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Crit Care Med. 2002 Jan;30(1):218-25.

Antithrombin effects on endotoxin-induced microcirculatory disorders are mediated mainly by its interaction with microvascular endothelium.

Author information

1
Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.

Abstract

OBJECTIVE:

To investigate whether the protective effect of antithrombin III, which has been shown to exert beneficial effects during septic disorders, including reduction of endotoxin-associated leukocyte/endothelial cell interaction and capillary perfusion failure, is mainly based on its anticoagulant capacity or direct effects on the microvascular endothelium.

DESIGN:

Animal study with three treatment groups.

SETTING:

Animal research facility.

SUBJECTS:

Syrian golden hamsters, 6-8 wks old with a body weight of 60-80 g.

INTERVENTIONS:

In skinfold preparations of hamsters, normotensive endotoxemia was induced by intravenous administration of 2 mg/kg endotoxin (lipopolysaccharide, 2 mg/kg). Antithrombin III (n = 7 animals; 250 units/kg) or tryptophan49-blocked antithrombin III (n = 6; 250 units/kg) was substituted intravenously 5 mins before lipopolysaccharide administration. Saline-treated animals (n = 11), receiving only lipopolysaccharide, served as controls. Tryptophan49-blocked antithrombin III binds to glycosaminoglycans at the endothelial surface to a significantly lower extent while retaining its progressive anticoagulant effects.

MEASUREMENTS AND MAIN RESULTS:

Compared with controls, antithrombin III significantly reduced lipopolysaccharide-induced arteriolar and venular leukocyte adherence (p < .01) and prevented depression of functional capillary density (p < .01), whereas tryptophan49-blocked antithrombin III failed to significantly improve both variables. As measured in vivo by a monoclonal fluorescein isothiocyanate-labeled anti-antithrombin III antibody and intravital microscopy, the lack of effect of tryptophan49-blocked antithrombin III was associated with significantly lower antithrombin III/endothelium binding coefficients after 1 hr, 3 hrs, and 24 hrs of endotoxemia (p < .01).

CONCLUSIONS:

We conclude that specific antithrombin III interactions with cell-surface glycosaminoglycans on the endothelium rather than anticoagulant properties are the mechanism of antithrombin III-mediated attenuation of leukocyte/endothelial cell interaction and capillary perfusion failure.

PMID:
11902265
[Indexed for MEDLINE]

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