Effect of phenylglyoxal-modified alpha2-antiplasmin on urokinase-induced fibrinolysis.
One of the functions of activated blood clotting factor XIII (FXIIIa) is the crosslinking of alpha2-antiplasmin (alpha2AP) to fibrin. This process results in localization and concentration of alpha2AP throughout fibrin, thereby making fibrin more resistant to digestion by plasmin. We reasoned that competition by chemically-modified inactive alpha2AP (mod alpha2AP) with native alpha2AP would diminish the resistance of fibrin to digestion by plasmin. Mod alpha2AP was prepared by treating native alpha2AP with an Arg-specific reagent, phenylglyoxal. An average of four of the total nineteen Arg residues in alpha2AP reacted with phenylglyoxal and resulted in complete loss of plasmin inhibitory activity; however, mod alpha2AP competed effectively with native alpha2AP for becoming crosslinked to fibrin by FXIIIa catalysis. In the presence of mod alpha2AP, urokinase (UK)-induced plasma clot lysis time shortened significantly. Mod alpha2AP enhanced UK-induced clot lysis in a whole blood system as shown by the similarities of rates of clot lysis for a mixture of 20 U/ml UK and 1.5 microM mod alpha2AP versus that induced by 100 U/ml UK without mod alpha2AP. Less fibrinogenolysis occurred in whole blood when mod alpha2AP was present since much lower UK concentrations were needed to achieve the same level of fibrinolysis than when only native alpha2AP was present. Our results indicate that mod alpha2AP enhances UK-induced fibrinolysis by competitive inhibition of factor XIIIa-mediated incorporation of native alpha2AP into fibrin.
Lee
K N
KN
William K. Warren Medical Research Institute and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.
Lee
S C
SC
Jackson
K W
KW
Tae
W C
WC
Schwartzott
D G
DG
McKee
P A
PA
D000933:Antifibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D010658:Phenylglyoxal; D010960:Plasminogen Activators / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*; D000979:alpha-2-Antiplasmin / Q000737:chemistry / Q000494:pharmacology*
D000933:Antifibrinolytic Agents; D000979:alpha-2-Antiplasmin; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator; D010658:Phenylglyoxal