Differences between neonates and adults in the urokinase-plasminogen activator (u-PA) pathway of the fibrinolytic system.
This study deals with plasminogen activation kinetics of fetal and adult Glu-plasminogen types 1 and 2 as well as fetal and adult Lys-plasminogen by urokinase in the presence and absence of the lysine analogues epsilon-amino-n-caproic acid (EACA) and tranexamic acid. In addition, activation kinetics of single-chain urokinase-plasminogen activator (scu-PA) by adult and fetal plasmin types were investigated in the absence and presence of soluble fibrin. All Lys-plasminogen isoforms were more readily activated by urokinase than their corresponding Glu-plasminogen types. No substantial differences of the catalytic constants of urokinase-catalyzed plasminogen activation could be obtained when all fetal plasminogen types were compared to the respective adult types. In the case of all Glu-plasminogen isoforms, EACA as well as tranexamic acid first stimulated the activation process and, at higher concentrations, showed inhibitory properties. Again, the relative ability of all fetal plasminogen types to interact with lysine analogues revealed no differences compared to the respective adult glycoforms. In the absence of soluble fibrin, the catalytic efficiency of scu-PA activation by plasmin was significantly lower for both fetal plasmin isoforms. However, there were no differences in catalytic efficiency between fetal and adult plasmin types in the presence of 4 microM soluble fibrin. In conclusion, no substantial differences exist in urokinase-catalyzed plasminogen activation between neonates and adults, which is in contrast to reported data on plasminogen activation by tissue-type plasminogen activator. In the absence of soluble fibrin, scu-PA activation by fetal plasmin is markedly slower than by adult plasmin. However, this is compensated when fibrin is added at a concentration that is close to the physiological fibrinogen concentration in plasma. It can be summarized that the differences in carbohydrate structures of fetal and adult plasminogen are not associated with major differences in the global function of this part of fibrinolysis, despite functional alterations of scu-PA activation.
Ries
M
M
Division of Haematology, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Hertfordshire EN6 3QG, United Kingdom. martin.ries@kinder.imed.uni-erlangen.de
Zenker
M
M
Gaffney
P J
PJ
D000328:Adult; D000375:Aging / Q000502:physiology*; D015119:Aminocaproic Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005312:Fetal Blood / Q000737:chemistry; D005337:Fibrin / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D010958:Plasminogen / Q000187:drug effects / Q000378:metabolism; D010960:Plasminogen Activators / Q000494:pharmacology; D020033:Protein Isoforms; D012995:Solubility; D014148:Tranexamic Acid / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
D010446:Peptide Fragments; D020033:Protein Isoforms; C018998:lysyl-plasminogen; D014148:Tranexamic Acid; D005337:Fibrin; D010958:Plasminogen; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator; D015119:Aminocaproic Acid