Oxidative modification of fibrinogen inhibits thrombin-catalyzed clot formation.
Plasma fibrinogen plays a central role in controlling hemostasis. In an earlier report, we found that fibrinogen is oxidized when whole plasma is treated with a metal-catalyzed oxidation system. These studies show that oxidative modification of purified human fibrinogen leads to an exposure-dependent loss of thrombin-induced clot formation. Inhibition of clotting occurred when either metal-catalyzed oxidation or gamma-irradiation was employed to generate oxidizing radicals. Both systems caused covalent modification of fibrinogen, assessed by measuring incorporation of protein carbonyls. Thrombin-catalyzed fibrinopeptide release was normal in irradiated fibrinogen and was only slightly diminished in protein exposed to metal-catalyzed oxidation, indicating that the inhibition of clotting activity was due to impaired fibrin monomer polymerization. Thus, oxidative modification of normal fibrinogen causes dysfibrinogenemia and constitutes a novel mechanism for inhibition of thrombosis.
Shacter
E
E
Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Williams
J A
JA
Levine
R L
RL
D001205:Ascorbic Acid / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003018:Clot Retraction; D004307:Dose-Response Relationship, Radiation; D005340:Fibrinogen / Q000187:drug effects*; D005609:Free Radicals; D006801:Humans; D007501:Iron / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism
D005609:Free Radicals; D016877:Oxidants; D005340:Fibrinogen; D007501:Iron; D013917:Thrombin; D001205:Ascorbic Acid