Hydroxyl radical-modified fibrinogen as a marker of thrombosis: the role of iron.
Excessive free iron in blood and in organ tissues (so called iron overload) has been observed in degenerative diseases such as atherosclerosis, cancer, neurological, and certain autoimmune diseases, in which fibrin-like deposits are also found. Although most of the body iron is bound  to hemoglobin and myoglobin in a divalent ferrous form, a certain amount of iron exists in blood as a trivalent (ferric) ion. This particular chemical state of iron has been shown to be toxic to the human body when not controlled by endogenous and/or dietary chelating agents. Experiments described  in this paper show for the first time that ferric ions (Fe(3+)) can generate hydroxyl radicals without participation of any redox agent, thus making it a special case of the Fenton reaction. Ferric chloride was also demonstrated to induce aggregation of purified fibrinogen at the  same molar concentrations that were used for the generation of hydroxyl radicals. Iron-aggregated fibrinogen, by contrast to native molecule, could not be dissociated into polypeptide subunit chains as shown in a polyacrylamide gel electrophoresis. The mechanism of this phenomenon is very  likely based on hydroxyl radical-induced modification of fibrinogen tertiary structure with the formation of insoluble aggregates resistant to enzymatic and chemical degradations. Soluble modified fibrinogen species can be determined in blood of thrombotic patients by the reaction with protamine  sulfate and/or by scanning electron microscopy. In view of these findings, it is postulated that iron-induced alterations in fibrinogen structure is involved in pathogenesis of certain degenerative diseases associated with iron overload and persistent thrombosis. It is concluded that the detection  of hydroxyl radical-modified fibrinogen may be utilized as a marker of a thrombotic condition in human subjects.
Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
B
B
Lipinski
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E
Pretorius
D000328:Adult; D015415:Biomarkers; D005260:Female; D005337:Fibrin / Q000378:metabolism / Q000648:ultrastructure; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012995:Solubility; D013927:Thrombosis / Q000097:blood / Q000175:diagnosis*; D055815:Young Adult
D015415:Biomarkers; D017665:Hydroxyl Radical; D005337:Fibrin; D005340:Fibrinogen; D007501:Iron