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)

Plasminogen activator inhibitor-1 (PAI-1) is a member of the serpin superfamily of proteins and is the fast acting inhibitor of both urinary plasminogen activator and tissue-type plasminogen activator. We have assessed the functional significance of reactive center residues on the carboxy-terminal side of the cleavage site of recombinant human PAI-1. Using site-directed mutagenesis, the P1'-P5' residues (P1' is the first residue on the carboxy-terminal side of the protease cleavage site) of the wild-type PAI-1 reactive center sequence were replaced with the corresponding sequences of plasminogen activator inhibitor-2, antithrombin, alpha 2-antiplasmin and protease nexin I. Rate constants of inhibition of the serine proteases urinary plasminogen activator, tissue-type plasminogen activator, plasmin and thrombin by the variants were determined. The results suggest a crucial role for both reactive center length and sequence in the inhibition of plasminogen activators by PAI-1. Analysis of substitutions at positions P4' and P5' both confirms and extends our previous work demonstrating a favorable electrostatic interaction between these residues and tissue-type plasminogen activator. None of the variants show dramatic increases in the rate constants of inhibition of other serine proteases, suggesting that these residues alone are not sufficient to confer protease specificity on PAI-1. Apparently, the determinants of the rapid inhibitory specificity of PAI-1 are localized to the P1'-P5' region of the reactive center and these residues act synergistically to produce the exquisite specificity of PAI-1 for plasminogen activators.
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PMID:Sequence requirements in the reactive-center loop of plasminogen-activator inhibitor-1 for recognition of plasminogen activators. 862 Aug 72

The aim of the present study was to evaluate some metabolic, coagulation and fibrinolytic parameters in 35 patients (24 males and 11 females, mean age 57 +/- 4 years) suffering from myocardial infarction more than 6 months before with or without carotid atherosclerotic lesions. After evaluation by B-mode duplex scanning system of extracranial carotid arteries, the patients were subdivided into two groups: Group 1 (n = 16, with carotid plaques or intima-media thickening) and Group 2 (n = 19, without carotid plaques or intima-media thickening). Eighteen age- and sex-matched subjects were recruited as controls (Group 3). Groups 1 and 2 displayed significantly higher levels of total cholesterol and apolipoprotein B and significantly lower levels of HDL-cholesterol and apolipoprotein A1 than Group 3, while serum triglyceride and lipoprotein (a)-Lp (a) levels were significantly higher in Group 1 as compared to the control group. Moreover, Group 1 and 2 displayed significantly higher levels of factor VII, fibrinogen, F1+2, thrombin-antithrombin complex and plasminogen activator inhibitor (PAI) post venous occlusion and significantly lower levels of tissue plasminogen activator (t-PA) post venous occlusion than Group 3. Significantly higher levels of t-PA and PAI pre venous occlusion and significantly lower levels of antithrombin III, C-protein and S-protein were observed in Group 1 as compared to controls. In patients with highest Lp(a) level, the lowest t-PA level post venous occlusion and the highest PAI level post venous occlusion were observed. Our data show an activation of coagulation and a deficient fibrinolysis in survivors of myocardial infarction, particularly in those with associated carotid atherosclerotic lesions. We speculate that this thrombophilic state may play a key role in the pathogenesis of atherosclerotic vascular disease and thromboembolic complications.
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PMID:[Thrombophilic state inpatients suffering from myocardial infarction with or without carotid atherosclerotic lesions]. 870 61

We studied exercise-induced changes in coagulation and fibrinolytic factors and activation products in different age categories. Thirty-eight sedentary males, divided in three age categories (cats I-III; 20-30, 35-45 and 50-60 y) were subjected to a standardized exercise test. Pre-exercise levels (cats I-III resp) of FVII:c (105 +/- 5, 121 +/- 6 and 123 +/- 7% NP), fibrinogen (2.35 +/- 0.12, 2.55 +/- 0.10 and 2.66 +/- 0.09 mg/ml), prothrombin activation fragment F1 + 2 (0.80 +/- 0.10, 0.80 +/- 0.11 and 1.22 +/- 0.16 nM), t-PA (5.2 +/- 0.6, 9.2 +/- 1.0, 8.6 +/- 1.2 ng/ml) and PAI-I (42.8 +/- 7.5, 67.6 +/- 7.6, 62.2 +/- 10.9 ng/ml) showed differences that seemed related to age. Regression analysis revealed associations with anthropometry (FVII:c, fibrinogen, F1+2, t-PA, PAI-1) rather than with age. Exercise-induced changes in coagulation (increase in von Willebrand factor and FVIII:c and a shortening of APTT) and fibrinolytic potential (increase in t-PA and u-PA) were of comparable magnitude for the three age categories. Hardly any change in F1 + 2 (6%) was observed, while thrombin-antithrombin complexes (93%), plasmin-antiplasmin complexes (79%) and D-dimer (77%) almost doubled during maximal exercise. We conclude that anthropometric differences play a more significant role than age on constitutive levels of haemostatic factors in participants up to 60 years of age. The magnitude of exercise-induced changes is comparable in the age categories under study, and simply super-imposed on constitutive (pre-exercise) levels. Clear evidence for prothrombin activation is lacking, but plasmin formation is enhanced during exercise.
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PMID:Changes in haemostatic factors and activation products after exercise in healthy subjects with different ages. 877 20

Hip arthroplasty is associated with a high frequency of postoperative solitary proximal deep vein thrombosis which seems most frequently observed when bone cement is used for prosthesis fixation. Eighteen pigs underwent hemiarthroplasty, eight with cement-fixed prostheses and eight with non-cement prosthesis installation. Levels of thrombin-antithrombin (TAT) complexes, tissue plasminogen activator (t-PA) activity and plasminogen activator inhibitor 1 (PAI-1) activity were determined in femoral vein blood from both limbs during and after surgery. On the operated side, TAT increased during bone traumatization followed by a substantial rise in t-PA activity and a gradual decline in PAI-1 activity. This indicates a local per- and post-operative sequential activation of coagulation and fibrinolysis followed by a fibrinolytic shutdown, all reflected in femoral vein blood on the operated side. In the animals receiving noncemented hip prostheses, the same pattern of activation of coagulation and fibrinolysis occurred on the operated side. This was, however, less marked than with the cement-fixed prostheses. Postoperative scanning electron microscopic (SEM) examination of the femoral veins showed thrombi on the operated side in 62% of the animals in the cement group and 25% in the non-cement group. In an additional study with eight animals undergoing cement-anchored hip prosthesis operations the levels of TAT, t-PA and PAI-I were analysed in femoral vein blood, mixed venous blood and arterial blood. Significantly higher levels were found in femoral vein blood compared with mixed venous blood while no significant change was found in arterial blood compared with mixed venous blood. The hyperthermia induced by curing bone cement was effectively conducted by the implanted prosthesis and did not seem to exert major influence on the activation of coagulation. Extreme rotation of the limbs during surgery did not in itself induce visible vein wall damage as judged by SEM. These studies indicate that traumatization of bone marrow during hip surgery induce a marked local activation of coagulation and a high incidence of deep vein thrombosis in proximal veins, in particular if bone cement is used for prosthesis fixation.
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PMID:The role of bone traumatization in the initiation of proximal deep vein thrombosis during cemented hip replacement surgery in pigs. 882 20

Cancer is often associated with abnormal activation of coagulation leading to a prothrombotic state. Some chemotherapeutic agents used for cancer may induce thrombosis but their biological alterations in the hemostatic system are not yet well understood. This study evaluated alterations of coagulative and fibrinolytic parameters following chemotherapy. In plasma samples of 38 patients (median age: 49 years) receiving CMF (schedule 1-21 or 1-8) for Stage II breast cancer, we evaluated: PT, aPTT, antithrombin III (AT-III), protein C (PC), protein S (PS), thrombin-antithrombin complex (TAT), prothrombin fragment F 1 + 2 (F 1 + 2), fibrinogen (Fbg), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1) and D-dimer (D-D). PT, aPTT, and Fbg were determined with routine methods; AT-III, PC, and PS were measured with coagulative tests; PC and PS were also evaluated with immunoenzymatic methods, t-PA, PAI-1, D-D, TAT, and F 1 + 2 were measured with immunoenzymatic methods. All tests were performed immediately before starting therapy and after each cycle. A PC antigen decrease appeared soon after beginning therapy and lasted throughout chemotherapy. The lowest values were present after the first treatment both in the CMF 1-21 group (mean +/- SD = 72.5 +/- 10.8%) and in the CMF 1-8 group (mean +/- SD = 77.2 +/- 6.9%): PC activity was also decreased. PS antigen decreased after the first administration (mean +/- SD = 73.3 +/- 10% in CMF 1-21 group, and 72.5 +/- 4.9% in CMF 1-8 group): PS activity also decreased. PAI-1 antigen levels increased (mean +/- SD = 43.1 +/- 20.4 ng/ml in the CMF 1-21 group, and 37.5 +/- 12.2 ng/ml in CMF 1-8 group) lasting up to the last cycle. CMF provokes a trend toward hypercoagulability; this effect should be considered when chemotherapy is employed in advanced cancer patients at high risk for thrombosis, or in patients with other risk factors.
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PMID:A prothrombotic state in breast cancer patients treated with adjuvant chemotherapy. 887 81

The syndrome of growth hormone deficiency (GHD) in adults is associated with premature atherosclerosis, increased cardiovascular mortality, abnormal lipoprotein patterns and abnormal body composition. We have previously shown that GH-deficient adults have increased concentrations of fibrinogen and plasminogen activator inhibitor (PAI-1) activity. The aim of the present investigation was to study coagulation and fibrinolysis in 17 patients with adult-onset GHD during two years of treatment with recombinant human GH (12 micrograms/kg body weight/day). The impact of the contemporary changes in metabolic variables and body composition on coagulation and fibrinolysis was studied. The patients received conventional thyroid, adrenal and gonadal hormone replacement therapy. PAI-1 activity, PAI-1 antigen and tissue plasminogen activator (t-PA) antigen levels decreased during the GH treatment period (p < 0.05). The decrease was more pronounced in patients with high pre-treatment levels of the different variables. alpha 2-antiplasmin decreased (p < 0.05), while plasminogen was unchanged during two years of GH treatment. Fibrinogen concentrations tended to decrease after two years of GH treatment (p = 0.06), while the coagulation factors VII and VIII were unchanged. von Willebrand factor demonstrated a transient decrease after 18 months of GH treatment. The coagulation inhibitor, protein C, decreased (p < 0.05), while antithrombin was unchanged. Fasting plasma insulin increased (p < 0.01), but blood glucose did not differ after two years of GH treatment. Serum high-density lipoprotein cholesterol, total cholesterol and triglycerides were unaltered. Body fat decreased during the initial GH treatment but was unaltered after two years, while lean body mass increased (p < 0.001) and the waist over hip circumference ratio tended to decrease (p = 0.06). In conclusion, PAI-1 activity, PAI-1 antigen and t-PA antigen decreased during long-term GH treatment. These changes may be a direct effect of GH itself or may be secondary to the favourable changes in body composition. It remains to be seen whether changes in these fibrinolytic variables during rhGH treatment reduces the cardiovascular risk in patients with GHD. The present results suggest that GH plays a role in the regulation of fibrinolysis.
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PMID:Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults. 888 81

The efficacy of the local delivery of an antithrombotic drug in preventing thrombosis and enabling thrombolysis was investigated in 29 dogs. An antithrombotic drug (heparin, 25 U/kg), or an antithrombin (argatroban, 0.05 mg/kg) was infused into injured canine iliac arteries, using a double-occlusion balloon catheter, and the preventive effect of the drug was evaluated. Local delivery of low-dose tissue-type plasminogen activator (t-PA; Tisokinase, 50,000 U; Kowa, Nagoya and Asahi Chemical Industries, Fuji, Japan) into thrombosed canine iliac arteries, using the same catheter, or intravenous infusion of low-dose or high-dose t-PA (30,000 U/kg) was also performed. Angiographically, stenotic thrombosis was 2% by local delivery of argatroban and 7% by local delivery of heparin (P < 0.01 vs each control; 47% and 51% respectively). Thrombotic stenosis, as observed by angiography, decreased from 91% to 9% after local delivery of t-PA, and from 94% to 52% in controls. Local delivery of t-PA effectively reduced the thrombus size (P < 0.01 vs control). After systemic intravenous delivery of low-dose t-PA, no reduction of residual thrombotic stenosis, was observed. Reduction of residual thrombotic stenosis after intravenous delivery of high-dose t-PA, was similar to that achieved by local delivery of the drug. Angioscopy demonstrated a similar trend. High-dose drug delivery reduced systemic coagulability. Local delivery of an antithrombotic drug, using a double-occlusion balloon catheter, effectively prevented thrombus formation, and local delivery of t-PA induced thrombolysis without exerting a significant influence on coagulability.
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PMID:Induction of thrombolysis and prevention of thrombus formation by local drug delivery with a double-occlusion balloon catheter. 889 61

A 10-month-old boy with major left atrial thrombus following cardiac surgery was treated with intravenously administered recombinant tissue-type plasminogen activator (rt-PA; Actilyse, Thomae-Behring, Germany). The left atrial thrombus was diagnosed by Doppler echocardiography 8 days after complete correction of a ventricular septal defect. rt-PA therapy was administered over a 10-day period. Significant hemopericardium occurred 50 h after the start of thrombolytic therapy. rt-PA infusion was discontinued for 20 h to insert a pericardial drainage. The initial rt-PA dose was 0.1 mg/kg over 10 min followed by a continuous daily infusion of 1.7 mg/kg together with low-dose heparin. Thrombolytic therapy was restarted 20 h after pericardial drainage was inserted. The daily rt-PA dose was gradually raised to 3 mg/kg (total dose: 18 mg/kg). On day 7 and 8 a clear decrease in P-plasminogen and P-antithrombin occurred, requiring additional fresh frozen plasma and P-antithrombin concentrate substitution. One day later, without further side effects, complete thrombolysis occurred. Although hemopericardium demanded discontinuation of thrombolytic therapy, rt-PA administration, closely monitored by Doppler echocardiography, was continued, leading to complete thrombolysis of the left atrial thrombus in the early postoperative period. We consider the literature dealing with rt-PA thrombolysis in infancy we discuss this case report.
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PMID:Left atrial thrombus in a 10-month-old boy--successful thrombolysis with recombinant tissue-type plasminogen activator after open-heart surgery: review of the literature. 890 35

We studied the influence of age on mortality and severity of clotting abnormalities in 79 children (median age: 3.1 years) with meningococcal sepsis. Parameters of coagulation and fibrinolysis and plasma levels of cytokines were prospectively measured on admission. The mortality rate was 27%. The age of survivors was significantly different from that of non-survivors (p = 0.013). With the exception of FVII, vWF and t-PA, parameters of coagulation and fibrinolysis, as well as plasma cytokine levels were related to outcome. Patients were divided in two groups: younger and older than median age. The mortality in children < or = 3.1 years was 40% versus 13% in children > 3.1 years (p = 0.006). In contrast to cytokine levels, which were not different between the two age groups, fibrinogen, prothrombin, factors V, VII, VIII, vWF, protein C, antithrombin, FDP, and the ratio PA1-1/t-PA were related to age, indicating a more severe coagulopathy in children < or = 3.1 years despite a similar degree of inflammatory response. A relative deficiency of coagulation factors due to an immature state of the clotting system, as well as an inadequate fibrinolytic response, both related to age may have caused this more severe coagulative response in younger children, and may have contributed to the higher mortality rate.
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PMID:Age-related differences in outcome and severity of DIC in children with septic shock and purpura. 897 13

15-Hydroperoxyeicosatetraenoic acid (15-HPETE), an arachidonate lipoxygenase product, is reported to induce severe endothelial injury. In this study, we examined the effect of 15-HPETE on the release of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) from cultured human umbilical vein endothelial cells (HUVEC). The addition of 15-HPETE to the serum-free medium reduced the release of t-PA antigen from HUVEC, while the release of PAI-1 antigen was significantly enhanced. However, treatment of the cultured HUVEC with alpha-tocopherol or nordihydroguaiaretic acid completely suppressed the 15-HPETE-induced change in t-PA and PAI-1 antigen release. 15-Hydroxyeicosatetraenoic acid (15-HETE) had no effect on the release of either antigen from cultured HUVEC. The HUVEC surfaces exposed to 15-HPETE decreased the potency for binding antithrombin III. In a reconstituted system with heparin and phosphatidylcholine, 15-HPETE decreased the ability of heparin to inactivate thrombin activity. These results suggest that the fibrinolytic factor release and the antithrombin binding of vascular endothelial cells are impaired by the attack of 15-HPETE, and that the presence of antioxidants prevents the injurious action of lipid hydroperoxide.
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PMID:Effect of 15-hydroperoxyeicosatetraenoic acid on the fibrinolytic factor release and the antithrombin binding of vascular endothelial cells. 901 99


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