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Normal levels of anticoagulant heparan sulfate are not essential for normal hemostasis
Sassan HajMohammadi, … , Robert D. Rosenberg, Nicholas W. Shworak
Sassan HajMohammadi, … , Robert D. Rosenberg, Nicholas W. Shworak
Published April 1, 2003
Citation Information: J Clin Invest. 2003;111(7):989-999. https://doi.org/10.1172/JCI15809.
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Article Hematology

Normal levels of anticoagulant heparan sulfate are not essential for normal hemostasis

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Abstract

Endothelial cell production of anticoagulant heparan sulfate (HSact) is controlled by the Hs3st1 gene, which encodes the rate-limiting enzyme heparan sulfate 3-O-sulfotransferase-1 (3-OST-1). In vitro, HSact dramatically enhances the neutralization of coagulation proteases by antithrombin. The in vivo role of HSact was evaluated by generating Hs3st1–/– knockout mice. Hs3st1–/– animals were devoid of 3-OST-1 enzyme activity in plasma and tissue extracts. Nulls showed dramatic reductions in tissue levels of HSact but maintained wild-type levels of tissue fibrin accumulation under both normoxic and hypoxic conditions. Given that vascular HSact predominantly occurs in the subendothelial matrix, mice were subjected to a carotid artery injury assay in which ferric chloride administration induces de-endothelialization and occlusive thrombosis. Hs3st1–/– and Hs3st1+/+ mice yielded indistinguishable occlusion times and comparable levels of thrombin•antithrombin complexes. Thus, Hs3st1–/– mice did not show an obvious procoagulant phenotype. Instead, Hs3st1–/– mice exhibited genetic background–specific lethality and intrauterine growth retardation, without evidence of a gross coagulopathy. Our results demonstrate that the 3-OST-1 enzyme produces the majority of tissue HSact. Surprisingly, this bulk of HSact is not essential for normal hemostasis in mice. Instead, 3-OST-1–deficient mice exhibited unanticipated phenotypes suggesting that HSact or additional 3-OST-1–derived structures may serve alternate biologic roles.

Authors

Sassan HajMohammadi, Keiichi Enjyoji, Marc Princivalle, Patricia Christi, Miroslav Lech, David Beeler, Helen Rayburn, John J. Schwartz, Samad Barzegar, Ariane I. de Agostini, Mark J. Post, Robert D. Rosenberg, Nicholas W. Shworak

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Figure 2

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Hs3st1 disruption reduces tissue HSact level but does not alter fibrin a...
Hs3st1 disruption reduces tissue HSact level but does not alter fibrin accumulation. (a) HSact content of HS purified from tissues was measured as in vitro anti-Xa activity, where HS containing AT-binding sites catalyzes AT neutralization of factor Xa. Inset shows the activity of tissue HS to catalyze HCII neutralization of T. Activities were calibrated to the USP units of a heparin standard; n = 3 littermates per group. (b) Tissue fibrin accumulation was determined by first preparing urea-insoluble extracts, which selectively enriches for cross-linked fibrin. Fibrin was quantified by Western blots probed with a mAb specific to the cleaved β-chain of fibrin II. Each group contained five young adult mice and five middle-aged mice (∼10 or ∼24 weeks of age, respectively) with no significant effect of age on fibrin accumulation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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