Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A massive hypertriglyceridemia associated with low post heparin lipolytic activity, was demonstrated during the growth of a transplanted lymphoma in Hamsters. An immunoglobulin, with high anti-heparin activity, was extracted from the tumor. It could inhibit both the anti-thrombin and prolipase activity of heparin. The role of this anti-heparin immunoglobulin in triglyceride metabolism allows us to consider the hypertriglyceridemia of lymphoma-bearing Hamsters as one of the two previously described types of auto-immune hyperlipidemia.
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PMID:[Antiheparin immunoglobulin in malignant lymphoma with hypertriglyceridemia, in the hamster]. 82 49

Interaction of T and B lymphocytes, platelets, granulocytes, macrophages and mast cells with the subendothelial extracellular matrix (ECM) is associated with degradation of heparan sulfate (HS) by a specific endoglycosidase (heparanase) activity. The enzyme is released from intracellular compartments (i.e., lysosomes, specific granules) in response to various activation signals (i.e., thrombin, calcium ionophore, immune complexes, antigens, mitogens), suggesting its regulated involvement in inflammation and cellular immunity. In contrast, various tumor cells appear to express and secrete heparanase in a constitutive manner, in correlation with their metastatic potential. Heparanase enzymes produced by different cell types may exhibit different molecular properties and substrate cleavage specificities. The platelet enzyme appears also in a latent form. It can be activated by tumor cells and thereby facilitate their extravasation in the process of metastasis. Degradation of ECM-HS by all cell types was facilitated by a proteolytic activity residing in the ECM and/or expressed by the invading cells. This proteolytic activity produced a more accessible substrate for the heparanase enzymes. Heparanase-inhibiting, nonanticoagulant species of heparin markedly reduced the incidence of lung metastasis in experimental animals. These species of heparin also significantly impaired the traffic of T lymphocytes and suppressed cellular immune reactivity and experimental autoimmune diseases. Heparanase activity expressed by intact cells (i.e., platelets, mast cells, neutrophils, lymphoma cells) was found to release active HS-bound basic fibroblast growth factor from ECM and basement membranes. Heparanase may thus elicit an indirect neovascular response in processes such as wound repair, inflammation and tumor development. The significant anticancerous effect of heparanase-inhibiting molecules may therefore be attributed to their potential inhibition of both tumor invasion and angiogenesis. Both normal leukocytic cells and metastatic tumor cells can enter the bloodstream, travel to distant sites and extravasate to the parenchyma at these sites. We suggest that heparanase is utilized for this purpose by both types of cells. Other functions (i.e., enzyme activities, adhesive interactions, chemotactic and proliferative responses) of metastatic tumor cells seem to mimic the equivalent functions of leukocytes as they migrate across blood vessels to gain access to sites of inflammation.
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PMID:Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. 139

avWD is a rare entity that is primarily associated with lymphoproliferative disorders, most commonly with multiple myeloma, lymphoma, and the myeloproliferative diseases. Various pathogenetic mechanisms have been postulated. The most commonly seen is antibodies directed against the FVIII complex, resulting in either its accelerated destruction or its accelerated clearance by the reticuloendothelial system. There may be immunoadsorption of the FVIII complexes onto the clones of malignant cells, as has been reported in several cases, or proteolysis may be causing the peripheral destruction of the FVIII complex. Lastly, as seen in hypothyroidism, global decrease in production of the multimers also results in avWD. The treatment, in general, should be aimed at controlling the underlying disorder and at stopping any life-threatening hemorrhage. The treatment includes any or all of the following: DDAVP, cryoprecipitate, FVIII concentrates, extracorporeal immunoadsorption, and chemotherapy as needed to control the underlying disorders. The screening tests that will allow for the detection of the avWD include measurement of the bleeding time, the FVIII:C, FVIII:vWF, and the FVIII:RCoF. FVIII:C inhibitors can be demonstrated by mixing the patient plasma with normal plasma. A normal prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) are expected. Clinically, these patients present with mucosal bleeding, and in avWD tend to have an association with lymphoproliferative malignancies. They tend to be elderly patients with no prior history of bleeding diathesis and to have negative family histories for coagulopathies. Further study of these patients is warranted, because this disorder appears to have a multifactorial etiology. Increasing our understanding of avWD may increase our understanding of congenital vWD, thus allowing us to more effectively treat all patients with von Willebrand's disease.
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PMID:Acquired von Willebrand's disease. 145 20

The ability of normal and malignant blood-borne cells to extravasate correlates with the activity of an endo-beta-D-glucuronidase (heparanase) which degrades heparan sulfate (HS) in the subendothelial extracellular matrix (ECM). The association of malignancy with different types of coagulopathies prompted us to study the effect of thrombin (EC 3.4.21.5), a serine protease elaborated during activation of the clotting cascade, on the ability of heparanase to degrade the ECM-HS. The circulating zymogen form of thrombin, prothrombin, was converted to proteolytically active thrombin during incubation with ECM. Thrombin generation by the ECM was time and dose dependent, reaching maximal conversion by 6 h incubation at 3 U/ml of prothrombin. Heparanase-mediated release of low Mr HS cleavage products from sulfate-labeled ECM was stimulated four- to sixfold in the presence of alpha-thrombin, but there was no effect on degradation of soluble HS. Similar results were obtained with heparanase preparations derived from mouse lymphoma and human hepatoma cell lines and from human placenta. Incubation of ECM with alpha-thrombin alone resulted in release of nearly intact high-Mr labeled proteoglycans. Thrombin stimulation of heparanase action was dose and time dependent, reaching a maximal value at 24 h incubation with 1 microM alpha-thrombin. The effect of modified thrombin preparations correlated with their proteolytic activity. Catalytically blocked preparations of thrombin (e.g., DIP-alpha-thrombin, MeSO2-alpha-thrombin) failed to facilitate heparanase action, while catalytically modified preparations (e.g., gamma-thrombin, NO2-alpha-thrombin) exerted only a slight enhancement. Antithrombin III (ATIII) and hirudin both inhibited thrombin-stimulated heparanase degradation of ECM-bound HS. Heparanase action was also facilitated by ECM-immobilized thrombin to an extent which was similar to that induced by soluble thrombin. This result implies that thrombin sequestered by the subendothelial ECM and protected from interaction with its natural inhibitor ATIII (Bar-Shavit et al., 1989, J. Clin. Invest. 84, 1096-1104) may participate locally in cellular invasion during tumor metastasis, inflammation, and autoimmunity.
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PMID:Thrombin enhances degradation of heparan sulfate in the extracellular matrix by tumor cell heparanase. 161 23

Despite the ubiquitous presence of basic fibroblast growth factor (bFGF) in normal tissues, endothelial cell proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Immunohistochemical staining revealed the localization of bFGF in basement membranes of diverse tissues, suggesting that the extracellular matrix (ECM) may serve as a reservoir for bFGF. Moreover, functional studies indicated that bFGF is an ECM component required for supporting endothelial cell proliferation and neuronal differentiation. We have found that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by heparanase expressed by normal and malignant cells (i.e. platelets, neutrophils, lymphoma cells). It is proposed that restriction of bFGF bioavailability by binding to ECM and local regulation of its release provide a novel mechanism for neovascularization in normal and pathological situations. The subendothelial ECM contains also tissue type- and urokinase type-plasminogen activators which participate in cell invasion and tissue remodeling. These results and studies on the properties of other ECM-immobilized enzymes (i.e. thrombin, plasmin, lipoprotein lipase) and growth factors (GM-CSF, IL-3, osteogenin), suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized and persistent mode of action, as compared to the same molecules in a fluid phase.
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PMID:Extracellular matrix-resident basic fibroblast growth factor: implication for the control of angiogenesis. 171 29

Nonmalignant lymphoid tissue and tissue from patients with nodular sclerosis, Hodgkin's disease, and large cell lymphocytic lymphoma was examined by immunohistochemical techniques for the occurrence in situ of components of coagulation and fibrinolysis reaction pathways. Staining for material interpreted as fibrinogen was observed in abundance in both malignant and reactive lymphoid tissue. Fibrin also occurred to a variable extent but focally in all tissues. Components of coagulation pathways, including tissue factor, factor VII, factor X, and factor XIII ("a" subunit), were restricted to tissue macrophages. Double-labeling techniques revealed fibrin in direct apposition to tissue macrophages. We conclude that fibrinogen and fibrin occur in both benign and malignant lymphoid tissue and that the transformation of fibrinogen to fibrin is attributable to macrophage-initiated thrombin formation. We postulate that both systemic and local hypercoagulability associated with these disorders may be attributable to macrophage activation resulting in expression of procoagulant activity.
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PMID:Fibrinogen deposition and macrophage-associated fibrin formation in malignant and nonmalignant lymphoid tissue. 174 Jun 24

To evaluate the occurrence of hypercoagulability during treatment with L-asparaginase (L-ase), thrombin-antithrombin complex (TAT) and D-dimer levels in plasma were serially measured in 15 consecutive adult patients with acute lymphoblastic leukaemia or lymphoblastic lymphoma who had recently completed a chemotherapy cycle with cytosine arabinoside and methotrexate. The first eight patients (group A) received i.v. L-ase alone (20,000 U/m2 on alternate days over 10 d); the last seven patients (group B) received, in addition to L-ase, bolus injection of antithrombin concentrate (2000 U) on alternate days for a total of six administrations, beginning with the second L-ase infusion. Increased levels of TAT (P less than 0.05) and D-dimer (P less than 0.01) were observed prior to L-ase, possibly related to inflammation and cytolysis secondary to previous chemotherapy. In patients treated with L-ase alone, further elevation of TAT (P less than 0.05) and persistence of increased D-dimer were observed, associated with marked reduction of the anticoagulant activities of protein C, protein S and antithrombin III. At variance, in patients receiving antithrombin III supplementation there was no increase of TAT and a normalization of D-dimer levels occurred during L-ase treatment. In these patients, mean plasma antithrombin III activity was maintained at levels higher than 70% of normal throughout the treatment. The rate of decline of fibrinogen, factor IX, protein C and protein S was unaffected by antithrombin III supplementation, indicating that hypercoagulability has little if any relevance for the reduction of coagulation factors and inhibitors induced by L-ase treatment. The usefulness of antithrombin III concentrates in preventing thromboembolic complications in patients submitted to L-ase treatment remains to be determined.
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PMID:Hypercoagulability during L-asparaginase treatment: the effect of antithrombin III supplementation in vivo. 218 89

To investigate the effects of protracted low-density lipoprotein (LDL) exposure on endothelial cell (EC) epoxyeicosatrienoic acid (EET) generation, human umbilical vein ECs were incubated in atherogenic concentrations of LDL (240 mg cholesterol per deciliter) (LDL-EC). After 4 days' incubation with LDL, EC were stimulated with human thrombin in the presence of 1-[14C]-arachidonic acid. Substantially more EET products were generated by LDL-ECs than by cells not exposed to high levels of LDL (C-EC). Thrombin stimulation caused LDL-EC to produce five- to eightfold more in 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET, with 14,15-EET as the major product. This is the first demonstration, to date, that EETs can be induced in EC. Metapyrone (SKF-525A) markedly inhibited EC EET generation, indicating a role for the cytochrome P-450 enzyme system in human EC arachidonic acid metabolism. One EET product, 14,15-EET, has been found to be chemotactic and to promote adhesion of U937 cells, a human monocytic lymphoma cell line, to EC. Thus, protracted exposure to atherogenic LDL concentrations increases the generation of chemotactic and adhesion factors (ie, 14,15-EET) after thrombin stimulation, possibly through the cytochrome P-450 enzyme system.
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PMID:Atherogenic concentrations of low-density lipoprotein enhance endothelial cell generation of epoxyeicosatrienoic acid products. 235 65

Both acidic and basic fibroblast growth factor (FGF), although devoid alone of growth-promoting ability on resting or activated human lymphoid B cells, were found to markedly increase the proliferative response of anti-mu-chain or SAC preactivated B cell blasts to the low molecular weight B cell growth factor (LMW-BCGF) and to enhance the costimulatory response of resting B cells to anti-mu-chain and LMW-BCGF. This potentiating effect was also observed for a LMW-BCGF-dependent B cell tumor derived from a lymphocytic nodular lymphoma. Other growth factors acting on fibroblasts, such as epidermal growth factor, alpha-thrombin, platelet-derived growth factor, and insulin-like growth factor-I did not display such enhancing effect on LMW-BCGF-driven proliferation. Activated, but not resting B cells were found to bear receptor sites for FGFs and from kinetics experiments, it is suggested that LMW-BCGF induces competence expression for FGFs in those cells. Moreover, the LMW-BCGF-elicited generation of inositoltrisphosphate resulting from polyphosphoinositides hydrolysis was increased in the presence of FGF.
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PMID:Potentiation of the proliferative response of human B lymphocytes to low molecular weight B cell growth factor (LMW-BCGF) by fibroblast growth factors (FGFs). 254 39

We have measured the procoagulant activity (PCA) of four T lymphoblastoid cell lines (Jurkat, CEM, HSB-2 and Molt 4) as well as normal peripheral blood T lymphocytes, before and after stimulation with phytohaemagglutinin (PHA), using clotting and amidolytic methods. Of the four cell lines only one, Jurkat, gave enhanced PCA after stimulation with PHA. This activity was shown to be tissue factor-like by its dependence on factor VII in plasma and in an amidolytic assay with purified factors VII and X. Jurkat was also the only one of the four cell lines to secrete interleukin-2. All four cell lines promoted the generation of large amounts of thrombin in platelet-free plasma in glass tubes. This activity was dependent on the presence of plasma factor VIII, and was probably due to phospholipids in the cell membranes. Normal T lymphocytes gave intrinsic PCA in the thrombin generation test which was only 15% of that of the lymphoma cells. These results show that some T lymphocytes can develop PCA in both intrinsic and extrinsic systems and this should be taken into account in studies of the PCA of mixed leukocyte populations.
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PMID:Procoagulant activity of T lymphoblastoid cells in extrinsic and intrinsic coagulation systems. 259 62


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