Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Citations to this article

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.
View: Text | PDF
Article Hematology Article has an altmetric score of 6

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

  • Text
  • PDF
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

×

Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 Total
Citations: 2 4 2 4 1 3 1 3 3 3 4 3 4 5 6 2 1 3 1 2 2 3 1 1 64
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article (64)

Title and authors Publication Year
Alveolar glycocalyces during health and critical illness
Yang Y, Schmidt EP
Proteoglycan research 2025
The interaction between antithrombin and endothelial heparan sulfate mitigates pulmonary thromboinflammation after trauma and hemorrhagic shock
del Pilar Huby Vidaurre M, Mokhtari AK, Osborn BK, Cotton BA, Wang YW, Xu Y, Arnold K, Liu J, Richter JR, Cardenas JC
Shock (Augusta, Ga.) 2025
Trauma promotes heparan sulfate modifications and cleavage that disrupt homeostatic gene expression in microvascular endothelial cells
Richter RP, Odum JD, Margaroli C, Cardenas JC, Zheng L, Tripathi K, Wang Z, Arnold K, Sanderson RD, Liu J, Richter JR
Frontiers in Cell and Developmental Biology 2024
Epigenetic Targeting of Heparan Sulfate 3-O- and 6-O-Sulfation in Breast Cancer Cells: Prospects for Attenuating Prothrombotic Tumor Cell Activities
Bückreiß N, Schulz-Fincke M, König P, Maccarana M, van Kuppevelt TH, Li JP, Götte M, Bendas G
2024
The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis.
Swart M, Redpath AN, Ogbechi J, Cardenas R, Topping L, Compeer EB, Goddard M, Chanalaris A, Williams R, Brewer DS, Smart N, Monaco C, Troeberg L
Cellular and molecular life sciences : CMLS 2024
Physiological significance of antithrombin D-helix interaction with vascular GAGs
Biswas I, Panicker SR, Lupu F, Rezaie AR
Blood Advances 2024
A 3-O-sulfated heparan sulfate dodecasaccharide (12-mer) suppresses thromboinflammation and attenuates early organ injury following trauma and hemorrhagic shock
Vidaurre MD, Osborn BK, Lowak KD, McDonald MM, Wang YW, Pa V, Richter JR, Xu Y, Arnold K, Liu J, Cardenas JC
Frontiers in immunology 2023
Increased 3-O-sulfated heparan sulfate in Alzheimer’s disease brain is associated with genetic risk gene HS3ST1
Wang Z, Patel VN, Song X, Xu Y, Kaminski AM, Doan VU, Su G, Liao Y, Mah D, Zhang F, Pagadala V, Wang C, Pedersen LC, Wang L, Hoffman MP, Gearing M, Liu J
Science Advances 2023
Physiology and Pathophysiology of Heparan Sulfate in Animal Models: Its Biosynthesis and Degradation
R Mashima, T Okuyama, M Ohira
International journal of molecular sciences 2022
Antithrombin protects against Plasmodium falciparum histidine-rich protein II-mediated inflammation and coagulation.
Biswas I, Panicker SR, Giri H, Cai XS, Rezaie AR
Blood Advances 2022
N-Acetylcysteine and Other Sulfur-Donors as a Preventative and Adjunct Therapy for COVID-19.
du Preez HN, Aldous C, Kruger HG, Johnson L
2022
Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function
Pretorius D, Richter RP, Anand T, Cardenas JC, Richter JR
2022
Loss of Hs3st3a1 or Hs3st3b1 enzymes alters heparan sulfate to reduce epithelial morphogenesis and adult salivary gland function.
Patel VN, Pineda DL, Berenstein E, Hauser BR, Choi S, Prochazkova M, Zheng C, Goldsmith CM, van Kuppevelt TH, Kulkarni A, Song Y, Linhardt RJ, Chibly AM, Hoffman MP
Matrix biology : journal of the International Society for Matrix Biology 2021
Transdifferentiation of tumor infiltrating innate lymphoid cells during progression of colorectal cancer
S Wang, Y Qu, P Xia, Y Chen, X Zhu, J Zhang, G Wang, Y Tian, J Ying, Z Fan
Cell Research 2020
The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives
N Veraldi, N Zouggari, A de Agostini
Molecules (Basel, Switzerland) 2020
Anticoagulant and signaling functions of antithrombin
Rezaie AR, Giri H
Journal of Thrombosis and Haemostasis 2020
Antithrombin: An anticoagulant, anti‐inflammatory and antibacterial serpin
AR Rezaie, H Giri
Journal of Thrombosis and Haemostasis 2019
Expression and functional characterization of two natural heparin-binding site variants of antithrombin
P Dinarvand, L Yang, BO Villoutreix, AR Rezaie
Journal of Thrombosis and Haemostasis 2018
The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis
PL Gordts, JD Esko
Matrix biology : journal of the International Society for Matrix Biology 2018
The Role of Heparan Sulfate in Inflammation, and the Development of Biomimetics as Anti-Inflammatory Strategies
BL Farrugia, M S., J Melrose, JM Whitelock
Journal of Histochemistry & Cytochemistry 2018
HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis
NC Smits, T Kobayashi, PK Srivastava, S Skopelja, JA Ivy, DJ Elwood, RV Stan, GJ Tsongalis, FW Sellke, PL Gross, MD Cole, JT DeVries, AV Kaplan, JF Robb, SM Williams, NW Shworak
Matrix Biology 2017
More than a biomarker: the systemic consequences of heparan sulfate fragments released during endothelial surface layer degradation (2017 Grover Conference Series)
K Oshima, SM Haeger, JA Hippensteel, PS Herson, EP Schmidt
Pulmonary circulation 2017
Synthesis of 3- O -Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate
Z Wang, PH Hsieh, Y Xu, D Thieker, EJ Chai, S Xie, B Cooley, RJ Woods, L Chi, J Liu
Journal of the American Chemical Society 2017
The role of heparan sulphate in development: the ectodermal story
VJ Coulson-Thomas
International Journal of Experimental Pathology 2016
Expanding the 3- O -Sulfate Proteome—Enhanced Binding of Neuropilin-1 to 3- O -Sulfated Heparan Sulfate Modulates Its Activity
BE Thacker, E Seamen, R Lawrence, MW Parker, Y Xu, J Liu, CW Kooi, JD Esko
ACS chemical biology 2016
What Have We Learned from Glycosyltransferase Knockouts in Mice?
P Stanley
Journal of Molecular Biology 2016
High-resolution probing heparan sulfate–antithrombin interaction on a single endothelial cell surface: single-molecule AFM studies
C Guo, X Fan, H Qiu, W Xiao, L Wang, B Xu
Physical Chemistry Chemical Physics 2015
Expression and Characterization of Gly-317 Variants of Factor IX Causing Variable Bleeding in Hemophilia B Patients
Q Lu, L Yang, C Manithody, X Wang, AR Rezaie
Biochemistry 2015
Can We Produce Heparin/Heparan Sulfate Biomimetics Using “Mother-Nature” as the Gold Standard?
B Farrugia, M Lord, J Melrose, J Whitelock
Molecules (Basel, Switzerland) 2015
Heparan sulfate proteoglycans: a sugar code for vertebrate development?
FE Poulain, HJ Yost
Development (Cambridge, England) 2015
Hs3st3-Modified Heparan Sulfate Controls KIT+ Progenitor Expansion by Regulating 3-O-Sulfotransferases
VN Patel, IM Lombaert, SN Cowherd, NW Shworak, Y Xu, J Liu, MP Hoffman
Developmental Cell 2014
Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan
S Mizumoto, S Yamada, K Sugahara
BioMed Research International 2014
Neurotrophic tyrosine kinase receptor 1 is a direct transcriptional and epigenetic target of IL-13 involved in allergic inflammation
M Rochman, AV Kartashov, JM Caldwell, MH Collins, EM Stucke, K KC, JD Sherrill, J Herren, A Barski, ME Rothenberg
Mucosal Immunology 2014
Immobilization of Actively Thromboresistant Assemblies on Sterile Blood-Contacting Surfaces
Z Qu, V Krishnamurthy, CA Haller, BM Dorr, UM Marzec, S Hurst, MT Hinds, SR Hanson, DR Liu, EL Chaikof
Advanced Healthcare Materials 2013
Heparan sulfate 3-O-sulfation: A rare modification in search of a function
BE Thacker, D Xu, R Lawrence, JD Esko
Matrix Biology 2013
Differential roles for 3-OSTs in the regulation of cilia length and motility
JM Neugebauer, AB Cadwallader, JD Amack, BW Bisgrove, HJ Yost
Development (Cambridge, England) 2013
Distinct 3- O -Sulfated Heparan Sulfate Modification Patterns Are Required for kal-1 −Dependent Neurite Branching in a Context-Dependent Manner in Caenorhabditis elegans
E Tecle, CA Diaz-Balzac, HE Bülow
G3: Genes|Genomes|Genetics 2013
Heparan sulfate 6-O-sulfotransferase isoform-dependent regulatory effects of heparin on the activities of various proteases in mast cells and the biosynthesis of 6-O-sulfated heparin
MF Anower-E-Khuda, H Habuchi, N Nagai, O Habuchi, T Yokochi, K Kimata
The Journal of biological chemistry 2012
N-sulfation of heparan sulfate regulates early branching events in the developing mammary gland
KT Bush, BE Crawford, OB Garner, KB Nigam, JD Esko, SK Nigam
The Journal of biological chemistry 2012
Heparan Sulfate Biosynthesis: Regulation and Variability
J Kreuger, L Kjellén
Journal of Histochemistry & Cytochemistry 2012
Heparanase Regulates Thrombosis in Vascular Injury and Stent-Induced Flow Disturbance
AB Baker, WJ Gibson, VB Kolachalama, M Golomb, L Indolfi, C Spruell, E Zcharia, I Vlodavsky, ER Edelman
Journal of the American College of Cardiology 2012
A synthetic heparan sulfate oligosaccharide library reveals the novel enzymatic action of d -glucosaminyl 3-O-sulfotransferase-3a
TK Nguyen, S Arungundram, VM Tran, K Raman, K Al-Mafraji, A Venot, GJ Boons, B Kuberan
Molecular BioSystems 2012
Heparan sulfate proteoglycans
S Sarrazin, WC Lamanna, JD Esko
Cold Spring Harbor perspectives in biology 2011
Stage-Dependent Regulation of Mammary Ductal Branching by Heparan Sulfate and HGF-cMet Signaling
OB Garner, KT Bush, KB Nigam, Y Yamaguchi, D Xu, JD Esko, SK Nigam
Developmental Biology 2011
Growth factor-dependent branching of the ureteric bud is modulated by selective 6-O sulfation of heparan sulfate
MM Shah, H Sakurai, TF Gallegos, DE Sweeney, KT Bush, JD Esko, SK Nigam
Developmental Biology 2011
Engineering of routes to heparin and related polysaccharides
U Bhaskar, E Sterner, AM Hickey, A Onishi, F Zhang, JS Dordick, RJ Linhardt
Applied Microbiology and Biotechnology 2011
Vascular Smooth Muscle Jak2 Deletion Prevents Angiotensin II-mediated Neointima Formation Following Injury in Mice
A Kirabo, SP Oh, H Kasahara, KU Wagner, PP Sayeski
Journal of Molecular and Cellular Cardiology 2011
Heparin Is a Major Activator of the Anticoagulant Serpin, Protein Z-dependent Protease Inhibitor*
X Huang, AR Rezaie, GJ Broze, ST Olson
The Journal of biological chemistry 2011
Biology of the adult hepatic progenitor cell: "ghosts in the machine"
H Darwiche, BE Petersen
Progress in molecular biology and translational science 2010
Screening for Anticoagulant Heparan Sulfate Octasaccharides and Fine Structure Characterization Using Tandem Mass Spectrometry
H Naimy, N Leymarie, J Zaia
Biochemistry 2010
The signature 3-O-sulfo group of the anticoagulant heparin sequence is critical for heparin binding to antithrombin but is not required for allosteric activation
B Richard, R Swanson, ST Olson
The Journal of biological chemistry 2009
Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II
L He, TK Giri, CP Vicente, DM Tollefsen
Blood 2008
Tetrasulfated disaccharide unit in heparan sulfate: enzymatic formation and tissue distribution
H Mochizuki, K Yoshida, Y Shibata, K Kimata
The Journal of biological chemistry 2008
Human follicular fluid heparan sulfate contains abundant 3-O-sulfated chains with anticoagulant activity
AI de Agostini, JC Dong, CV Arrighi, MA Ramus, I Dentand-Quadri, S Thalmann, P Ventura, V Ibecheole, F Monge, AM Fischer, S HajMohammadi, NW Shworak, L Zhang, Z Zhang, RJ Linhardt
The Journal of biological chemistry 2008
The principal neuronal gD-type 3-O-sulfotransferases and their products in central and peripheral nervous system tissues
R Lawrence, T Yabe, S Hajmohammadi, J Rhodes, M McNeely, J Liu, ED Lamperti, PA Toselli, M Lech, PG Spear, RD Rosenberg, NW Shworak
Matrix biology : journal of the International Society for Matrix Biology 2007
Isolation and characterization of heparan sulfate from various murine tissues
M Warda, T Toida, F Zhang, P Sun, E Munoz, J Xie, RJ Linhardt
Glycoconjugate Journal 2006
Specific and flexible roles of heparan sulfate modifications in Drosophila FGF signaling
K Kamimura, T Koyama, H Habuchi, R Ueda, M Masu, K Kimata, H Nakato
The Journal of Cell Biology 2006
Modification degrees at specific sites on heparan sulphate: an approach to measure chemical modifications on biological molecules with stable isotope labelling
ZL Wu, M Lech
Biochemical Journal 2005
Systemic coagulation parameters in mice after treatment with vascular targeting agents
M Unruh, A Grunow, C Gottstein
Thrombosis Journal 2005
Sulfation pattern in glycosaminoglycan: Does it have a code?
H Habuchi, O Habuchi, K Kimata
Glycoconjugate Journal 2004
Regulation of Notch signaling by Drosophila heparan sulfate 3-O sulfotransferase
K Kamimura, JM Rhodes, R Ueda, M McNeely, D Shukla, K Kimata, PG Spear, NW Shworak, H Nakato
The Journal of Cell Biology 2004
Heparin-Binding Domains in Vascular Biology
EM Muñoz, RJ Linhardt
Arteriosclerosis, thrombosis, and vascular biology 2004
Heparan sulfate: Antithrombotic or not?
JI Weitz
Journal of Clinical Investigation 2003
Mice deficient in heparan sulfate 3-O-sulfotransferase-1: normal hemostasis with unexpected perinatal phenotypes.
Shworak NW, HajMohammadi S, de Agostini AI, Rosenberg RD
Glycoconjugate Journal 2002

← Previous 1 2 3 Next →

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 2 patents
13 readers on Mendeley
See more details