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)

Protease inhibitors regulate a variety of physiological and pathological processes including angiogenesis, embryo implantation, intravascular fibrinolysis, wound healing, and tumor invasion. Tissue factor pathway inhibitor (TFPI) 2 is a Mr 32,000 Kunitz-type serine protease inhibitor that inhibits plasmin, trypsin, chymotrypsin, cathepsin G, and plasma kallikrein but not urokinase-type plasminogen activator, tissue plasminogen activator, or thrombin. In this study, we determined the relative amounts of TFPI-2 in low-, intermediate-, and high-grade human glioma cell lines and tumor tissue samples. TFPI-2 protein and mRNA levels (measured by Western and Northern blotting) were highest in low-grade glioma cells (Hs683), lower in anaplastic astrocytoma cells (SW1088 and SW1783), and undetectable in high-grade glioma cells (SNB19). Analysis of TFPI-2 protein in human normal brain and in glioma tumor tissues for TFPI-2 revealed the highest levels in normal brain, lesser amounts in low-grade gliomas and anaplastic astrocytomas, and undetectable amounts in glioblastomas. In situ hybridization of TFPI-2 mRNA with normal brain tissues revealed the greatest positivity in neurons, with moderate positivity in both glial and endothelial cells and moderate, little, or no TFPI-2 mRNA in low-grade glioma, anaplastic astrocytoma, and glioblastoma tumor tissue samples, respectively. We also found that recombinant TFPI-2 inhibited the invasiveness of SNB19 glioblastoma cells in a Matrigel assay in a dose-dependent manner. Collectively, these results suggest that TFPI-2 has a regulatory role in the invasiveness of gliomas in vitro and in vivo.
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PMID:Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas. 1129 50

To study the in vivo effect of all-trans-retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) on the expression of tissue factor (TF) and the other hemostatic disturbance, a series of parameters were measured either in bone marrow blasts or plasma from acute promyelocytic leukemia (APL) patients. The plasma parameters were measured by ELISA or chromogenic studies. The TF transcription was assessed using reverse transcription-polymerase chain reaction (RT-PCR) technique. The results indicated that the blast cell procoagulant activity (PCA), TF antigen of APL cell lysate, as well as the transcription of APL TF mRNA elevated at diagnosis, were reduced after ATRA or As(2)O(3) therapy. The plasma level of P-selectin, TF, thrombin-antithrombin complex (TAT), soluble fibrinmonomer complex, thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), plasmin-antiplasmin complex, tissue plasminogen activator (t-PA) activity, urokinase plasminogen activator (u-PA) and its receptor (u-PAR), and D-dimer (D-D) significantly increased. Fibrinogen (Fg), antigen level of protein C (PC), plasminogen (PLG) activity, alpha(2)-plasminogen inhibitor activity (alpha(2)-PI), and plasminogen activator inhibitor (PAI) activity were decreased at diagnosis. The protein C activity (PC:A) and protein S (PS) remained unchanged. All the parameters were restored to normal ranges after complete remission (CR) except elevation of TF and TAT in both groups, as well as PC:A, PS, and t-PA in the ATRA group. In conclusion, there existed activation of platelets and consumption of anticoagulants as well as activation of coagulation and fibrinolytic system before treatment. Both ATRA and As(2)O(3) therapy downregulated the expression of TF mRNA, decreased the PCA and TF level in APL cells, significantly inhibited coagulation activation, corrected secondary hyperfibrinolysis and the other hemostatic abnormalities, and thus greatly improved the bleeding symptom in early stage of the treatment.
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PMID:Effects of all-trans-retinoic acid and arsenic trioxide on the hemostatic disturbance associated with acute promyelocytic leukemia. 1136 12

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

In this short review, we describe the distribution of adrenomedullin (AM)-immunoreactive cells in human tissues and their related biological properties, focusing on the blood coagulation and mucosal defense systems. AM is widely distributed in human tissues, especially in cardiovascular and endocrine tissues. Within vessels, AM has been immunohistochemically detected in vascular smooth muscle cells (SMCs) and endothelial cells (ECs). In atherosclerotic lesions, the peptide is present not only in these cells, but also in macrophages, and the most intense AM immunoreactivity is detected in macrophages located in shoulder lesions of atheromatous plaque, which are considered to be rupture-prone regions. AM inhibits tissue factor production, and augments the production and release of tissue factor pathway inhibitor from aortic ECs. AM also induces the release of antithrombin and urokinase-type plasminogen activator from ECs. Taken together, these antithrombotic properties of the peptide are expected to play an important role in the maintenance of blood circulation. Furthermore, AM immunoreactivity is observed in mucosal and glandular epithelia of the gastrointestinal, respiratory and reproductive systems. AM and the proadrenomedullin N-terminal 20 peptide (PAMP) show strong antibacterial activity against Escherichia coli. In addition, AM is also present in the auditory system. These lines of evidence suggest that AM and its related peptides not only play a role in vasodilatation, but also exhibit multiple biological activities in mammals.
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PMID:Immunohistological localization and possible functions of adrenomedullin. 1263 Aug 9

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

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

Malignancy is characterized by the occurrence of components of coagulation reaction pathways in situ within tumor tissues detectable immunohistochemically. However, tumors vary in the details of this coagulation-cancer interaction. We have previously described tumor cell-associated tissue factor (TF), factor (F) VII, and F X in laryngeal carcinoma tissues. Fibrinogen and F XIIIa were found in the tumor connective tissue. Tissue factor pathway inhibitor (TFPI) occurred in the tumor connective tissue and on microvascular endothelial cells and normal squamous epithelial cells but not in the tumor cells. Fibrin (thrombin-cleaved fibrinogen) existed at the host-tumor interface and the margins of tumor nodules consistent with an active tumor cell-associated clotting pathway in this tumor type. Studies were extended here to detect components of fibrinolytic pathways. Plasminogen and tissue plasminogen activator (t-PA) were detected on laryngeal tumor cells, particularly in more well-differentiated cases. Low-molecular-weight urokinase plasminogen activator (LMW u-PA) was primarily a feature of more undifferentiated laryngeal carcinoma cells. Staining to a lesser extent was found for high-molecular-weight u-PA (HMW u-PA) on tumor cells and various normal cell types in the tumor tissue. Relatively weak and variable tumor cell staining was found for plasminogen activator inhibitors (PAI) 1, 2, and 3. Trace staining was found for u-PA receptor (u-PAR) in differentiated tumor cells. The significance of coagulation and fibrinolytic pathways present in situ to the economy of laryngeal carcinoma remains to be determined.
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PMID:Occurrence of components of fibrinolytic pathways in situ in laryngeal cancer. 1288 36

Intermittent pneumatic compression (IPC) is known to provide effective prophylaxis against post-surgical deep-vein thrombosis (DVT), and other procedures based on reducing venous stasis have been promoted recently to minimize the risk of thromboembolism after long-haul travel ('travellers thrombosis'). This study sought to measure the effects of IPC on systemic haemostasis, which are currently disputed. IPC was applied for 120 min on 21 male, non-smoking volunteers ranging in age from 19 to 47 years. IPC promoted a significant increase in global fibrinolytic potential. Levels of urokinase plasminogen activator activity (uPA) measured using an amidolytic assay were raised after IPC. However, enzyme-linked immunosorbent assays (ELISA) of uPA antigen, and the activities of tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) were not statistically different from those in control experiments. IPC led to highly significant falls in factor VIIa, associated with increased levels of tissue factor pathway inhibitor (TFPI). IPC enhances fibrinolysis and suppresses procoagulant activation. Measurements of specific fibrinolytic components do not reflect overall fibrinolytic activity and are highly dependent on the method of assay. The results provide important clues for detailed studies of the effects of haemodynamics on systemic haemostasis.
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PMID:Systemic haemostasis after intermittent pneumatic compression. Clues for the investigation of DVT prophylaxis and travellers thrombosis. 1527 64

Blood coagulation is essential to maintain hemostasis in organisms with a vascular network. Formation of a fibrin-rich clot at a site of vessel injury is a highly complex process that is orchestrated by the coagulation protease cascade. This cascade is regulated by 3 major anticoagulant pathways. Removal of a clot is mediated by the fibrinolytic system. Defects in the regulation of clot formation lead to either hemorrhage or thrombosis. Tissue factor, the primary cellular initiator of blood coagulation, is a transmembrane receptor that is expressed in a tissue-specific manner. The 3 major anticoagulants are tissue factor pathway inhibitor, antithrombin, and protein C, the latter requiring a transmembrane receptor called thrombomodulin for its activation. Tissue factor pathway inhibitor and thrombomodulin are expressed by endothelial cells in a tissue-specific manner, whereas antithrombin and protein C circulate in the plasma. Fibrinolysis requires the activation of plasminogen to plasmin, which is mediated by tissue-type plasminogen activator and urokinase-type plasminogen activator. Interestingly, tissue-type plasminogen activator is expressed by a subset of endothelial cells of discrete size and location. These observations, together with the phenotypes of mice that have defects in the procoagulant, anticoagulant, and fibrinolytic pathways, indicate that hemostasis is regulated in a tissue-specific manner.
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PMID:Tissue-specific hemostasis in mice. 1612 18


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