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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1629-1635.
Prepublished online as a Blood First Edition Paper on May 12, 2005; DOI 10.1182/blood-2005-01-0404.
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Submitted January 31, 2005
Accepted May 6, 2005
Inhibition of APC anticoagulant activity on oxidized phospholipid by anti- 2-glycoprotein I monoclonal antibodies
Omid Safa, Charles T Esmon, and Naomi L Esmon*
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Pathology, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA; Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center (OUHSC); Howard Hughes Medical Institute, Oklahoma City, OK, USA
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Pathology, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA
* Corresponding author; email: Naomi-Esmon{at}omrf.oushc.edu.
Activated protein C (APC) anticoagulant activity and the ability to be inhibited by autoantibodies associated with thrombosis are strongly augmented by the presence of phosphatidylethanolamine (PE) and phospholipid oxidation.  2-glycoprotein I (2-GPI) is a major antigen for antiphospholipid antibodies present in patients with the antiphospholipid syndrome. We therefore investigated whether anti-2-GPI monoclonal antibodies (mAbs) could inhibit APC with similar membrane specificity. Four mouse monoclonal antibodies which reacted with different epitopes on 2-GPI were examined. Each inhibited the PE, phospholipid oxidation dependent enhancement of APC anticoagulant activity. This inhibition required antibody divalency. A chimeric APC which retains anticoagulant activity but is relatively unaffected by the presence of protein S, PE or oxidation was not inhibited by the antibodies. In purified systems, anti-2-GPI mAb inhibition of factor Va inactivation was greater in the presence of protein S and required 2-GPI. Surprisingly, although the mAb did increase 2-GPI affinity for membranes, PE and oxidation had little influence on the affinity of the 2-GPI antibody complex for the membrane vesicles. We conclude these antibodies inhibit APC function specifically to lead to a hypercoaguable state by disrupting specific protein-protein interactions induced by oxidation of PE containing membranes.
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