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

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.

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 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.

scholarly journals Hemostatic Indices in Healthy Foals from Birth to One Month of Age

1995 ◽  
Vol 7 (3) ◽  
pp. 380-385 ◽  
Author(s):  
Michelle Henry Barton ◽  
Debra Deem Morris ◽  
Natalie Crowe ◽  
Chrysann Collatos ◽  
Keith W. Prasse
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Protein C ◽  
Antithrombin Iii ◽  
Degradation Products ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Fibrin Degradation Products ◽  
Tissue Plasminogen ◽  
Activator Inhibitor

Hemostatic indices were determined in 45 healthy light breed foals, from birth to 1 month of age, and in 20 healthy adult (>2 years of age) light breed horses. Blood samples were obtained from each foal at 4 ages: 1) < 24 hours, 2) 4-7 days, 3) 10-14 days, and 4) 25-30 days. The following hemostatic indices were determined: platelet count; prothrombin and activated partial thromboplastin times; activity concentrations of protein C, antithrombin III, plasminogen, alpha-2 antiplasmin, tissue plasminogen activator, and plasminogen activator inhibitor- 1; plasma protein C antigen and fibrinogen concentrations; and serum fibrin degradation products concentration. Prothrombin and activated partial thromboplastin times were significantly longer at birth than in older foals. The plasma concentrations of the following were significantly lower at birth than in older foals: antithrombin III, plasminogen and tissue plasminogen activator activities, protein C antigen, and fibrinogen. Concentrations of the following were significantly higher at birth than in older foals: protein C and plasminogen activator inhibitor-1 activities and fibrin degradation products. These results indicate that hemostatic indices of neonatal foals differ significantly from those of older foals and adults. With the exceptions of antithrombin III and tissue plasminogen activator activities, all hemostatic indices measured in foals at 1 month of age were equivalent to adult values.

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