(Circulation. 1999;100:1533-1539.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Heparin Inhibits Ligand Binding to the Leukocyte Integrin Mac-1 (CD11b/CD18)
Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-242).
From the Departments of Internal Medicine III and Biometry (C.C.), University of Heidelberg, Germany.
Correspondence to Karlheinz Peter, MD, Innere Medizin III, Albert-Ludwigs-Universität Freiburg, Hugstetter Str 55, 79106 Freiburg, Germany. E-mail peter{at}mm31.ukl.uni-freiburg.de
Background—The clinical benefits
of heparin reach beyond its anticoagulative properties. Recently, it
has been described that leukocytes adhere on immobilized
heparin mediated by the integrin Mac-1 (CD11b/CD18,
Mß2, or CR3). Because inhibition of this
versatile adhesion molecule could explain various aspects of the
beneficial clinical effects of heparin, we evaluated whether soluble
heparin modulates Mac-1 function in vitro and in vivo.
Methods and Results—Binding of unfractionated heparin to Mac-1 on PMA-stimulated monocytes and granulocytes was directly demonstrated in flow cytometry, whereas no binding of heparin was detected on unstimulated leukocytes. Unfractionated heparin inhibited binding of the soluble ligands fibrinogen, factor X, and iC3b to Mac-1. Adhesion of the monocytic cell line THP-1 and of peripheral monocytes and granulocytes to immobilized ICAM-1 was impaired by unfractionated heparin, to the same extent as with inhibition of Mac-1 by monoclonal antibodies such as c7E3. Low-molecular-weight heparin also inhibits binding of fibrinogen to Mac-1. Additionally, flow cytometry of whole blood preparations of patients treated with unfractionated heparin revealed an inhibitory effect of heparin on the binding of fibrinogen to Mac-1 that correlates (n= 48, r=0.63, P<0.001) to the extent of prolongation of the activated partial thromboplastin time.
Conclusions—We describe a pharmacologically relevant property of heparin that may contribute to its benefits in clinical use. The binding of heparin to Mac-1 and the resulting inhibition in binding of Mac-1 ligands may directly modulate coagulation, inflammation, and cell proliferation.
Key Words: heparin • cell adhesion molecules • leukocytes • fibrinogen
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