The frequent Marburg I polymorphism impairs the pro-urokinase activating potency of the factor VII activating protease (FSAP).
The recently reported plasmatic, Factor Seven Activating Protease (FSAP), has also been found to be a potent activator of pro-urokinase [single-chain plasminogen activator, urinary type (scuPA)]. An initial epidemiological study surprisingly showed that plasmas of 5-10% of healthy blood donors had an impaired potential to activate scuPA. Analysis of the respective genomic DNAs revealed one particular single nucleotide polymorphism of FSAP resulting in an identical amino acid exchange (G511E), which correlates with the reduced activities. The corresponding mutation was named FSAP Marburg I. Thrombelastographies of wild-type and mutant plasmas were performed, facilitating the auto-activation of the intrinsic FSAP pro-enzymes by addition of dextran sulfate (DXS) and accelerated clot lysis by addition of scuPA. On these conditions, tissue-factor-induced coagulation revealed that clot lysis was significantly delayed in the Marburg I mutant plasmas as compared with wild-type plasmas. Furthermore, in the presence of DXS and scuPA, a FSAP-deficient plasma revealed significantly prolonged plasma clot lysis times, whereas the addition of purified FSAP pro-enzyme plus scuPA reversed this effect. These results support the hypothesis that FSAP contributes to the scuPA-dependent plasma fibrinolytic potential, which can be impaired in plasmas containing the FSAP Marburg I polymorphism, for instance.
Aventis Behring GmbH, Preclinical Research & Development, Marburg, Germany. Juergen.Roemisch@aventis.com
J
J
Roemisch
A
A
Feussner
C
C
Nerlich
H-A
HA
Stoehr
T
T
Weimer
D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D003062:Codon / Q000235:genetics; D016264:Dextran Sulfate / Q000494:pharmacology; D004789:Enzyme Activation; D005167:Factor VII / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000235:genetics; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000235:genetics* / Q000502:physiology; D013916:Thrombelastography; D019851:Thrombophilia / Q000235:genetics*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology
D003062:Codon; D011994:Recombinant Proteins; D005167:Factor VII; D006493:Heparin; D016264:Dextran Sulfate; C433550:HABP2 protein, human; D012697:Serine Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase