Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial dysfunction is defined as the loss of endothelium properties, e.g. alteration of protein synthesis, increased vascular tone and permeability, acquisition of prothrombotic and antifibrinolytic properties. Endothelium, a primary target of unbalanced glycaemic control, is involved in the pathogenesis of vascular complications in patients with type 1 diabetes mellitus (DM). Vascular endothelium damage is characterised by an increase of endothelium-derived regulatory proteins. vWF and t-PA may be useful to investigate early endothelium involvement. However, impaired endothelium-dependent vasodilatation may be a more sensitive marker. Abnormal markers of endothelial cell activation and impaired endothelium-dependent vasodilatation have been observed in young patients with type I DM. Hyperglycaemia may alter normal endothelium functions, either directly or indirectly, by inducing different metabolic pathways. Complete understanding of the pathophysiology of endothelial dysfunction may lead to timely therapeutic intervention to prevent its development and to slow the progression of diabetic complications.
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PMID:Endothelial dysfunction in children with type 1 diabetes mellitus. 1200 80

Sudden physical exertion is associated with an increased risk of acute myocardial infarction (MI) and sudden cardiac death. In addition, activation of the coagulation cascade and/or reduced fibrinolytic capacity after physical exercise has been reported in patients with cardiovascular disease. We investigated the haemostatic responses to an acute submaximal physical exercise in middle-aged women with a history of MI compared with healthy, age-matched controls. Resting plasma von Willebrand factor antigen (vWF Ag) and tissue plasminogen activator (tPA) antigen concentrations and plasminogen activator inhibitor-1 (PAI-1) activity were higher in the patients compared with control subjects. After 30 min of submaximal exercise on a bicycle ergometer, small, but still significant, increases in fibrinogen and vWF Ag concentrations were found in both groups. However, exercise did not induce thrombin generation and fibrin formation, as assessed by thrombin-antithrombin complex and fibrin D-dimer, in either group. Both tPA antigen concentration and activity increased and PAI-1 activity decreased significantly with exercise in both groups. Interestingly, the magnitude of changes in these latter variables did not differ between the groups (P=.99, P=.88 and P=.24, respectively). The present study demonstrates that some middle-aged women with previous MI have no signs of coagulation activation and retained fibrinolytic response after submaximal exercise. The clinical implication of these results might be that women with stable coronary heart disease can participate in rehabilitative exercise training without exhibiting a procoagulative state.
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PMID:Retained fibrinolytic response and no coagulation activation after acute physical exercise in middle-aged women with previous myocardial infarction. 1209 Oct 46

Altered endothelial anti-thrombotic properties have been observed in primary and secondary pulmonary hypertension. In the Eisenmenger syndrome, correlations of these abnormalities with the clinical status and occurrence of chronic intravascular coagulation (CIC) have not been confirmed. The purpose of this study was to investigate whether the occurrence of CIC, as determined by circulating levels of D-dimer is associated with changes in endothelial markers in Eisenmenger patients; and to identify variables that correlate with the severity of clinical presentation. Twenty-one patients were enrolled (ages, 4-52 years). Plasma levels of D-dimer, tissue plasminogen activator (t-PA), thrombomodulin, and von Willebrand factor antigen (vWF:Ag) were measured with enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to differentiate patients with stable (group 1, N=12) from those with unstable disease (group 2, N=9). Increased t-PA (p<0.0001) and vWF:Ag (p=0.001) and decreased thrombomodulin (p<0.0001) were associated with increased D-dimer levels (p=0.0201) in patients. Group 2 had a higher prevalence of affected women (p=0.0242), lower arterial oxygen saturation, and higher t-PA levels compared with group 1 (p<0.0001, discriminant analysis). t-PA and vWF:Ag correlated positively in group 2 (r=0.71, p=0.0309), but not in group 1 (r=0.25, p=NS). Two patients in group 2 but none in group 1 had episodes of pulmonary arterial thrombosis. Endothelial dysfunction is associated with evidence of CIC and correlates to some extent with the severity of symptoms in these patients.
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PMID:Endothelial dysfunction associated with chronic intravascular coagulation in secondary pulmonary hypertension. 1251 85

The influence of hypothyroidism on haemostasis is controversial; both hypocoagulable and hypercoagulable states have been reported. Hypothyroidism has been associated with atherosclerosis; a hypercoagulable state in addition might represent a risk factor for thromboembolic disease. The aim of the present study was to investigate the markers of endogenous coagulation and vascular endothelial cell function and to evaluate the relationship between serum lipid profile, thyroid hormones and haemostatic parameters in hypothyroid patients. We investigated various haemostatic parameters in 20 patients with hypothyroidism and compared them with 20 euthyroid controls. The relationship between serum thyroid hormones and the haemostatic parameters was examined. The plasma levels of fibrinogen, AT III and PAI-1 were significantly increased in hypothyroid patients compared with the control group, whereas factors VIII and X activity was decreased. We showed that free T3 levels correlated with factor IX activity. Free T4, FT3 and TSH did not correlate with fibrinogen, vWF, AT III, t-PA, or PAI-1. aPTT correlated inversely with t-PA activity and positively with protein C activity. Anti-Tg correlated inversely with FV. There was a positive correlation between triglycerides and protein C. Protein S correlated inversely with high density lipoprotein cholesterol. We found a hypofibrinolytic state in patients with hypothyroidism. Our results suggest that the risk of developing thrombosis and ultimately myocardial infarction via high PAI-1 levels may be increased in patients with hypothyroidism, a result in line with recent epidemiological data. However, thyroid hormones may play a role at different levels of the complex haemostatic system.
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PMID:Blood coagulation and fibrinolytic activity in hypothyroidism. 1266 86

Pulmonary arterial thrombosis (PAT) may complicate the clinical course of pulmonary hypertension associated with congenital heart disease (so-called Eisenmenger syndrome, ES). In this study, variables were sought that could represent risk factors for the occurrence of this complication. Twenty patients aged 11 to 53 (median, 33) years were studied. The presence of PAT (spiral computed tomography angiography) was correlated with age, gender group, PAP, hematocrit, peripheral oxygen saturation (SpO(2)), and plasma levels of endothelial and coagulation dysfunction markers: von Willebrand factor antigen (vWF:Ag), tissue plasminogen activator (t-PA), and D-dimer (enzyme immunoassay). Patients were classified according to the presence (group 1, N=7), or absence (group 2, N=13) of PAT. Group 1 patients were older (42+/-8 vs. 27+/-10 years in group 2, p=0.0051), had lower SpO(2) (82+/-7% vs. 89+/-6% in group 2, p=0.0462) and increased D-dimer levels (637 vs. 149 ng/mL in group 2, median values, p=0.0235). A trend was observed toward an increase in vWF:Ag (125+/-29 vs. 103+/-18 U/dL in group 2, p=0.0789) and t-PA (15.7 vs. 9.4 ng/mL in group 2, median values, p=0.0689). Age was the main variable influencing the occurrence of PAT in multivariate analysis (p=0.0026), with odds ratio of 1.204 per year. The age of 35 years was 86% sensitive and 85% specific for occurrence of PAT. Age correlated positively with t-PA (r=0.57, p=0.0111). Thus, PAT is highly prevalent in ES as an age-dependent event, probably associated with endothelial dysfunction. Prophylactic anticoagulation should be considered before the age of 30 years, in particular in subjects with low SpO(2) and increased D-dimer levels.
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PMID:Age-dependent likelihood of in situ thrombosis in secondary pulmonary hypertension. 1524 78

Systemic thromboembolism is a major complication of mitral stenosis (MS), especially in those patients having atrial fibrillation (AF). Recent evidence has suggested that regional left atrial coagulation activity may be increased in MS and may contribute to the pathophysiology of left atrial thrombus. However, the relation of left atrial coagulation activity to factors that predispose to left atrial thrombus formation is unknown. Also, the relations between left atrial and systemic coagulation activity, fibrinolysis, and platelet activation remain unresolved. Left atrial and peripheral venous levels of fibrinogen, antithrombin III, factor VII and factor VIII for coagulation, D-dimer, tPA and PAI-I, plasmin and antiplasmin for fibrinolysis, and platelet factor 4 and vWF for platelet activation, and endothelial dysfunction were measured in 46 patients with MS and normal clotting times who were undergoing percutaneous mitral valvuloplasty. Left atrial tPA, plasmin, PAI-I, antiplasmin, PF4, and vWF levels exceeded the corresponding peripheral venous levels (P < 0.05) in patients with MS, being more significant in the AF subgroup. There were no significant differences between left atrial and peripheral venous levels of fibrinogen, D-dimer, factor VII, and factor VIII within the patient group (P > 0.05). The results suggest that there are significant variations in the indices of coagulation, fibrinolytic system and platelet activation, and endothelial dysfunction between left atrial and peripheral venous blood samples of patients with MS that may be due to limited spillover from the left atrium to the systemic circulation.
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PMID:Regional left atrial coagulation and fibrinolytic activities in patients with mitral stenosis. 1555 19

The two-kringle domain of tissue-type plasminogen activator (t-PA) has previously been shown to contain anti-angiogenesis activity. In this study, we explored the potential in vivo anti-tumor effects of the recombinant kringle domain (TK1-2) of human t-PA. Anti-tumor effects of purified Pichia-driven TK1-2 were examined in nude mice models by subcutaneous implantation of human lung (A-549) and colon (DLD-1, HCT-116) cancer cell lines. Mice bearing the tumors were injected with PBS or purified TK1-2 (30 mg/kg) i.p. every day for 22 days. TK1-2 treatment suppressed the A-549, DLD-1, and HCT-116 tumor growth by 85.3%, 52.4%, and 62.5%, respectively. Immunohistological examination of the tumor tissues showed that TK1-2 treatment decreased the vessel density and also the expression of angiogenesis-related factors including angiogenin, VEGF, alpha-SMA, vWF, and TNF-alpha, and increased the apoptotic fraction of cells. TK1-2 neither inhibited in vitro growth of these cancer cells nor affected t-PA-mediated fibrin clot lysis. These results suggest that TK1-2 inhibits the tumor growth by suppression of angiogenesis without interfering with fibrinolysis.
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PMID:The kringle domain of tissue-type plasminogen activator inhibits in vivo tumor growth. 1565 16

Virchow rightly recognised that blood flow plays an important role in thrombosis. The roles of blood flow in haemostasis, and in arterial, intra-cardiac, and venous thrombosis are reviewed. In streamline (laminar) flow, shear stresses are maximal at the vessel wall, and affect endothelial cell morphology and function (e.g. secretion of NO, prostacyclin,t-PA and vWF). Platelets are also concentrated at the vessel wall (due to axial concentration of red cells)where they can be activated by high shear stresses and are well-placed to interact with vWF and subendothelium,resulting in platelet adhesion and the initial stages of haemostasis. On the other hand, increasing wall shear forces increase removal of thrombin and fibrin monomer, hence stasis (induced by internal or external pressure) is required to allow fibrin formation and secondary haemostasis. Atherogenesis occurs in areas of arterial flow separation,which promotes platelet, leucocyte, LDL and fibrinogen adhesion and wall infiltration. Rheological variables (e.g. wall shear stress, viscosity, haematocrit,fibrinogen, LDL) have been correlated with the extent of ultrasonic carotid intima-media thickening. Arterial thrombosis usually follows rupture of atherosclerotic plaques and intra-plaque haemorrhage: high intra-stenotic shear stresses may activate platelets,promoting the initial platelet-rich "white-head" of arterial thrombi, while low post-stenotic shear stresses may promote the subsequent, fibrin--and red cell-rich "red tail". Blood viscosity, platelet microemboli, and activated leucocytes may each reduce post-stenotic microcirculatory blood flow, promoting infarction. Such mechanisms may explain the associations of increased levels of blood and plasma viscosity, haematocrit, white cell count, fibrinogen and vWF with risk and outcome of myocardial, cerebral and limb infarction. Areas of recirculating blood flow under low shear stresses predispose to intracardiac thromboembolism(e.g. atrial fibrillation, in which elevated fibrin D-dimer levels are normalised after cardioversion) and venous thromboembolism (fibrin D-dimer levels are associated with most risk factors). There is good evidence that reduction of venous stasis in the legs reduces the risk of venous thromboembolism. There is increasing evidence that regular exercise and avoidance of immobility reduces the risk of both arterial and venous thrombosis and also has systemic antithrombotic and anti-inflammatory effects. So: "Go with the flow!"
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PMID:Virchow's triad revisited: abnormal flow. 1569 60

The aim of our study was to evaluate potential differences in the concentration of biochemical markers of endothelial dysfunction between essential hypertension, endocrine hypertension (pheochromocytoma, primary hyperaldosteronism) and control healthy group and to assess a potential relationship between these markers of endothelial dysfunction and vasopressor substances overproduced in endocrine hypertension. We have investigated 21 patients with moderate essential hypertension, 29 patients with primary hyperaldosteronism, 24 subjects with pheochromocytoma and 26 healthy volunteers. Following parameters of endothelial dysfunction were measured, von Willebrand factor (vWf), plasminogen activator (t-PA) and E-selectin (E-sel). Clinical blood pressure was measured according to the European Society of Hypertension recommendations. We found significantly higher levels of the von Willebrand factor in patients with essential hypertension in comparison with a control group (114+/-20 IU/dl vs 90+/-47 IU/dl; P=0.04) and patients with primary hyperaldosteronism (114+/-20 IU/dl vs 99+/-11 IU/dl; P=0.01). Patients with endocrine hypertension revealed increased levels of vWF compared to the control group, but these differences did not reach statistical significance. Levels of t-PA were increased in patients with pheochromocytoma in comparison with the control group (4.6+/-1.9 ng/ml vs 3.4+/-0.9 ng/ml; P=0.01) and with primary hyperaldosteronism (4.6+/-1.9 ng/ml vs 3.4+/-1.1 ng/ml; P<0.01). In case of E-selectin we found lower levels in patients with pheochromocytoma in comparison with other groups, but they differed significantly only with primary hyperaldosteronism (40.2+/-15.0 ng/ml vs 51.3+/-23.0 ng/ml; P=0.05). Our study did not reveal any convincing evidence of differences in the levels of biochemical markers of endothelial dysfunction between essential and endocrine hypertension. No correlation between the biochemical markers of endothelial dysfunction and vasopressor substances activated in endocrine hypertension was found.
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PMID:Biochemical markers of endothelial dysfunction in patients with endocrine and essential hypertension. 1649 5

The long-term behavior of endothelial markers was studied in patients with Eisenmenger syndrome who were subjected to conventional therapy (no vasodilators) and observed for 18 months. Biochemical markers were analyzed comparatively in patients with class II or III symptoms (group 1, n=10) and patients with class IV symptoms (group 2, n=7). Plasma von Willebrand factor antigen (vWF:Ag), thrombomodulin, tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1), and D-dimer were determined by immunoenzymatic assay at baseline, and at 6, 12, and 18 months. At baseline, the main clinical difference between groups was a decreased peripheral oxygen saturation in group 2 versus group 1 (77+/-5% and 86+/-4%, respectively, p=0.001). Basal vWF:Ag and t-PA were increased and thrombomodulin was decreased in both groups in comparison with controls (p<0.0001), while D-dimer was increased in group 2 only (p=0.0003). In response to treatment, there was a decrease in vWF:Ag in both groups (19% and 23%, respectively in groups 1 and 2, at 18 months vs. baseline, p<0.0001) and t-PA in group 1 (38% vs. baseline, p=0.0485). Plasma vWF:Ag tended to be higher in group 2 in comparison with group 1 during the whole follow-up. Levels of PAI-1 greater than 38.4 ng/mL (upper 90% limit for normals) and D-dimer greater than 500 ng/mL were detected in individual patients (both groups) during the follow-up period. Thrombomodulin remained decreased in both groups. Thus, severity of symptoms in the Eisenmenger syndrome appears to correlate with low oxygen saturation and higher vWF:Ag levels. Improvement of endothelial dysfunction may occur in response to treatment, although increased risk for thrombosis persists, in view of residual abnormalities.
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PMID:Long-term behavior of endothelial and coagulation markers in Eisenmenger syndrome. 1670 19


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