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(Circulation. 1999;99:1997-2002.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Antiphospholipid Antibodies From Antiphospholipid Syndrome Patients Activate Endothelial Cells In Vitro and In Vivo
From the Department of Microbiology and Immunology, Antiphospholipid Standardization Laboratory (S.S.P.), the Department of Physiology (M.C.-S., X.L.), and the Department of Internal Medicine, Office of the Dean (E.N.H.), Morehouse School of Medicine, Atlanta, Ga; and the Department of Surgery (J.H.B.) and Department of Physiology (G.L.A.), University of Louisville, Louisville, Ky.
Correspondence to Silvia S. Pierangeli, PhD, Associate Professor, Department of Microbiology and Immunology, Room 1236, Morehouse School of Medicine, 720 Westview Dr, SW, Atlanta, GA 30310-1495. E-mail pierans{at}msm.edu
Background—Antiphospholipid (aPL) antibodies are associated with thrombosis in patients diagnosed with antiphospholipid syndrome (APS) and enhance thrombus formation in vivo in mice, but the mechanism of thrombosis by aPL is not completely understood. Although aPL antibodies have been shown to inhibit protein C activation and activate endothelial cells (ECs) in vitro, no study has examined whether these antibodies activate ECs in vivo. Therefore, human affinity-purified aPL (ap aPL) antibodies from APS patients were tested in a mouse model of microcirculation using the cremaster muscle that allows direct microscopic examination of thrombus formation and adhesion of white blood cells (WBCs) to ECs as an indication of EC activation in vivo. Adhesion molecule expression on human umbilical vein endothelial cells (HUVECs) after aPL exposure was performed to confirm EC activation in vitro.
Methods and Results—All 6 ap aPL antibodies significantly increased the expression of VCAM-1 (2.3- to 4.4-fold), with one of the antibodies also increasing the expression of E-selectin (1.6-fold) on HUVECs in vitro. In the in vivo experiments, each ap aPL antibody except for 1 preparation increased WBC sticking (mean number of WBCs ranged from 22.7 to 50.6) compared with control (14.4), which correlated with enhanced thrombus formation (mean thrombus size ranged from 1098 to 6476 versus 594 µm2 for control).
Conclusions—Activation of ECs by aPL antibodies in vivo may create a prothrombotic state on ECs, which may be the first pathophysiological event of thrombosis in APS.
Key Words: antiphospholipid antibodies • thrombosis • endothelial cells • cell adhesion molecules
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