Title | The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Rand JH, Wu X-X, Quinn AS, Taatjes DJ |
Journal | Lupus |
Volume | 19 |
Issue | 4 |
Pagination | 460-9 |
Date Published | 2010 Apr |
ISSN | 1477-0962 |
Keywords | Abortion, Habitual, Animals, Annexin A5, Antibodies, Antiphospholipid, Antiphospholipid Syndrome, beta 2-Glycoprotein I, Blood Coagulation, Female, Humans, Lipid Bilayers, Phospholipids, Pregnancy, Pregnancy Complications, Thrombosis |
Abstract | Annexin A5 (AnxA5) binds to phospholipid bilayers, forming two-dimensional crystals that block the phospholipids from availability for coagulation enzyme reactions. Antiphospholipid (aPL) antibodies cause gaps in the ordered crystallization of AnxA5 which expose phospholipids and thereby accelerate blood coagulation reactions. The aPL antibody-mediated disruption of AnxA5 crystallization has been confirmed on artificial phospholipid bilayers and on cell membranes including endothelial cells, placental trophoblasts and platelets. Recently, we reported that hydroxychloroquine, a synthetic antimalarial drug, can reverse this antibody-mediated process through two mechanisms: (1) by inhibiting the formation of aPL IgG-beta2glycoprotein I complexes; and (2) by promoting the formation of a second layer of AnxA5 crystal 'patches' over areas where the immune complexes had disrupted AnxA5 crystallization. In another translational application, we have developed a mechanistic assay that reports resistance to AnxA5 anticoagulant activity in plasmas of patients with aPL antibodies. AnxA5 resistance may identify a subset of aPL syndrome patients for whom this is a mechanism for pregnancy losses and thrombosis. The elucidation of aPL-mediated mechanisms for thrombosis and pregnancy complications may open new paths towards addressing this disorder with targeted treatments and mechanistic assays. |
DOI | 10.1177/0961203310361485 |
Alternate Journal | Lupus |
PubMed ID | 20353989 |
Grant List | R01 HL061331 / HL / NHLBI NIH HHS / United States R01 HL096944 / HL / NHLBI NIH HHS / United States RC1 HL101031 / HL / NHLBI NIH HHS / United States |
Related Faculty:
Jacob H. Rand, M.D.