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Blood, 1 November 2004, Vol. 104, No. 9, pp. 2783-2790.
Prepublished online as a Blood First Edition Paper on July 8, 2004; DOI 10.1182/blood-2004-01-0203.
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Submitted January 20, 2004
Accepted June 21, 2004
Detection of Antibody-Mediated Reduction of Annexin A5 Anticoagulant Activity in Plasmas of Patients with the Antiphospholipid Syndrome
Jacob H Rand*, Xiao-Xuan Wu, Robert Lapinski, Waander L van Heerde, Chris P Reutelingsperger, Pojen P Chen, and Thomas L Ortel
Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY, USA
Central Hematology Laboratory, University Medical Center St Radboud, Nijmegen, The Netherlands
Department of Biochemistry, Cardiovascular Research Institute Maastricht, MAastricht University, Maastricht, The Netherlands
Division of Rheumatology, University of California at Los Angeles School of Medicine, Los Angeles, CA, USA
Department of Medicine and Pathology, Duke University Medical Center, Durham, NC, USA
* Corresponding author; email: jrand{at}montefiore.org.
ABSTRACT
Annexin A5 (A5) forms 2-dimensional crystals over phospholipid bilayers, blocking their availability for coagulation reactions. Recently, human antiphospholipid (aPL) mAbs have been demonstrated by atomic force microscopy (AFM) to disrupt this crystallization and accelerate coagulation. We therefore performed a study with small, well-defined groups of patients to investigate whether these effects on A5 binding and activity are also detectable in plasmas from patients with the aPL syndrome.
A5 binding to phospholipid was significantly reduced by plasmas of patients with aPL syndrome and thromboembolism compared to normal healthy controls (mean±SD: 26.7±4.3 ng/well, n=25 vs. 30.5±3.1 ng/well, n=20, p<0.01,) and the non-aPL thromboembolism group (29.9±3.2 ng/well, n=15, p<0.05). A5 anticoagulant activity was reduced by plasmas of patients with aPL syndrome and thromboembolism compared to aPL antibodies without thrombosis (182±31 %, n=25 vs. 210±35 %, n=26, p<0.01), non-aPL thromboembolism (229±16 %, n=15, p<0.001), and normal healthy controls (231±14 %, n=30, p<0.001).
In conclusion, in accordance with recent AFM data with monoclonal human aPL antibodies, plasmas from patients with aPL antibodies with thromboembolism reduce both A5 binding to phospholipid and A5 anticoagulant activity. This "annexin A5 resistance" identifies a novel mechanism for thrombosis in the aPL syndrome.
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