Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a "lupus procoagulant" phenomenon.
The antiphospholipid syndrome is a thrombophilic condition marked by antibodies that recognize anionic phospholipid-protein cofactor complexes. We recently reported that exposure to IgG fractions from antiphospholipid patients reduces the level of annexin-V, a phospholipid-binding anticoagulant protein, on cultured trophoblasts and endothelial cells and accelerates coagulation of plasma exposed to these cells. Therefore, we asked whether antiphospholipid antibodies might directly reduce annexin-V binding to noncellular phospholipid substrates. Using ellipsometry, we found that antiphospholipid IgGs reduce the quantity of annexin-V bound to phospholipid bilayers; this reduction is dependent on the presence of beta2-glycoprotein I. Also, exposure to plasmas containing antiphospholipid antibodies reduces annexin-V binding to phosphatidyl serine-coated microtiter plates, frozen thawed washed platelets, activated partial thromboplastin time (aPTT) reagent and prothrombin time reagent and reduces the anticoagulant effect of the protein. These studies show that antiphospholipid antibodies interfere with the binding of annexin-V to anionic phospholipid and with its anticoagulant activity. This acceleration of coagulation, due to reduced binding of annexin V, stands in marked contrast to the "lupus anticoagulant effect" previously described in these patients. These results are the first direct demonstration of the displacement of annexin-V and the consequent acceleration of coagulation on noncellular phospholipid surfaces by antiphospholipid antibodies.
Department of Medicine, the Divisions of Hematology and Thrombosis, and the Department of Biochemistry, Mount Sinai School of Medicine, New York, NY, USA. j_rand@smtplink.mssm.edu
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Rand
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Wu
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Andree
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Ross
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Rusinova
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Gascon-Lema
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Calandri
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Harpel
D017304:Annexin A5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017152:Antibodies, Antiphospholipid / Q000494:pharmacology*; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007202:Indicators and Reagents; D008051:Lipid Bilayers / Q000378:metabolism; D016682:Lupus Coagulation Inhibitor / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D010718:Phosphatidylserines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011517:Prothrombin Time; D013925:Thromboplastin / Q000378:metabolism
D017304:Annexin A5; D017152:Antibodies, Antiphospholipid; D005456:Fluorescent Dyes; D007074:Immunoglobulin G; D007202:Indicators and Reagents; D008051:Lipid Bilayers; D016682:Lupus Coagulation Inhibitor; D010718:Phosphatidylserines; D010743:Phospholipids; D013925:Thromboplastin; D016650:Fluorescein-5-isothiocyanate