Heparin inhibits ligand binding to the leukocyte integrin Mac-1 (CD11b/CD18)

Background-The clinical benefits of heparin reach beyond its anticoagulativ e properties. Recently, it has been described that leukocytes adhere on imm obilized heparin mediated by the integrin Mac-1 (CD11b/CD18, alpha(M)beta(2 ), or CR3). Because inhibition of this versatile adhesion molecule could ex plain various aspects of the beneficial clinical effects of heparin, we eva luated whether soluble heparin modulates Mac-1 function in vitro and in viv o. Methods and Results-Binding of unfractionated heparin to Mac-1 on PMA-stimu lated monocytes and granulocytes was directly demonstrated in flow cytometr y, whereas no binding of heparin was detected on unstimulated leukocytes. U nfractionated 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 in hibits binding of fibrinogen to Mac-1. Additionally, flow cytometry of whol e blood preparations of patients treated with unfractionated heparin reveal ed an inhibitory effect of heparin on the binding of fibrinogen to Mac-1 th at correlates (n = 48, r = 0.63, P < 0.001) to the extent of prolongation o f the activated partial thromboplastin time. Conclusions-We describe a pharmacologically relevant property of heparin th at may contribute to its benefits in clinical use. The binding of heparin t o Mac-1 and the resulting inhibition in binding of Mac-1 ligands may direct ly modulate coagulation, inflammation, and cell proliferation.