antiplatelets are directed at an integrin cell surface receptor--glycoprotein (GP) IIb/IIIa--which represents the final common pathway for platelet aggregation. The monoclonal F(ab) antibody c7E3, a chimeric murine-human immunoglobulin G (IgG) fragment, is the most intensively studied to date. c7E3 was assessed by the Evaluation of Platelet Monoclonal Antibody to Prevent Ischemic Complications (EPIC) trial in which 2,099 high-risk angioplasty patients were randomized to bolus (placebo) plus infusion (placebo), bolus (c7E3, 0.25 mg/kg) plus infusion (placebo), and bolus (c7E3, 0.25 mg/kg) plus infusion (c7E3, 10 micrograms/min; 12 hours). The overall event rate at 30 days was significantly decreased from 12.8% (placebo) to 8.3% (c7E3), a 36% relative reduction (p = 0.009). Integrelin is a cyclic heptapeptide with marked specificity for GP IIb/IIIa integrin. It was studied during the Integrelin to Manage Platelet Aggregation to Prevent Coronary Thrombosis (IMPACT) trial, which enrolled 150 routine coronary intervention patients. At endpoint, overall event rate was reduced from 11.9% (placebo) to 5.6% (integrelin). The much larger (4,010 patients) IMPACT-II trial has just completed enrollment to confirm and extend these encouraging results. Hirudin is the prototype of the direct antithrombins; it binds to the active catalytic site and the substrate recognition site (exosite) of thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Novel antithrombotic approaches to coronary artery disease. 786 68

Endothelial cell products contribute to many aspects of the regulation of haemostasis. They include potent inhibitors of platelet aggregation (prostacyclin and nitric oxide) rapidly released in response to agonists such as thrombin. Similar agonists also induce the formation of platelet-activating factor by endothelium. Endothelial cell surface ectonucleotidase enzymes control the catabolism of platelet-active adenine nucleotides. The main source of the circulating coagulant cofactor von Willebrand factor is the endothelium, where it is stored in granules for agonist-triggered exocytosis and also secreted constitutively. Surface anticoagulant activities are due to the presence of antithrombin and thrombomodulin. Endothelial cells also secrete plasminogen activator and its inhibitor. Many of these reactions are significantly modulated by exposure of endothelium to cytokines or bacterial endotoxin, the most striking example being the new synthesis and surface expression of the procoagulant tissue factor (thromboplastin).
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PMID:The control of production and release of haemostatic factors in the endothelial cell. 802 46

Endothelial release of tissue plasminogen activator (t-PA) may initiate fibrinolysis. Fibrinolysis and coagulation were investigated in 12 patients undergoing elective coronary artery bypass surgery. Cardiopulmonary bypass (CPB) was 108 +/- 7 min (mean +/- SEM), the time of cold, crystalloid, retrograde cardioplegia 53 +/- 5 min. Arterial and coronary sinus blood were sampled concomitantly before cardioplegia and after release of the aortic cross-clamp, for measurement of t-PA antigen (Ag) and activity, plasminogen activator inhibitor (PAI-1) Ag and activity, t-PA/PAI-1 complex, single chain urokinase (sc-uPA) and urokinase (uPA) plasminogen activators, the fibrin split product D-dimer, thrombin-antithrombin complex (TAT), and the prothrombin split product F 1 + 2. Cardiopulmonary bypass significantly increased t-PA Ag and activity, t-PA/PAI complex, D-dimer, TAT, and F 1 + 2, and decreased PAI-1 Ag and activity in arterial blood; uPA and sc-uPA were unchanged. The tissue plasminogen activator antigen was higher in coronary sinus than arterial blood after 1 (39 +/- 5 vs 24 +/- 4 ng/ml, P < 0.003), 4 (P < 0.003), and 10 min (P < 0.004) reperfusion. Tissue plasminogen activator activity and t-PA/PAI complex increased, PAI-1 activity decreased, while all other parameters were unchanged across the coronary circulation. In conclusion, CPB induces fibrinolysis and coagulation. Cold cardioplegia induces t-PA release in the coronary circulation, denoting a postischemic antithrombotic function of the coronary endothelium. Tissue plasminogen activator may be used to evaluate endothelial stimulation or injury induced by CPB, or by different regimens of myocardial protection.
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PMID:Fibrinolysis during cardiac surgery. Release of tissue plasminogen activator in arterial and coronary sinus blood. 808 78

The roles for the fibrinolytic activation and disorder of coagulation in formation of gastric ulcer induced by microvascular derangement were investigated. The rat stomach was exposed and repeated electrical stimuli (RES) were applied on the small arterial wall close to the lesser curvature to induce mucosal microcirculatory disturbances. The level of tissue-type plasminogen activator (t-PA), a key enzyme for fibrinolytic activity, in the regional blood of the stomach was significantly elevated immediately after RES. At 5 min after RES, the leakage of FITC-labeled albumin and thrombus formation in the mucosal microvasculature were visually demonstrated by using an intravital microscopic system. At 30 min, hemorrhagic erosions and linear ulcers were observed in the gastric mucosa. Pretreatment with human antithrombin-III (AT-III) in the range of 0.1-10 U/kg dose-dependently attenuated both the fibrinolytic activation and microvascular alteration promoted by RES. Human AT-III also prevented RES-induced gastric mucosal injury. Thrombin inhibitory activity in the gastric vein decreased (69.0 +/- 2.1%) just after RES, and further reduced at 30 min (47.7 +/- 5.3%). The present study suggests a hypothesis that human AT-III has a preventive effect on the gastric mucosal hemorrhagic changes via attenuating the fibrinolytic activation and subsequent microcirculatory disturbances.
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PMID:Attenuating effect of antithrombin III on the fibrinolytic activation and microvascular derangement in rat gastric mucosa. 816 29

This article has stressed the common hereditary and acquired blood protein defects associated with thrombosis. The commonest hereditary defects appear to be antithrombin, protein C, and protein S deficiency, and the commonest acquired defects are anticardiolipin antibodies and the lupus anticoagulant. Therefore these are the defects that should first be looked for in an individual with unexplained thrombosis. If these commoner defects are not found, the rarer defects, including HC-II, plasminogen or t-PA deficiency, dysfibrinogenemia, or elevated PAI-1, should next be sought. The incidence of activated protein C cofactor deficiency is not yet clear but may also represent a common defect. Likewise, PAI-1 defects may, with time, be shown to be quite common. The importance of finding these defects has significant implications for therapy of the individual patient and for institution of family studies to identify, inform, and possibly treat others at risk. It is expected that as knowledge of hemostasis expands, more hereditary and acquired defects, such as elevated lipoprotein (a) or defects of extrinsic (tissue factor) pathway inhibitor may be associated with enhanced risks of thrombosis.
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PMID:Hypercoagulability and thrombosis. 817 Feb 63

Severe thrombotic alterations, such as veno-occlusive disease of the liver, may occur in the early phase following high-dose chemoradiotherapy and BMT. In this study, performed in patients with hematological malignancies subjected to allogeneic (10 cases) and autologous (20 cases) BMT, we have monitored laboratory hemostatic parameters to better understand the pathogenetic mechanism of thrombosis and particularly of veno-occlusive disease. Prothrombin time, activated partial thromboplastin time, plasma fibrinogen, markers of hypercoagulability (thrombin-antithrombin complex and prothrombin fragment F1+2); natural anticoagulants (protein C, protein S and antithrombin) together with fibrinolytic parameters (plasminogen, alpha 2-antiplasmin, tissue-plasminogen activator, plasminogen activator inhibitor and D-dimer) were assessed before transplant, on day 0 and weekly for 1 month thereafter. A hypercoagulability state, not related to an impairment of the anticoagulant and fibrinolytic systems, was documented before and after autologous and allogeneic transplant. Two patients developed veno-occlusive disease: they did not show any difference from the other patients before transplant while they presented a decrease of the natural anticoagulants along with altered fibrinolytic parameters only at the clinical onset of veno-occlusive disease. In conclusion, in this study a state of marked hypercoagulability was documented in BMT patients and the hemostatic laboratory parameters evaluated were not able to predict the occurrence of the thrombotic complications.
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PMID:Hypercoagulability in patients undergoing autologous or allogeneic BMT for hematological malignancies. 824 85

Molecular biology approaches have brought considerable progress to the development of novel plasminogen activators and antithrombin agents. While the modification of t-PA itself and the construction of chimeras between t-PA and pro-urokinase by molecular techniques have not resulted in enhanced efficacy, this can be achieved by constructing hybrids consisting of plasminogen activator domains and domains of monoclonal "targeting" antibodies. This and alternative approaches offer the promise of improved therapy in the future. Of equal importance is effective anticoagulant therapy through new antithrombin agents, platelet fibrinogen receptor inhibitors, or alternative approaches, among them gene therapy. Prevention of short-term thrombotic complications of invasive procedures such as PTCA or stent implantation may be better attained with the new antithrombins, while prevention of longer term complications (restenosis) may require inhibition of the thrombin receptor.
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PMID:Inhibition of platelets and thrombin: implications for treatment of coronary artery thrombosis. 832 14


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