5474766 Methods and compositions for inhibition of hepatic clearance of tissue-type plasminogen activator

1997 ◽  
Vol 15 (1) ◽  
pp. 240
Keyword(s):  
Plasminogen Activator ◽  
Hepatic Clearance ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

scholarly journals Evidence for carbohydrate-independent endocytosis of tissue-type plasminogen activator by liver cells

1992 ◽  
Vol 285 (3) ◽  
pp. 799-804 ◽  
Author(s):  
E Stang ◽  
N Roos ◽  
M Schlüter ◽  
T Berg ◽  
J Krause
Keyword(s):  
Plasminogen Activator ◽  
Liver Cell ◽  
Hepatic Clearance ◽  
Mannose Receptor ◽  
Cell Types ◽  
Tissue Type ◽  
Side Chains ◽  
Tissue Type Plasminogen Activator ◽  
Hepatic Cells ◽  
Type Plasminogen Activator

In the liver, tissue-type plasminogen activator (t-PA) is endocytosed by hepatic parenchymal (PC), endothelial (EC) and Kupffer (KC) cells. Although the endocytosis is receptor-mediated, it remains a matter of discussion which receptors are involved in this catabolic process. To evaluate the role of a protein-specific receptor, as well as the possible involvement of the galactose receptor on PC and the mannose receptor on EC, we have employed different glycosylation variants of t-PA in biochemical and immunocytochemical studies. Partial or total removal of carbohydrate side-chains by endoglycosidases did not prevent clearance and hepatic endocytosis of t-PA by either of the liver cell types. Blockade of the galactose and mannose receptors by co-application of a large excess of the glycoprotein ovalbumin remained without effect on the binding and uptake of t-PA by hepatic cells. However, the contribution of different liver cell types to the hepatic clearance of t-PA was to a certain extent dependent on the type of oligosaccharide chains removed. The mannose receptor on EC is partially responsible for the clearance of t-PA by this cell type, whereas the galactose receptor does not seem to be involved in this process. The results obtained in this study further demonstrate that the major portion of the hepatic catabolism of t-PA is independent of its carbohydrate side-chains.

scholarly journals Fibrinolysis during liver transplantation in humans: role of tissue- type plasminogen activator

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1090-1095
Author(s):  
WH Dzik ◽  
CF Arkin ◽  
RL Jenkins ◽  
DC Stump
Keyword(s):  
Liver Transplantation ◽  
Plasminogen Activator ◽  
Degradation Products ◽  
Hepatic Clearance ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Anhepatic Phase ◽  
Fibrinolytic Parameters

Human liver transplantation is frequently associated with a coagulopathy and bleeding diathesis developing during the anhepatic phase of surgery. The hemostatic defect has been attributed in part to accelerated fibrinolysis. In this study we evaluated changes in specific blood fibrinolytic parameters occurring in eight adult patients undergoing first-time orthotopic liver transplantation. Five of the eight patients experienced moderate to severe systemic fibrinolysis as reflected by alpha 2-antiplasmin consumption and fibrinogen degradation with the concomitant appearance of fibrin(ogen) degradation products. In association with these changes, an increase in tissue-type plasminogen activator (t-PA) activity and t-PA antigen levels was also observed. Fibrinolysis was most pronounced during the anhepatic phase of surgery and decreased after revascularization of the grafted liver. Three additional patients who underwent the same procedure manifested much less evidence of systemic fibrinolytic activation and had minimal elevation of t-PA antigen levels or activity. Urokinase-type plasminogen activator levels, although elevated in three patients, were disassociated from increased t-PA levels and concomitant systemic fibrinolysis. The operative course of those patients developing t-PA-associated fibrinolysis was characterized by shock, acidosis, generalized bleeding, and a need for substantially greater blood product support during surgery. These findings suggest that the observed fibrinolytic defect is related to increased circulating plasma levels of t-PA, presumably resulting from a combination of increased intravascular release and decreased hepatic clearance of t-PA. These observations may have implications for intraoperative therapy for the transplant-related coagulopathy and its associated bleeding.

Hepatic Clearance of Tissue-Type Plasminogen Activator in Rats

1985 ◽  
Vol 54 (03) ◽  
pp. 661-664 ◽  
Author(s):  
J J Emeis ◽  
C M van den Hoogen ◽  
D Jense
Keyword(s):  
Plasminogen Activator ◽  
Liver Perfusion ◽  
Liver Blood Flow ◽  
Hepatic Clearance ◽  
Tissue Type ◽  
Functional Assay ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Fast Acting ◽  
Isolated Liver

SummaryThe clearance of tissue-type plasminogen activator (t-PA) was studied, in rats, by use of a functional assay for t-PA. Half-lives in the circulation were about one minute both for human (melanoma cell-derived) t-PA and for the rat’s own t-PA. The clearance of t-PA required an intact liver blood flow. In isolated liver perfusion experiments the hepatic extraction of t-PA did not require any plasma proteins, including fast-acting t-PA inhibitor. Competition experiments, using monosaccharides, suggested that known hepatic glycoprotein receptors were not involved in hepatic t-PA extraction.

scholarly journals Fibrinolysis during liver transplantation in humans: role of tissue- type plasminogen activator

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1090-1095 ◽  
Author(s):  
WH Dzik ◽  
CF Arkin ◽  
RL Jenkins ◽  
DC Stump
Keyword(s):  
Liver Transplantation ◽  
Plasminogen Activator ◽  
Degradation Products ◽  
Hepatic Clearance ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Anhepatic Phase ◽  
Fibrinolytic Parameters

Abstract Human liver transplantation is frequently associated with a coagulopathy and bleeding diathesis developing during the anhepatic phase of surgery. The hemostatic defect has been attributed in part to accelerated fibrinolysis. In this study we evaluated changes in specific blood fibrinolytic parameters occurring in eight adult patients undergoing first-time orthotopic liver transplantation. Five of the eight patients experienced moderate to severe systemic fibrinolysis as reflected by alpha 2-antiplasmin consumption and fibrinogen degradation with the concomitant appearance of fibrin(ogen) degradation products. In association with these changes, an increase in tissue-type plasminogen activator (t-PA) activity and t-PA antigen levels was also observed. Fibrinolysis was most pronounced during the anhepatic phase of surgery and decreased after revascularization of the grafted liver. Three additional patients who underwent the same procedure manifested much less evidence of systemic fibrinolytic activation and had minimal elevation of t-PA antigen levels or activity. Urokinase-type plasminogen activator levels, although elevated in three patients, were disassociated from increased t-PA levels and concomitant systemic fibrinolysis. The operative course of those patients developing t-PA-associated fibrinolysis was characterized by shock, acidosis, generalized bleeding, and a need for substantially greater blood product support during surgery. These findings suggest that the observed fibrinolytic defect is related to increased circulating plasma levels of t-PA, presumably resulting from a combination of increased intravascular release and decreased hepatic clearance of t-PA. These observations may have implications for intraoperative therapy for the transplant-related coagulopathy and its associated bleeding.

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