Pathology & Laboratory Medicine

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Antiphospholipid Syndrome (APS) Research Laboratory

Jacob H. Rand, MD, Principal Investigator

The antiphospholipid (aPL) syndrome (APS) is an enigmatic autoimmune thrombophilic disorder that can manifest as vascular thrombosis and/or pregnancy complications and losses. The cause of the condition has not been established. Current diagnosis is based primarily on coagulation tests that paradoxically report an in vitro anticoagulant effect in the patients’ plasmas (the “lupus anticoagulant” phenomenon), and on immunoassays for aPL autoantibodies. The condition is currently treated with anticoagulants – a treatment that carries an inherent risk of bleeding complications.

The major research interest of our laboratory is the investigation of pathogenic mechanisms in APS with an eye toward translating these into innovative diagnostic assays and to develop targeted treatments for the disorder. We were the first to propose and demonstrate that aPL antibodies disrupt a 2-dimensional anticoagulant crystal shield composed of annexin A5 that forms over phospholipid bilayers and thereby promote a procoagulant effect. This knowledge was translated into clinical tests, named “the annexin A5 resistance assays” that identifies a subset of APS patients with this mechanism. We have also demonstrated that the synthetic antimalarial drug, hydroxychloroquine (HCQ) is able to disintegrate aPL immune complexes and restore “patches” on the previously disrupted annexin A5 shield.

APS ACTION!, the international network of APS centers, is currently performing a prospective randomized controlled clinical trial to determine whether HCQ can be effective to prevent a first thrombotic event in a cohort of aPL-positive patients.

Active Projects

  • Novel biomarkers for mechanistic diagnosis of aPL syndrome
  • Investigation of the effects of aPL antibodies on vascular and placental cells
  • Imaging of the effects of aPL antibodies and cofactors on Annexin A5 crystallization over phospholipid bilayers with binding studies, coagulation studies, and, in collaboration with the imaging facility at the University of Vermont, through atomic force microscopy and super-resolution fluorescence microscopy
  • Characterization of the role of β2-glocoprotein I and other cofactors in the APS disease process
  • Development of novel translational tests for APS
  • Development of novel nonanticoagulant targeted treatments for APS

Selected Publications

Annexin A5 anticoagulant activity in children with systemic lupus erythematosus and the association with antibodies to domain I of β2-glycoprotein I.

Xiao-Xuan Wu, MD

Annexin A5 anticoagulant activity in children with systemic lupus erythematosus and the association with antibodies to domain I of β2-glycoprotein I.

Lupus. 2013 Jun;22(7):702-11.

Wahezi DM, Ilowite NT, Wu XX, Pelkmans L, Laat B, Schanberg LE, Rand JH. Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators.

PMID: 23690366; PMCID: PMC4138827

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