title: Heparin-induced leukocytosis requires 6-O-sulfation and is caused by blockade of selectin- and CXCL12 protein-mediated leukocyte trafficking in mice.
abstract: Leukocytosis refers to an increase in leukocyte count above the normal range in the blood and is a common laboratory finding in patients. In many cases, the mechanisms underlying leukocytosis are not known. In this study, we examined the effects, the structural determinants, and the underlying mechanisms of heparin-induced leukocytosis, a side effect occurring in 0.44% of patients receiving heparin. We observed that heparin induced both lymphocytosis and neutrophilia, and the effects required heparin to be 6-O-sulfated but did not require its anticoagulant activity. Cell mobilization studies revealed that the lymphocytosis was attributable to a combination of blockage of lymphocyte homing and the release of thymocytes from the thymus, whereas the neutrophilia was caused primarily by neutrophil release from the bone marrow and demargination in the vasculature. Mechanistic studies revealed that heparin inhibits L- and P-selectin, as well as the chemokine CXCL12, leading to leukocytosis. Heparin is known to require 6-O-sulfate to inhibit L- and P-selectin function, and in this study we observed that 6-O-sulfate is required for its interaction with CXCL12. We conclude that heparin-induced leukocytosis requires glucosamine 6-O-sulfation and is caused by blockade of L-selectin-, P-selectin-, and CXCL12-mediated leukocyte trafficking.
authors.affiliation: Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Eduard
authors.initials: E
authors.lastname: Condac
authors.forename: Hong
authors.initials: H
authors.lastname: Qiu
authors.forename: Junlin
authors.initials: J
authors.lastname: Jiang
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gutierrez-Sanchez
authors.forename: Carl
authors.initials: C
authors.lastname: Bergmann
authors.forename: Tracy
authors.initials: T
authors.lastname: Handel
authors.forename: Lianchun
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005944:Glucosamine / Q000378:metabolism; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D036904:Leukocyte Rolling / Q000187:drug effects*; D007964:Leukocytosis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008218:Lymphocytosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019087:Selectins / Q000378:metabolism*; D013431:Sulfates / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D005944:Glucosamine; D006493:Heparin; D006497:Heparan Sulfate; D019087:Selectins; D013431:Sulfates