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A novel urokinase receptor-targeted inhibitor for plasmin and matrix metalloproteinases suppresses vein graft disease

Eefting, D. (author), Seghers, L. (author), Grimbergen, J.M. (author), de Vries, M.R. (author), de Boer, H.C. (author), Lardenoye, J.W.H.P. (author), Jukema, J.W. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

Aims Matrix metalloproteinases (MMP) and plasminogen activator (PA)/plasmin-mediated proteolysis, especially at the cell surface, play important roles in matrix degeneration and smooth muscle cell migration, which largely contributes to vein graft failure. In this study, a novel hybrid protein was designed to inhibit both protease systems...

article 2010

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Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables

Kluft, C. (author), Meijer, P. (author), LaGuardia, K.D. (author), Fisher, A.C. (author), TNO Kwaliteit van Leven (author)

Purpose: The aim of this study was to compare effects of the transdermal contraceptive patch, a desogestrel/ethinyl estradiol (EE)-containing, monophasic combination oral contraceptive (COC) and a levonorgestrel/EE-containing, triphasic COC on hemostasis variables. Study Design: This was a randomized, open-label study of 104 young women who...

article 2008

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Inhibitors and activation markers of the haemostatic system during hormone therapy: A comparative study of oral estradiol (2 mg)/ dydrogesterone and estradiol (2 mg)/ trimegestone

Norris, L.A. (author), Brosnan, J. (author), Bonnar, J. (author), Conard, J. (author), Kluft, C. (author), Hellgren, M. (author), TNO Kwaliteit van Leven (author)

Epidemiological studies have shown that hormone therapy (HT) increases the risk of venous thromboembolism in post menopausal women. The mechanism of this increased risk is unknown; however, activation of the haemostatic system is known to contribute to the pathogenesis of venous thromboembolism. In post-menopausal women the estrogen /progestogen...

article 2008

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Clot penetration and fibrin binding of amediplase, a chimeric plasminogen activator (K2tu-PA)

Rijken, D.C. (author), Barrett-Bergshoeff, M.M. (author), Jie, A.F.H. (author), Criscuoli, M. (author), Sakharov, D.V. (author), Gaubius Instituut TNO (author)

Amediplase (K2tu-PA) is a hybrid plasminogen activator, consisting of the kringle 2 domain of alteplase and the protease domain of urokinase. The objective of this study was to determine the in vitro clot penetration of amediplase in relation to its fibrin binding and to compare the properties with those of alteplase. The clot lysis activity of...

article 2004

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Involvement of Membrane-Type Matrix Metalloproteinases (MT-MMPs) in capillary tube formation by human endometrial microvascular endothelial Cells: Role of MT3-MMP

Plaisier, M. (author), Kapiteijn, K. (author), Koolwijk, P. (author), Fijten, C. (author), Hanemaaijer, R. (author), Grimbergen, J.M. (author), Mulder-Stapel, A. (author), Quax, P.H.A. (author), Helmerhorst, F.M. (author), van Hinsbergh, V.W.M. (author), Gaubius Instituut TNO (author)

In the endometrium, angiogenesis is a physiological process, whereas in most adult tissues neovascularization is initiated only during tissue repair or pathological conditions. Pericellular proteolysis plays an important role in angiogenesis being required for endothelial cell migration, invasion, and tube formation. We studied the expression of...

article 2004

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Gene transfer of the urokinase-type plasminogen activator receptor-targeted matrix metalloproteinase inhibitor TIMP-1.ATF suppresses neointima formation more efficiently than tissue inhibitor of metalloproteinase-1

Lamfers, M.L.M. (author), Grimbergen, J.M. (author), Aalders, M.C. (author), Havenga, M.J. (author), de Vries, M.R. (author), Huisman, L.G.M. (author), van Hinsbergh, V.W.M. (author), Quax, P.H.A. (author), Gaubius instituut TNO (author)

Proteases of the plasminogen activator (PA) and matrix metalloproteinase (MMP) system play an important role in smooth muscle cell (SMC) migration and neointima formation after vascular injury. Inhibition of either PAs or MMPs has previously been shown to result in decreased neointima formation in vivo. To inhibit both protease systems...

article 2002

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Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and intratumoral fluid

van Hensbergen, Y. (author), Broxterman, H.J. (author), Hanemaaijer, R. (author), Jorna, A.S. (author), van Lent, N.A. (author), Verheul, H.M.W. (author), Pinedo, H.M. (author), Hoekman, K. (author), Gaubius Instituut TNO (author)

Purpose: On the basis of the finding of marked overexpression in angiogenic microvessels, aminopeptidase N/CD13 has recently been suggested to play a prominent role in tumor angiogenesis. A soluble form of CD13 (sCD13) is present in human plasma, but its role in cancer has not been addressed. We hypothesized that sCD13 would be shed by tumor...

article 2002

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Adenoviral expression of a urokinase receptor - Targeted protease inhibitor inhibits neointima formation in murine and human blood vessels

Quax, P.H.A. (author), Lamfers, M.L.M. (author), Lardenoye, J.H.P. (author), Grimbergen, J.M. (author), de Vries, M.R. (author), Slomp, J. (author), de Ruiter, M.C. (author), Kockx, M.M. (author), Verheijen, J.H. (author), van Hinsbergh, V.W.M. (author), Gaubius Instituut TNO (author)

Background - Smooth muscle cell migration, in addition to proliferation, contributes to a large extent to the neointima formed in humans after balloon angioplasty or bypass surgery. Plasminogen activator/plasmin-mediated proteolysis is an important mediator of this smooth muscle cell migration. Here, we report the construction of a novel hybrid...

article 2001

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In vivo suppression of restenosis in balloon-injured rat carotid artery by adenovirus-mediated gene transfer of the cell surface-directed plasmin inhibitor ATF.BPTI

Lamfers, M.L.M. (author), Lardenoye, J.H.P. (author), de Vries, M.R. (author), Aalders, M.C. (author), Engelse, M.A. (author), Grimbergen, J.M. (author), van Hinsbergh, V.W.M. (author), Quax, P.H.A. (author), Gaubius Instituut TNO (author)

Injury-induced neointimal development results from migration and proliferation of vascular smooth muscle cells (SMC). Cell migration requires controlled proteolytic degradation of extracellular matrix surrounding the cell. Plasmin is a major contributor to this process by degrading various matrix proteins directly, or indirectly by activating...

article 2001

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Reduced activity of TAFI (thrombin-activatable fibrinolysis inhibitor) in acute promyelocytic leukaemia

TNO Preventie en Gezondheid (author), Meijers, J.C.M. (author), Oudijk, E.J.D. (author), Mosnier, L.O. (author), Bos, R. (author), Bouma, B.N. (author), Nieuwenhuis, H.K. (author), Fijnheer, R. (author)

Acute promyelocytic leukaemia (APL) is a disease that is distinguished from other leukaemias by the high potential for early haemorrhagic death. Several processes are involved, such as disseminated intravascular coagulation and hyperfibrinolysis. Recently, TAFI (thrombin-activatable fibrinolysis inhibitor) was identified as a link between...

article 2000

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Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: Implications for capillary-like tube formation in a fibrin matrix

Kroon, M.E. (author), Koolwijk, P. (author), van der Vecht, B. (author), van Hinsbergh, V.W.M. (author), Gaubius Instituut TNO (author)

Hypoxia stimulates angiogenesis, the formation of new blood vessels. This study evaluates the direct effect of hypoxia (1% oxygen) on the angiogenic response of human microvascular endothelial cells (hMVECs) seeded on top of a 3-dimensional fibrin matrix, hMVECs stimulated with fibroblast growth factor-2 (FGF-2) or vascular endothelial growth...

article 2000

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Specific determination of plasmin inhibitor activity in plasma: Documentation of specificity of manual and automated procedures

Clason, S.B. (author), Meijer, P. (author), Kluft, C. (author), Ersdal, E. (author), Gaubius instituut TNO (author)

Recently, a chromogenic kit for determination of plasmin inhibitor activity, Coamatic® Plasmin Inhibitor, has been developed with the aim to increase specificity and to allow application to a wide range of automates. The highly sensitive plasmin substrate S-2403 is used and, to further improve specificity, a low level of plasmin and a short...

article 1999

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Effect of steroid hormones and retinoids on the formation of capillary-like tubular structures of human microvascular endothelial cells in fibrin matrices is related to urokinase expression

Lansink, M. (author), Koolwijk, P. (author), van Hinsbergh, V. (author), Kooistra, T. (author), Gaubius Instituut TNO (author)

Angiogenesis, the formation of new capillary blood vessels, is a feature of a variety of pathological processes. To study the effects of a specific group of hormones (all ligands of the steroid/retinoid/thyroid hormone receptor superfamily) on the angiogenic process in humans, we have used a model system in which human microvascular endothelial...

article 1998

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Evaluation of the factors contributing to fibrin-dependent plasminogen activation

Mosesson, M.W. (author), Siebenlist, K.R. (author), Voskuilen, M. (author), Nieuwenhuizen, W. (author), Gaubius Instituut TNO (author)

Polymerized fibrin strongly enhances tissue plasminogen activator (tPA)-mediated plasminogen activation, concomitant with exposure of 'fibrin-specific' epitopes at 'Aα148-160' and 'γ312-324'. To investigate which aspects of polymerization are involved in these activities, we explored the fibrin polymerization process by evaluating the ability of...

article 1998

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Analysis of activation markers off coagulation, fibrinolysis and inflammation in unstable angina by probit transformation

Biasucci, L.M. (author), de Maat, M.P.M. (author), Meo, A. (author), van der Greet, W. (author), Summaria, F. (author), Quaranta, G. (author), Liuzzo, G. (author), Kluft, C. (author), Maseri, A. (author), Gaubius Instituut TNO (author)

In order to investigate the role of the hemostatic, fibrinolytic and inflammatory system in unstable angina, we assessed the levels of thrombin-antithrombin III (TAT), Prothrombin Fragment 1+2 (F1+2), plasmin-antiplasmin (PAP) and D-Dimer (DD) and of C-reactive protein (CRP) in 51 patients admitted to our CCU with severe unstable angina. Thirty...

article 1996

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Criteria for a specific plasmin inhibition test (SPIT) in human plasma

Meijer, P. (author), Kluft, C. (author), Gaubius Laboratory TNO Preventie en Gezondheid (author)

Test procedures of several commercially available functional test kits for α2-antiplasmin were investigated. The importance of the plasmin concentration, the amount of plasma used in the test and the preincubation time for a specific test for the determination of α2-antiplasmin were discussed. A Specific Plasmin Inhibition Test (SPIT) suitable...

article 1996

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Interactions between staphylokinase, plasmin(ogen), and fibrin. Staphylokinase discriminates between free plasminogen and plasminogen bound to partially degraded fibrin

Gaubius Instituut TNO (author), Sakharov, D.V. (author), Lijnen, H.R. (author), Rijken, D.C. (author)

Staphylokinase (STA), a protein of bacterial origin, induces highly fibrin-specific thrombolysis both in human plasma in vitro and in pilot clinical trials. Using fluorescence microscopy, we investigated the spatial distribution of fluorescein isothiocyanate (FITC)-labeled STA during lysis of a plasma clot and its binding to purified fibrin...

article 1996

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In vitro stabililty of a tissue-type plasminogen activator mutant, BM 06.022, in human plasma

Rijken, D.C. (author), Groeneveld, E. (author), Barrett-Bergshoeff, M.M. (author), Gaubius Laboratory TNO Preventie en Gezondheid (author)

BM 06.022 is a non-glycosylated mutant of human tissue-type plasminogen activator (t-PA) comprising only the kringle-2 and proteinase domains. The in vivo half-life of BM 06.022 antigen is 4- to 5-fold longer than that of t-PA antigen. The in vitro half-life of the activity of BM 06.022 at therapeutic concentrations in plasma is shorter than...

article 1994

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An improved method for the detection of α2-antiplasmin activity on the automated coagulation analyzer MLA Electra 1000C

Meijer, P. (author), Westerveld, W. (author), Huisman, L.G.M. (author), Gaubius Laboratory TNO Preventie en Gezondheid (author)

Comparison of the results for α2-antiplasmin activity of plasma samples (n = 61, range 0-125%) obtained by the 'immediate plasmin inhibition test' (IPIT) and by the automated method for the MLA Electra 1000C of Dade® shows a good correlation (R = 0.935) but a systematic disagreement especially relevant in the range below 40%. An improved method...

article 1994

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Introduction of lysine and clot binding properties in the kringle one domain of tissue-type plasminogen activator

Gaubius Instituut TNO (author), Bakker, A.H.F. (author), van der Greef, W. (author), Rehberg, E.F. (author), Marotti, K.R. (author), Verheijen, J.H. (author)

Despite the high overall similarity in primary structure between kringle one (K1) and kringle two (K2) of tissue-type plasminogen activator (t-PA) there exists an enormous functional difference. It is thought that, in contrast to K1, K2 mediates lysine binding and fibrin binding and is involved in stimulation of plasminogen activation by fibrin...

article 1993