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Antibody blockade or mutation of the fibrinogen gamma-chain C-terminus is more effective in inhibiting murine arterial thrombus formation than complete absence of fibrinogen.

Abstract
An elevated plasma fibrinogen level is a risk factor for thrombotic cardiovascular disease, but which of fibrinogen's functions is responsible for the increased risk is unknown. To define better the contribution of fibrinogen to large vessel thrombus formation, we studied carotid artery thrombosis in wild-type mice, mice lacking fibrinogen (fbg-/-), mice treated with 7E9 (a blocking antibody to the fibrinogen gamma-chain C-terminus), and mice expressing a mutant fibrinogen (gamma delta 5) that lacks the gamma-chain platelet-binding motif QADGV. In control mice, thrombus formation resulted in occlusion in 8 +/- 2 minutes (mean +/- SD). In fbg-/- mice, thrombi grew to large sizes, but then they abruptly embolized, confirming previous observations by others in an arteriolar thrombus model. In contrast, mice treated with 7E9 and gamma delta 5 mice developed only small, nonoclusive mural thrombi and embolization was limited. These findings reveal that a fibrinogen antibody, 7E9, or a fibrinogen mutant retaining clotting function, can limit thrombus formation more effectively than the complete absence of fibrinogen. We hypothesize that the smaller thrombi in these animals result from the ability of fibrin to bind and sequester thrombin and/or the ability of the altered fibrinogen molecules, which cannot recruit platelets, to bind to and passivate the surface.
AuthorsMarkéta Jirousková, Igor Chereshnev, Heikki Väänänen, Jay L Degen, Barry S Coller
JournalBlood (Blood) Vol. 103 Issue 6 Pg. 1995-2002 (Mar 15 2004) ISSN: 0006-4971 [Print] United States
PMID14644995 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Immunoglobulin G
  • Fibrinogen
Topics
  • Animals
  • Bleeding Time
  • Blood Cell Count
  • Carotid Artery Thrombosis (physiopathology, prevention & control)
  • Cricetinae
  • Female
  • Fibrinogen (genetics, immunology, metabolism)
  • Gene Expression
  • Immunoglobulin G (pharmacology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Platelet Aggregation (immunology)

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