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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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Categories: 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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