We recently discovered a thrombogenic mechanism for pregnancy loss in the antiphospholipid antibody syndrome that antiphospholipid antibodies displace the placental anticoagulant protein, annexin-V, from the anionic phospholipid surfaces of trophoblasts and accelerate coagulation reactions at that site. The core hypotheses of this grant are: a) Annexin-V serves a thromboregulatory role at the anatomic site where maternal blood and placental villi interface by shielding anionic phospholipids (which markedly accelerate coagulation enzyme reactions) from participation in coagulation reactions and; b) antiphospholipid antibodies competitively displace annexin-V from that phospholipid surface, disrupting the annexin-V """"""""shield"""""""", thereby increasing the exposure of the thrombogenic anionic phospholipid. This process leads to thrombosis in the maternal circulation at the sites of interface with fetal trophoblasts and to ultimately to pregnancy complications and losses and determine their clinical efficacy.
Our specific aims are: 1) To determine the mechanism(s) by which antiphospholipid antibodies and cofactors reduce the quantity of annexin-V on trophoblast apical membrane and accelerate coagulation reactions and 2) To develop tests for the reduction of annexin-V binding to phospholipids and the inhibition of annexin-V anticoagulant activity. This innovative project opens a new path toward elucidating the mechanism of pregnancy loss in the antiphospholipid syndrome and is likely to lead to improved diagnosis and treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061331-02
Application #
6184887
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1999-08-01
Project End
2003-07-31
Budget Start
2000-08-15
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$447,339
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Bezati, E; Wu, X-X; Quinn, A S et al. (2015) A new trick for an ancient drug: quinine dissociates antiphospholipid immune complexes. Lupus 24:32-41
Taatjes, Douglas J; Quinn, Anthony S; Rand, Jacob H et al. (2013) Atomic force microscopy: High resolution dynamic imaging of cellular and molecular structure in health and disease. J Cell Physiol 228:1949-55
Wahezi, D M; Ilowite, N T; Wu, X X et al. (2013) Annexin A5 anticoagulant activity in children with systemic lupus erythematosus and the association with antibodies to domain I of ?2-glycoprotein I. Lupus 22:702-11
Quinn, Anthony S; Wu, Xiao-Xuan; Rand, Jacob H et al. (2012) Insights into the pathophysiology of the antiphospholipid syndrome provided by atomic force microscopy. Micron 43:851-62
Rand, Jacob H; Wu, Xiao-Xuan; Lin, Elaine Y et al. (2012) Annexin A5 binds to lipopolysaccharide and reduces its endotoxin activity. MBio 3:
Wahezi, Dawn M; Ilowite, Norman T; Rajpathak, Swapnil et al. (2012) Prevalence of annexin A5 resistance in children and adolescents with rheumatic diseases. J Rheumatol 39:382-8
Wu, Xiao-Xuan; Guller, Seth; Rand, Jacob H (2011) Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol 205:576.e7-14
Hunt, Beverley J; Wu, Xiao-Xuan; de Laat, Bas et al. (2011) Resistance to annexin A5 anticoagulant activity in women with histories for obstetric antiphospholipid syndrome. Am J Obstet Gynecol 205:485.e17-23
Bertolaccini, M L; Amengual, O; Atsumi, T et al. (2011) 'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010. Lupus 20:191-205
Rand, J H; Wu, X-X; Quinn, A S et al. (2010) The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis. Lupus 19:460-9

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