scholarly journals An Activated Protein C Analog With Reduced Anticoagulant Activity Extends the Therapeutic Window of Tissue Plasminogen Activator for Ischemic Stroke in Rodents

Stroke ◽  
2012 ◽  
Vol 43 (9) ◽  
pp. 2444-2449 ◽  
Author(s):  
Yaoming Wang ◽  
Zhenggang Zhang ◽  
Nienwen Chow ◽  
Thomas P. Davis ◽  
John H. Griffin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Therapeutic Window ◽  
Tissue Plasminogen

Specificity of the Thrombin-Induced Release of Tissue Plasminogen Activator from Cultured Human Endothelial Cells

1986 ◽  
Vol 56 (02) ◽  
pp. 115-119 ◽  
Author(s):  
Eugene G Levin ◽  
David M Stern ◽  
Peter P Nawroth ◽  
Richard A Marlar ◽  
Daryl S Fair ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Protein C ◽  
Primary Cultures ◽  
Activated Protein C ◽  
Specific Inhibitor ◽  
Factor Xa ◽  
Human Endothelial Cells ◽  
Tissue Plasminogen

SummaryThe addition of thrombin (9 nM) to primary cultures of human endothelial cells induces a 6- to 7-fold increase in the rate of release of tissue plasminogen activator (tPA). Several other serine proteases which specifically interact with endothelial cells were also analyzed for their effect on tPA release. Gamma-thrombin, an autocatalytic product of α-thrombin, promoted tPA release but was less effective than α-thrombin. A maximum increase of 5.5-fold was observed, although a concentration of γ-thrombin 20 times greater than α-thrombin was required. The response to Factor Xa was similar to α-thrombin, although the stimulation was significantly reduced by the addition of hirudin or DAPA suggesting that prothrombin activation was occurring. The simultaneous addition of prothrombin with Factor Xa resulted in enhanced tPA release equal to that observed with an equimolar concentration of active α-thrombin. Thus, under these conditions, Factor Xa-cell surface mediated activation of prothrombin can lead to a secondary effect resulting from cell-thrombin interaction. Activated protein C, which has been implicated as a profibrinolytic agent, was also tested. No change in tPA release occurred after the addition of up to 325 nM activated protein C in the presence or absence of proteins. Factor IXa and plasmin were also ineffective. The effect of thrombin on the endothelial cell derived plasminogen activator specific inhibitor was also studied. Thrombin produced a small but variable release of the inhibitor with an increase of less than twice that of non-thrombin treated controls.

Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C

2004 ◽  
Vol 10 (12) ◽  
pp. 1379-1383 ◽  
Author(s):  
Dong Liu ◽  
Tong Cheng ◽  
Huang Guo ◽  
José A Fernández ◽  
John H Griffin ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Protein C ◽  
Activated Protein C ◽  
Tissue Plasminogen

scholarly journals Anticoagulant and fibrinolytic activities are promoted, not retarded, in vivo after thrombin generation in the presence of a monoclonal antibody that inhibits activation of protein C

Blood ◽  
1992 ◽  
Vol 79 (7) ◽  
pp. 1720-1728 ◽  
Author(s):  
FB Jr Taylor ◽  
H Hoogendoorn ◽  
AC Chang ◽  
G Peer ◽  
ME Nesheim ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Protein C ◽  
Thrombin Generation ◽  
Activated Protein C ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tissue Plasminogen

Abstract This study examines the assumption that both the anticoagulant and fibrinolytic activity that follow the generation of thrombin induced by infusion of factor Xa/PCPS are due to generation of activated protein C. Untreated controls or animals given unrelated antibody were compared with animals pretreated with a specific monoclonal antibody to protein C (HPC4). Compared with untreated controls excess HPC4 substantially reduced the level of protein C activation as observed by protein C immunoblotting and enzyme-linked immunosorbent assay for antitrypsin/activated protein C complexes. Despite this, the anticoagulant activity as reflected by the decline of factors Va and VIIIa levels (as observed by coagulation assays and by factor V immunoblotting) was significantly greater than controls. The fibrinolytic activity (as observed by assays of tissue plasminogen activator, D-Dimer, alpha 2-antiplasmin) also was significantly greater than controls. We conclude that neutralization of the protein C anticoagulant system while resulting in a significantly more intense coagulant response to Xa/PCPS does not preclude inactivation of factors Va and VIIIa and the full expression of the fibrinolytic response. We conclude further that after thrombin generation in vivo, protein C activation is not a prerequisite for the promotion of the fibrinolytic response previously observed, and that the inactivation of factors Va/VIIIa may be mediated by enzymes other than activated protein C. The reduction in alpha 2-antiplasmin levels in association with increased tissue plasminogen activator activity suggests that plasmin is a likely candidate.

Endogenous Activated Protein C Predicts Hemorrhagic Transformation and Mortality after Tissue Plasminogen Activator Treatment in Stroke Patients

2009 ◽  
Vol 28 (2) ◽  
pp. 143-150 ◽  
Author(s):  
Maite Mendioroz ◽  
Israel Fernández-Cadenas ◽  
José Alvarez-Sabín ◽  
Anna Rosell ◽  
Dorita Quiroga ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Protein C ◽  
Activated Protein C ◽  
Hemorrhagic Transformation ◽  
Stroke Patients ◽  
Tissue Plasminogen

Activated protein C inhibits tissue plasminogen activator–induced brain hemorrhage

2006 ◽  
Vol 12 (11) ◽  
pp. 1278-1285 ◽  
Author(s):  
Tong Cheng ◽  
Anthony L Petraglia ◽  
Zhang Li ◽  
Meenakshisundaram Thiyagarajan ◽  
Zhihui Zhong ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Protein C ◽  
Activated Protein C ◽  
Brain Hemorrhage ◽  
Tissue Plasminogen

scholarly journals Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial

2019 ◽  
Vol 25 ◽  
pp. 107602961987135 ◽  
Author(s):  
Limin Wang ◽  
Di Cao ◽  
Huijun Wu ◽  
Hongning Jia ◽  
Chaoping Yang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Ischemic Stroke ◽  
Treatment Outcomes ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Serum Levels ◽  
Therapeutic Window ◽  
Secondary Outcome ◽  
Narrow Therapeutic Window ◽  
Tissue Plasminogen

Recombinant tissue plasminogen activator (rt-PA) can be utilized to treat ischemic stroke with safety and effectiveness but limited by a narrow therapeutic window. In the present clinical trial among patients with stroke, we sought to evaluate the potential of fisetin to extend the therapeutic window of rt-PA treatment. Patients with stroke were divided based on their onset-to-treatment time (OTT) and then randomly assigned to receive the rt-PA treatment combined with fisetin or placebo. Primary outcome was evaluated using the National Institutes of Health Stroke scale (NIHSS), and secondary outcome was assessed by serum levels of matrix metalloproteinase (MMP) 2, MMP 9, and C-reactive protein (CRP). Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT strata, as revealed by lower NIHSS scores. The beneficial effect of fisetin was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum, as evidenced by strong linear correlations between serum levels of such markers with the NIHSS scores in all enrolled patients. Fisetin may possess the potential to supplement traditional rt-PA treatments among patients with stroke, particularly for those with delayed OTT, and thereby extend the otherwise narrow therapeutic window and improve the treatment outcomes.

scholarly journals Anticoagulant and fibrinolytic activities are promoted, not retarded, in vivo after thrombin generation in the presence of a monoclonal antibody that inhibits activation of protein C

Blood ◽  
1992 ◽  
Vol 79 (7) ◽  
pp. 1720-1728 ◽  
Author(s):  
FB Jr Taylor ◽  
H Hoogendoorn ◽  
AC Chang ◽  
G Peer ◽  
ME Nesheim ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Protein C ◽  
Thrombin Generation ◽  
Activated Protein C ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tissue Plasminogen

This study examines the assumption that both the anticoagulant and fibrinolytic activity that follow the generation of thrombin induced by infusion of factor Xa/PCPS are due to generation of activated protein C. Untreated controls or animals given unrelated antibody were compared with animals pretreated with a specific monoclonal antibody to protein C (HPC4). Compared with untreated controls excess HPC4 substantially reduced the level of protein C activation as observed by protein C immunoblotting and enzyme-linked immunosorbent assay for antitrypsin/activated protein C complexes. Despite this, the anticoagulant activity as reflected by the decline of factors Va and VIIIa levels (as observed by coagulation assays and by factor V immunoblotting) was significantly greater than controls. The fibrinolytic activity (as observed by assays of tissue plasminogen activator, D-Dimer, alpha 2-antiplasmin) also was significantly greater than controls. We conclude that neutralization of the protein C anticoagulant system while resulting in a significantly more intense coagulant response to Xa/PCPS does not preclude inactivation of factors Va and VIIIa and the full expression of the fibrinolytic response. We conclude further that after thrombin generation in vivo, protein C activation is not a prerequisite for the promotion of the fibrinolytic response previously observed, and that the inactivation of factors Va/VIIIa may be mediated by enzymes other than activated protein C. The reduction in alpha 2-antiplasmin levels in association with increased tissue plasminogen activator activity suggests that plasmin is a likely candidate.

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