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)

Sepsis is commonly associated with disturbances of the hemostatic balance. Most of the pathophysiological changes in sepsis are caused by endotoxin acting directly through endothelial injury or indirectly through release of cytokines with procoagulant effects. The relation between cytokines and hemostatic parameters was assessed in 32 patients with sepsis. Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complexes (TAT), tissue type plasminogen activator (t-PA) functional and antigen, plasminogen activator inhibitor-1 (PAI-1), plasminalpha2-antiplasmin complexes (PAP), D-Dimer, thrombomodulin (TM) and von Willebrand factor (vWF) were measured in patients and in 30 healthy subjects. The levels of cytokines TNF-alpha and interleukin-6 (IL-6) also were determined. A significant increase of F1+2, TAT, PAI-1, PAP, and D-Dimer was observed in septic patients as compared with controls (p<0.0001), whereas t-PA activity was significantly reduced (p<0.01). The markers of endothelial cell activation TM, vWF, and t-PA antigen also were elevated significantly as compared with the control group (p<0.01). Finally, we found a marked increase of TNF-alpha and IL-6 (p<0.0001). Whereas the increase of cytokine levels could be partially responsible for the hemostatic activation, it did not correlate with markers of endothelial activation in patients with sepsis.
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PMID:Endothelial cell and hemostatic activation in relation to cytokines in patients with sepsis. 1023 Aug 94

The vascular endothelium is a biologically active monolayer of cells providing an interface between the blood flow and tissues. Vascular Endothelial Cells (VEC) have two functional states. The endothelium is normally anti-thrombotic and anti-adhesive to ensure blood fluidity. During aggressions, such as atherosclerosis, inflammation states, metabolic diseases (through chemical or mechanical stimuli), VEC can reverse its functions by expressing stored material or by slower involvement of previously are repressed genes. Endothelial cells have three types of anti-thrombotic properties: vaso regulating properties: VEC release vasomotor components, such as endothelin (vasoconstriction), prostacyclin and nitric oxide, (vasodilatation). Endothelial cells also have antithrombotic and hemostatic properties. They express proteoglycans on their surface, including some negative-charge, plasminogen, sulfate glycosaminoglycans (heparan-sulfate), and secrete plasminogen tissular activator (t-PA) and tissular factor inhibitor. One fundamental action of the endothelium in that area is the production and expression of thrombomodulin, a thrombin receptor. This function has a major anticoagulation effect, controlling continual thrombin generation at the sub-endothelium and blood cell interface. Moreover, endothelial cells show anti-adhesion properties. During cardio-vascular diseases, all of these properties may be reversed. Thus the VEC have a determinant role in hemodynamic control through these various metabolic activities, such as control of homeostasis, vascular tone, blood fluidity, coagulating properties, cellular adhesion. Otherwise, many studies have demonstrated that local blood flow conditions have a crucial role on the VEC properties (mechanoactivation and mechanotransduction concept). In conclusion, knowledge of all the properties of the endothelial cells and control of the phenomena which define their functions is a key element in understanding cardiovascular diseases.
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PMID:[Hemorheology and vascular endothelial cells]. 1039 42

Clinical effects of recombinant human erythropoietin (rHuEPO) such as thrombosis, convulsions, hyperviscosity, hypertension, and angiogenic effect in culture cells have been described. We studied the rHuEPO effect on endothelial damage markers and endothelial function markers: tissue-type plasminogen activator (t-PA), nitrate (NO3), thrombomodulin (TM), and von Willebrand factor (vWF). Twenty-six peritoneal dialysis patients treated with rHuEPO and 19 controls were included. The study design for rHuEPO patients consisted of four periods: long-term treatment (rHuEPO-1); 2 months of withdrawal (rHuEPO-2); and 4 months on 5000 IU/week rHuEPO subcutaneously, with markers being measured after 2 months (rHuEPO-3) and after 4 months (rHuEPO-4). After 2 months of rHuEPO withdrawal, a decrease in hemoglobin level appeared (11+/-1.8 g/dL to 9.2+/-1.5 g/dL, p < 0.01). After rHuEPO reintroduction, this value reached 10.6+/-1.5 g/dL at two months, and 11.1+/-1.4 g/dL at four months. A significant increase in t-PA ratio was observed from two months without rHuEPO to two months on rHuEPO, returning to previous values after four months. Similarly, TM increased for patients with creatinine clearances (CrC) < 5 mL/min. No changes in the higher-than-normal plasma vWF levels were found during the various periods. A statistically significant lower value was found in controls compared with rHuEPO-4 patients. A statistically significant increase in NO3 levels was observed in the pre-venous occlusion (VO) test immediately after the re-introduction of rHuEPO. This increment returned to prior values four months after rHuEPO was reintroduced. Our results show that rHuEPO treatment causes an increase in some endothelial damage markers (TM, t-PA) and modifies endothelial function markers (t-PA ratio, NO3). These changes might favor thrombosis and atherosclerosis.
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PMID:Effects of recombinant human erythropoietin on functional and injury endothelial markers in peritoneal dialysis patients. 1040 11

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.
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PMID:A murine model of myocardial microvascular thrombosis. 1048 67

Plasma carboxypeptidase B (PCB) is an exopeptidase that exerts an antifibrinolytic effect by releasing C-terminal Lys and Arg residues from partially degraded fibrin. PCB is produced in plasma via limited proteolysis of the zymogen, pro-PCB. In this report, we show that the K(m) (55 nM) for plasmin-catalyzed activation of pro-PCB is similar to the plasma concentration of pro-PCB (50-70 nM), whereas the K(m) for the thrombin- or thrombin:thrombomodulin-catalyzed reaction is 10-40-fold higher than the pro-PCB level in plasma. Additionally, tissue-type plasminogen activator triggers activation of pro-PCB in blood plasma in a reaction that is stimulated by a neutralizing antibody versus alpha(2)-antiplasmin. Together, these results show that plasmin-mediated activation of pro-PCB can occur in blood plasma. Heparin (UH) and other anionic glycosaminoglycans stimulate pro-PCB activation by plasmin but not by thrombin or thrombin:thrombomodulin. Pro-PCB is a more favorable substrate for plasmin in the presence of UH (16-fold increase in k(cat)/K(m)). UH also stabilizes PCB against spontaneous inactivation. The presence of UH in clots prepared with prothrombin-deficient plasma delays tissue-type plasminogen activator-triggered lysis; this effect of UH on clot lysis is blocked by a PCB inhibitor from potato tubers. These results show that UH accelerates plasmin-catalyzed activation of pro-PCB in plasma and PCB, in turn, stabilizes fibrin against fibrinolysis. We propose that glycosaminoglycans in the subendothelial extracellular matrix serve to augment the levels of PCB activity thereby stabilizing blood clots at sites where there is a breach in the integrity of the vasculature.
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PMID:Characterization of plasmin-mediated activation of plasma procarboxypeptidase B. Modulation by glycosaminoglycans. 1057 83

Abnormalities in fibrinolysis have been reported in hypertension. Angiotensin converting enzyme (ACE) inhibitors have been shown to improve altered fibrinolytic balance in hypertensive patients. It has not been documented, however, whether this is due to a decrease in angiotensin II (Ang-II) generation or is a consequence of elevated local levels of bradykinin. Accordingly, the aim of this study was to determine the effects of an ACE inhibitor (perindopril) and an Ang-II receptor antagonist (losartan) on fibrinolytic kinetics. We have examined the serum levels of the plasminogen activator inhibitor type-1 (PAI-1) antigen and activity, tissue plasminogen activator (t-PA) antigen and activity, soluble thrombomodulin (sTM), and tissue factor pathway inhibitor (TFPI) before and after reaching the target blood pressure (<140/90 mm Hg) in 13 hypertensive patients receiving perindopril (mean age 40+/-11 years, 6 women, 7 men) and in 12 patients receiving losartan (mean age 38+/-9 years, 6 women, 6 men). We also compared the baseline fibrinolytic activity of hypertensive patients with that of 12 normotensive control persons (mean age 40+/-9 years, 6 women, 6 men). The mean basal plasma levels of PAI-1 antigen, PAI-1 activity, and sTM were significantly higher in the hypertensive patients than in normal controls (P<.005). The values of other analytes were similar in both groups. Increased plasma levels of PAI-1 antigen, PAI-1 activity, and sTM were reduced in patients after they were given perindopril and losartan (P<.005); the reductions in losartan-receiving group were more pronounced (P<.05). There were no significant effects on the plasma levels of t-PA antigen, t-PA activity, and TFPI in patients receiving the two therapeutic regimens (P>.05). In conclusion, chronic hypertension is associated with hypofibrinolysis. The beneficial effect of ACE inhibitors on fibrinolysis seems to be related to the blockade of Ang-II, and increased kinin activity does not appear to play a major role.
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PMID:Effects of angiotensin converting enzyme and angiotensin II receptor inhibition on impaired fibrinolysis in systemic hypertension. 1060 82

Most in vitro studies of human endothelial cells have relied on cells derived from human umbilical veins (HUVEC); however, heterogeneity of primary cultured endothelial cells can make critical interpretation of results difficult. Several endothelial cell lines have been produced to serve as a more constant source of endothelial cells. In this study, we characterized the endothelial cell lines EVLB3 and EVLC2 derived from HUVEC, and EVLK1 and EVLK2 derived from human iliac vein endothelial cells (HIVEC). These cell lines maintained the typical endothelial cell cobblestone morphology and appeared to be growth factor independent. They lost PECAM-1 and von Willebrand factor, GP96 was reduced to the level of vascular smooth muscle cells (SMC), but aSMC-actin was far less than in vascular SMC. Antigen levels of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) were comparable with young endothelial cells, and mRNA was present for tPA, PAI-1, tissue factor (TF), tissue factor pathway inhibitor and thrombomodulin. This study revealed that mRNA and protein expression of coagulation and fibrinolytic factors was influenced by the stage of cell confluence. No differences could be detected between the endothelial cell lines derived from HUVEC and HIVEC. These cell lines may be a useful tool for studies on cellular interactions of fibrinolytic components or exploring the regulation of TF expression.
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PMID:Characterization of immortalized human umbilical and iliac vein endothelial cell lines after transfection with SV40 large T-antigen. 1069 Oct 96

The present study was performed to analyze the relationship between portal hypertension and alterations of the endothelium-derived proteins thrombomodulin, plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1), which were determined in plasma samples of 28 alcoholic cirrhotic patients and 46 controls. Although cirrhotics showed lower levels of PAI-1, but higher thrombomodulin and t-PA levels than controls, no relationship was observed between thrombomodulin, t-PA or PAI-1 and portal pressure. Therefore, the hypothesis that splachnic endothelial damage secondary to portal hypertension leads to altered thrombomodulin, t-PA and PAI-1 levels in alcoholic cirrhosis is not supported by the results of this study.
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PMID:Lack of relationship between plasma thrombomodulin and portal hypertension in alcoholic liver disease. 1071

The endothelium is pivotal in the control of haemostasis and thrombosis because it is the primary source of many of the major haemostatic regulatory molecules. Healthy endothelial cells, unlike extravascular cells, are anticoagulant and antithrombotic. This is due to the regulated secretion of antiplatelet agents, including prostacyclin and nitric oxide. Following vessel injury, platelet adhesion to exposed matrix requires von Willebrand Factor, another endothelial cell product. Local generation of thrombin causes a series of receptor-mediated endothelial cell functional responses, while the surface of the endothelium is additionally the site for inactivation of thrombin by antithrombin, and its conversion to a coagulation inhibitor by interaction with thrombomodulin. Endothelial cells are also the source of circulating tissue-type plasminogen activator and its inhibitor, and Tissue Factor pathway inhibitor. In disease states, many of these endothelial cell properties are perturbed towards a more procoagulant and prothrombotic phenotype.
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PMID:Endothelial cell function and thrombosis. 1085 73

Several third-generation thrombolytic agents have been developed. They are either conjugates of plasminogen activators with monoclonal antibodies against fibrin, platelets, or thrombomodulin; mutants, variants, and hybrids of alteplase and prourokinase (amediplase); or new molecules of animal (vampire bat) or bacterial (Staphylococcus aureus) origin. These variations may lengthen the drug's half-life, increase resistance to plasma protease inhibitors, or cause more selective binding to fibrin. Compared with the second-generation agent (alteplase), third-generation thrombolytic agents such as monteplase, tenecteplase, reteplase, lanoteplase, pamiteplase, and staphylokinase result in a greater angiographic patency rate in patients with acute myocardial infarction, although, thus far, mortality rates have been similar for those few drugs that have been studied in large-scale trials. Bleeding risk, however, may be greater.
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PMID:Third-generation thrombolytic drugs. 1093 78


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