Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoclonal antibodies directed against recombinant apolipoprotein (a) (r-apo(a)) lacking plasminogen-like KIV-2 repeats were used to identify structurally related conformational epitopes in various members of the plasminogen-prothrombin gene family. A number of procedures including a fibrin-binding inhibition immunoassay and surface plasmon resonance studies were used. Two antibodies (A10.1 and A10.4) recognised common conformational structures in r-apo(a), prothrombin, factor XII, plasminogen and its tissue-type and urokinase-type activators. In contrast, two other antibodies recognised specifically an epitope comprising residues of the lysine-binding site (A10.2) or close to it (A10.5) and inhibited the fibrin-binding function of r-apo(a) (IC(50)=36 pmol/l and 9.76 nmol/l, respectively). Interestingly, these antibodies distinctly recognised the elastase-derived fragments of plasminogen K4 (A10.2) and K1+2+3 (A10.5) without affecting plasminogen binding to fibrin. These results suggest that highly conserved conformational regions are common to various proteins of the plasminogen-prothrombin gene family and are in agreement with the concept that these proteins constitute a monophyletic group derived from an ancestral gene.
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PMID:Kringles of the plasminogen--prothrombin gene family share conformational epitopes with recombinant apolipoprotein (a): specificity of the fibrin-binding site. 1145 40

Pigs are often used as animal models in research on blood coagulation and fibrinolysis. The usefulness of the assays applied within this field, and the knowledge of reference intervals are therefore essential and of utmost importance. In the study reported here, we investigated the applicability of commercial human coagulation and fibrinolysis assays for use with porcine plasma. In total, 22 functional and immunologic assays were applied to plasma obtained from domestic pigs, and the following blood coagulation and fibrinolysis variables were measured: prothrombin time, activated partial thromboplastin time, tissue factor, tissue factor pathway inhibitor, factor VII, protein C, protein S, prothrombin fragment 1+2, antithrombin, thrombin-antithrombin complexes, fibrinogen, soluble fibrin, urokinase-type plasminogen activator, plasmin inhibitor, plasminogen activator inhibitor 1, and D-dimer. We found that 11 of 12 functional assays, but only 3 of 10 immunoassays, were applicable to porcine plasma, and we determined the normal range of these variables. We conclude that human functional assays are useful in porcine plasma, whereas only a few immunologic assays can be used. However, precautions must be taken in interpretation of the results and in extrapolation toward human results because possible differences between porcine and human values can be due to species variations and/or methodologic errors.
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PMID:Usefulness of human coagulation and fibrinolysis assays in domestic pigs. 1190 Apr 11

A 24-year-old Japanese man was admitted because of massive haematemesis and melaena with persistent abdominal pain. Markedly bloody ascites and severely oedematous small intestine were recognized, and angiography then revealed superior mesenteric vein thrombosis. After resection of the necrotic small intestine, continuous intravenous infusion of heparin and urokinase was performed. This patient had no familial or personal history of thrombosis. On the 15th day after operation, an initial search for lupus anticoagulant revealed that the prothrombin time (PT) ratio and dilute activated partial thromboplastin time (aPTT) were positive under heparin treatment, without evidence of rheumatic or connective tissue disease. Thrombocytopenia was observed with a nearly normocellular bone marrow. A follow-up examination 1 year later still revealed an increased aPTT. However, all tests for antiphospholipid antibodies had been negative including dilute aPTT for about 2 years since the 15th day after operation. These findings suggest that, in this patient, superior mesenteric vein thrombosis has not been associated with primary antiphospholipid syndrome but is probably idiopathic. Positive tests for lupus anticoagulant in the initial period may be unreliable due to heparin treatment.
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PMID:Superior mesenteric vein thrombosis presented transient false positivity for lupus anticoagulant under heparin treatment. 1198 2

DPC423, 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, is a synthetic, orally bioavailable, competitive, and selective inhibitor of human coagulation factor Xa (K(i) [nM]: factor Xa, 0.15; trypsin, 60; thrombin, 6000; plasma kallikrein, 61; activated protein C, 1800; factor IXa, 2200; factor VIIa, >15,000; chymotrypsin, >17,000; urokinase, >19,000; plasmin, >35,000; tissue plasminogen activator, >45,000; complement factor I, 44,000 [IC(50)]). In vitro, DPC423 produced anticoagulant effects in human plasma in which it doubled prothrombin time, activated partial thromboplastin time, and Heptest clotting time at 3.1 +/- 0.4, 3.1 +/- 0.4, and 1.1 +/- 0.5 microM, respectively. In dogs, DPC423 had a good pharmacokinetic profile with an oral bioavailability of 57%, a plasma clearance of 0.24 L/kg/h, and a plasma half-life of 7.5 h. In rabbit and rat models of arteriovenous shunt thrombosis, DPC423 was an effective antithrombotic agent with an IC(50) of 150 and 470 nM, respectively. The antithrombotic effect of DPC423 is likely to be related to the inhibition of factor Xa but not to the inhibition of thrombin or due to direct inhibition of platelet aggregation. Therefore, based on potency, selectivity, efficacy, and oral bioavailability, DPC423 was selected for clinical development as an oral anticoagulant for the potential treatment of thrombotic disorders. Preliminary human data suggest that DPC423 is orally bioavailable in humans and has a long plasma half-life.
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PMID:Nonpeptide factor Xa inhibitors: DPC423, a highly potent and orally bioavailable pyrazole antithrombotic agent. 1217 91

Current trends in cardiac surgery have challenged perfusionists to seek diversification of services. Point-of-care coagulation (POCC) monitoring represents a desirable area of perfusion service expansion. The purpose of the study was to create a series of hemostatic conditions to assess the functionality of POCC monitors to identify specific coagulopathies with identifiable profiles for algorithm development. Fresh (< 4 h) bovine blood, anticoagulated with anticoagulant citrate dextrose, was adjusted to a hematocrit of 30.0 +/- 2.0%. Hypofibrinogenemia < or = 90 mg/dL), thrombocytopenia (< or = 70,000/mm3), platelet dysfunction (850 microg/mL of nitroglycerin/mL of blood) and hyperfibrinolysis (0.40 units of urokinase/mL of blood) were created. Five POCC devices were used to evaluate activated clotting time, thrombin time, fibrinogen, platelet function, prothrombin time, activated partial thromboplastin time and thromboelastograph. Results are reported as percentage change from control for each test (abtract table). [table: see text] Each test performed showed specificity and sensitivity for certain coagulopathies, however variability amongst monitors was encountered. In conclusion, the development of a mobile cart incorporating POCC monitors with knowledge of specific coagulopathic conditions may expand perfusion service.
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PMID:Expanding perfusion services through mobile point-of-care coagulation monitoring. 1239 65

In the search for new ligands for the plasminogen kringle 4 binding-protein tetranectin, it has been found by ligand blot analysis and ELISA that tetranectin specifically bound to the plasminogen-like hepatocyte growth factor and tissue-type plasminogen activator. The dissociation constants of these complexes were found to be within the same order of magnitude as the one for the plasminogen-tetranectin complex. The study also revealed that tetranectin did not interact with the kindred proteins: macrophage-stimulating protein, urokinase-type plasminogen activator and prothrombin. In order to examine the function of tetranectin, a kinetic analysis of the tPA-catalysed plasminogen activation was performed. The kinetic parameters of the tetranectin-stimulated enhancement of tPA were comparable to fibrinogen fragments, which are so far the best inducer of tPA-catalysed plasminogen activation. The enhanced activation was suggested to be caused by tetranectin's ability to bind and accumulate tPA in an active conformation.
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PMID:Tetranectin binds hepatocyte growth factor and tissue-type plasminogen activator. 1269 98

During normal pregnancy the hemostatic balance changes in the direction of hypercoagulability, thus decreasing bleeding complications in connection with delivery. The most important initial factor for acute hemostasis at delivery is, however, uterine muscle contractions, which interrupt blood flow. Global tests such as Sonoclot signature, the Thromboelastogram, and a new method analyzing overall plasma hemostasis, all show changes representative of hypercoagulability during pregnancy. Increased endogenous thrombin generation, acquired activated protein C resistance, slightly decreased activated partial thromboplastin time (aPTT) and increased prothrombin complex level (PT) measured as international normalized ratio (INR) of less than 0.9 have been reported as well. In normal pregnancy, the platelet count is within normal range except during the third trimester when benign gestational thrombocytopenia, 80 to 150 x 10 9/L, can be observed. Platelet turnover is usually normal. Activation of platelets and release of beta-thromboglobulin and platelet factor 4 are reported. The bleeding time is unchanged during normal pregnancy. Most blood coagulation factors and fibrinogen increase during pregnancy. Factor (F) XI is the only blood coagulation factor that decreases. Blood coagulation inhibitors are mainly unchanged but the level of free protein S decreases markedly and the level of tissue factor pathway inhibitor increases. Thrombomodulin levels increase during pregnancy. Fibrinolytic capacity is diminished during pregnancy, mainly because of markedly increased levels of plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and plasminogen activator inhibitor-2 (PAI-2) from the placenta. Thrombin-activated fibrinolysis inhibitor is reported to be unaffected. The total hemostatic balance has been studied by analyses of prothrombin fragment 1+2, thrombin-antithrombin complex, fibrinopeptide A, soluble fibrin, D-dimer, and plasmin-antiplasmin complex. There is activation of blood coagulation and a simultaneous increase in fibrinolysis without signs of organ dysfunction during normal pregnancy. These changes increase as pregnancy progresses. During delivery, there is consumption of platelets and blood coagulation factors, including fibrinogen. Fibrinolysis improves and increases fast following childbirth and expulsion of the placenta, resulting in increased D-dimer levels. These changes are self-limiting at normal delivery. The hemostatic changes, noted during pregnancy, normalize after delivery within 4 to 6 weeks. Platelet count and free protein S, however, can be abnormal longer. Hemostasis should not be tested earlier than 3 months following delivery and after terminating lactation to rule out influences of pregnancy. PAI-1 and PAI-2 levels decrease fast postpartum, but PAI 2 has been detected up to 8 weeks postpartum. alpha 2 -antiplasmin, urokinase, and kallikrein inhibitor levels have been reported to be increased 6 weeks postpartum.
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PMID:Hemostasis during normal pregnancy and puerperium. 1270 15

Acute myocardial infarction is a very rare event during pregnancy and bears the problem of misdiagnosis. However, about 150 cases have been published worldwide with a preponderance of anterior wall infarcts. With more women delaying childbearing until an older age and increasing prevalence of smoking in young women, it can be expected that all forms of coronary artery disease--including acute myocardial infarction--will be seen more often in the future. Among the causes of coronary artery occlusion in pregnancy are (1) rupture of very small coronary artery plaques triggered by different events, e.g., hypertension; (2) plain coronary artery disease; (3) dissection of coronary arteries; (4) coronary artery spasms with/without arterial thrombosis. Prompt diagnosis and immediate therapy are necessary to lower the high mortality of mother and fetus. The gold standard in the therapy of acute myocardial infarction during pregnancy is immediate coronary angiography and percutaneous transluminal coronary angioplasty (PTCA) with or without stent implantation. Application of thrombolytics (recombinant tissue plasminogen activator [rt-PA], r-PA, streptokinase [SK], urokinase [UK]) has been reported in single patients but should be limited to cases where acute PTCA is not available and where the infarct occurs before the 14th week of pregnancy because of possible embryopathy. If the patient is in the last 10 weeks of pregnancy, anticipation of delivery should be part of the medical planning. Consultation with an obstetrician must be obtained as soon as the patient enters the hospital. Besides bleeding complications, venous thrombosis with pulmonary embolism is among the most common causes of death during pregnancy. Pregnancy-related changes in physiology - increase in the resistance to flow from the lower extremities to the heart - and congenital coagulation abnormalities are most important to be recognized. This leads to the fact that superficial and deep venous thromboses occur more often in pregnancy than in the nonpregnant state. Among the coagulation abnormalities found in pregnancy are hypercoagulability (increased levels of fibrinogen, factor VII, factor VIII, factor X), decreased fibrinolytic activity due to an increased level of plasminogen activator inhibitor, increased adhesion and aggregation of platelets, decreased level of protein C and of the APC (activated protein C) ratio. Individual risks factors justifying diagnostic screening include contraception, smoking, immobilization, infection, adiposity, placental insufficiency, and a family history of thrombosis. It is even more important to establish/rule out the diagnosis of thrombosis in pregnancy than in the nonpregnant state, because the use of anticoagulants carries certain risks during pregnancy. Doppler vein studies should be used for diagnosis. If necessary, venography may be used with shielding of the maternal abdomen. Therapy consists of subcutaneous application of heparin, compression, and early mobilization. Alternatively, especially for long-term management, treatment with low molecular weight heparins is feasible. Thrombolytic treatment is contraindicated in most cases due to the high risk of bleeding complications. However, the application of thrombolytics can be contemplated in single cases after careful consideration of the pros and cons. Most cases of pulmonary embolism should also be handled conservatively with heparin. Only in massive pulmonary embolism with severe hemodynamic compromise, thrombolytic treatment is indicated. To guide future therapy in the patients, it is necessary to establish the lifetime risk of recurrent events by determining: APC resistance, prothrombin mutation 20210 A, homocysteine, AT III, protein C and S, antiphospholipid antibodies, and anticardiolipin antibodies.
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PMID:[Myocardial infarction and thromboembolism during pregnancy]. 1275 75

PURPOSE: To discuss the current rationale for the use of specific and nonspecific therapies for thrombotic microangiopathy in thrombocytopenia-associated pediatric multiple organ failure syndromes. Methods: Pertinent PubMed and MEDLINE citations and proceedings of recent critical care meeting presentations were reviewed. RESULTS: Critical care clinicians have reported using antithrombin III concentrate, protein C concentrate, activated protein C, prostacyclin and its analogues, heparin, tissue factor pathway inhibitor concentrate, plasma infusion, plasma exchange, whole blood exchange, pentoxifylline, tissue plasminogen activator, urokinase, and streptokinase with perceived therapeutic benefits in patients with thrombocytopenia-associated multiple organ failure, including those with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, disseminated intravascular coagulation syndrome, and secondary thrombotic microangiopathy syndrome without prolonged prothrombin time/activated partial thromboplastin time. CONCLUSION: Assuming that underlying disease is remediable, a consensus has developed that thrombotic microangiopathy is a therapeutic target in children with thrombocytopenia-associated multiple organ failure syndromes. Studies are warranted to delineate efficacious use of specific and nonspecific therapies to prevent and reverse thrombotic microangiopathy in these patients.
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PMID:Microvascular thrombosis in pediatric multiple organ failure: Is it a therapeutic target? 1279 40

Thromboembolism frequently complicates gastric cancer. This study examined the solid phase interaction between gastric cancer and coagulation proteins in situ that may explain coagulation activation and that may contribute to tumor progression and angiogenesis in this tumor type. Immunohistochemical techniques were applied to tissues from 37 cases of adenocarcinoma of the stomach obtained at surgical resection. Fibrinogen was present throughout the tumor stroma. Fibrin and its D-dimer cross-link sites occurred at the host-tumor interface. Subunit "a" of factor (F) XIII and F VII, IX, X, and XII were observed on cancer cells. Prothrombin and prothrombin fragment F1+2 (F1+2) were demonstrated in the tumor stroma on cancer cells and on small blood vessels. Tissue factor (TF) was present on cancer cells and tumor-associated macrophages. Protein C was observed on cancer cells and small blood vessels, whereas protein S was present only in the vascular bed. There was no staining for tissue factor pathway inhibitor (TFPI). High-molecular-weight (HMW) urokinase plasminogen activator (u-PA) antigen was not detected, but weak and inconsistent staining for low-molecular-weight (LMW) u-PA was demonstrated on cancer cells. Weak staining for tissue plasminogen activator (t-PA) occurred on cancer cells and in the tumor stroma. In contrast, plasminogen activator inhibitor-1 (PAI-1) expression was strong in the tumor stroma, along with PAI-2 and PAI-3. The endothelium of small stromal blood vessels, particularly near the host-tumor interface, demonstrated von Willebrand factor antigen (vWF Ag). Vascular endothelial growth factor (VEGF) was present on cancer cells and stromal macrophages. These results demonstrate tumor cell-associated TF-dependent extravascular coagulation activation in situ in gastric cancer that does not appear to be counterbalanced by TFPI or sufficient fibrinolytic activity. Colocalization of VEGF with hemostatic proteins suggests that they may cooperate in the pathogenesis of gastric cancer.
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PMID:Tissue factor-dependent coagulation activation and impaired fibrinolysis in situ in gastric cancer. 1288 33


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