title: Homocysteinylated fibrinogen forms disulfide-linked complexes with albumin.
abstract: We have shown that homocysteinemic rabbits have altered fibrinogen that forms fibrin clots with increased resistance to fibrinolysis. Homocysteine thiolactone is a metabolite of homocysteine (Hcys) that can react with amines and introduce a new sulfhydryl group into proteins. Recent evidence suggests that Hcys thiolactone-lysine adducts form in vivo. We have shown that in vitro reaction of Hcys thiolactone with human fibrinogen (Hcys-fibrinogen) alters fibrinogen function in a manner similar to that in homocysteinemic rabbits. Several naturally-occurring mutations that introduce a new cysteine into fibrinogen are associated with clinical thrombosis due to increased resistance of clots to fibrinolysis. In those cases the new cysteine mediates disulfide formation between the mutant fibrinogen and albumin. We now report that Hcys-fibrinogen similarly forms disulfides with albumin in vitro, specifically through sites in its D-domain. However, fibrin clots formed from Hcys-fibrinogen-albumin show a similarly reduced ability to support plasminogen activation and a similar resistance to fibrinolysis as clots formed from Hcys-fibrinogen. Thus, fibrinogen-albumin conjugates may result from N-homocysteinylation of fibrinogen in vivo. However, there is no evidence that conjugation to albumin further impairs fibrinogen function above the defect induced by homocysteinylation of critical lysines. Similar to the utility of glycated hemoglobin as a marker for the deleterious effects of hyperglycemia, the level of fibrinogen-albumin complexes might possibly be a clinically useful marker for the level of homocysteine-associated damage in vivo.
authors.affiliation: Research Service, Durham Veterans Affairs Medical Center, Durham, NC 27705, United States.
authors.forename: Derrick L
authors.initials: DL
authors.lastname: Sauls
authors.forename: Maria
authors.initials: M
authors.lastname: Warren
authors.forename: Maureane
authors.initials: M
authors.lastname: Hoffman
mesh_terms: D000418:Albumins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004220:Disulfides / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism*; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood* / Q000378:metabolism; D011817:Rabbits
chemical_list: D000418:Albumins; D004220:Disulfides; D006710:Homocysteine; D005340:Fibrinogen