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Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia.

Publication ,  Journal Article
Sauls, DL; Lockhart, E; Warren, ME; Lenkowski, A; Wilhelm, SE; Hoffman, M
Published in: Biochemistry
February 28, 2006

We have previously shown functional differences in fibrinogen from hyperhomocysteinemic rabbits compared to that in control rabbits. This acquired dysfibrinogenemia is characterized by fibrin clots that are composed of abnormally thin, tightly packed fibers with increased resistance to fibrinolysis. Homocysteine thiolactone is a metabolite of homocysteine (Hcys) that can react with primary amines. Recent evidence suggests that Hcys thiolactone-lysine adducts form in vivo. We now demonstrate that the reaction of Hcys thiolactone with purified fibrinogen in vitro produces fibrinogen (Hcys fibrinogen) with functional properties that are strikingly similar to those we have observed in homocysteinemic rabbits. Fibrinogen purified from homocysteinemic rabbits and Hcys fibrinogen are similar in that (1) they both form clots composed of thinner, more tightly packed fibers than their respective control rabbit and human fibrinogens; (2) the clot structure could be made to be more like the control fibrinogens by increased calcium; and (3) they both form clots that are more resistant to fibrinolysis than those formed by the control fibrinogens. Further characterization of human fibrinogens showed that Hcys fibrin had similar plasminogen binding to that of the control and an increased capacity for binding tPA. However, tPA activation of plasminogen on Hcys fibrin was slower than that of the control. Mass spectrometric analysis of Hcys fibrinogen revealed twelve lysines that were homocysteinylated. Several of these are close to tPA and plasminogen binding sites. Lysines are major binding sites for fibrinolytic enzymes and are also sites of plasmin cleavage. Thus, modification of lysines in fibrinogen could plausibly lead to impaired fibrinolysis. We hypothesize that the modification of lysine by Hcys thiolactone might occur in vivo, lead to abnormal resistance of clots to lysis, and thereby contribute to the prothrombotic state associated with homocysteinemia.

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Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

February 28, 2006

Volume

45

Issue

8

Start / End Page

2480 / 2487

Location

United States

Related Subject Headings

  • Tissue Plasminogen Activator
  • Thrombosis
  • Structure-Activity Relationship
  • Radiation-Protective Agents
  • Protein Binding
  • Plasminogen
  • Molecular Sequence Data
  • Models, Biological
  • Lysine
  • Hyperhomocysteinemia
 

Citation

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Sauls, D. L., Lockhart, E., Warren, M. E., Lenkowski, A., Wilhelm, S. E., & Hoffman, M. (2006). Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry, 45(8), 2480–2487. https://doi.org/10.1021/bi052076j
Sauls, Derrick L., Evelyn Lockhart, Maria Esteban Warren, Angela Lenkowski, Susan E. Wilhelm, and Maureane Hoffman. “Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia.Biochemistry 45, no. 8 (February 28, 2006): 2480–87. https://doi.org/10.1021/bi052076j.
Sauls DL, Lockhart E, Warren ME, Lenkowski A, Wilhelm SE, Hoffman M. Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry. 2006 Feb 28;45(8):2480–7.
Sauls, Derrick L., et al. “Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia.Biochemistry, vol. 45, no. 8, Feb. 2006, pp. 2480–87. Pubmed, doi:10.1021/bi052076j.
Sauls DL, Lockhart E, Warren ME, Lenkowski A, Wilhelm SE, Hoffman M. Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry. 2006 Feb 28;45(8):2480–2487.
Journal cover image

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

February 28, 2006

Volume

45

Issue

8

Start / End Page

2480 / 2487

Location

United States

Related Subject Headings

  • Tissue Plasminogen Activator
  • Thrombosis
  • Structure-Activity Relationship
  • Radiation-Protective Agents
  • Protein Binding
  • Plasminogen
  • Molecular Sequence Data
  • Models, Biological
  • Lysine
  • Hyperhomocysteinemia