Antiphospholipid Syndrome (APS)

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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

Body

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 EXPAND ALL ON THIS PAGE

Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression

December 1, 2014
Wu YY, V Nguyen A, Wu XX, Loh M, Vu M, Zou Y, Liu Q, Guo P, Wang Y, Montgomery LL, Orlofsky A, Rand JH, Lin EY.

Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression

Am J Pathol. 2014 Dec;184(12):3359-75.

Wu YY, V Nguyen A, Wu XX, Loh M, Vu M, Zou Y, Liu Q, Guo P, Wang Y, Montgomery LL, Orlofsky A, Rand JH, Lin EY.

PMID: 25451155

Atomic force microscopy: High resolution dynamic imaging of cellular and molecular structure in health and disease.

October 1, 2013
Taatjes DJ, Quinn AS, Rand JH, Jena BP.

Atomic force microscopy: High resolution dynamic imaging of cellular and molecular structure in health and disease.

J Cell Physiol. 2013 Oct;228(10):1949-55.

Taatjes DJ, Quinn AS, Rand JH, Jena BP.

PMID: 23526453.

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

June 1, 2013
Wahezi DM, Ilowite NT, Wu XX, Pelkmans L, Laat B, Schanberg LE, Rand JH. Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators.

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

Current diagnostic and therapeutic approaches to patients with acquired von Willebrand syndrome: a 2013 update

March 1, 2013
Federici AB, Budde U, Castaman G, Rand JH, Tiede A.

Current diagnostic and therapeutic approaches to patients with acquired von Willebrand syndrome: a 2013 update

Semin Thromb Hemost. 2013 Mar;39(2):191-201.

Federici AB, Budde U, Castaman G, Rand JH, Tiede A.

PMID: 23397553

Viewing dynamic interactions of proteins and a model lipid membrane with atomic force microscopy.

January 1, 2013
Quinn AS, Rand JH, Wu XX, Taatjes DJ.

Viewing dynamic interactions of proteins and a model lipid membrane with atomic force microscopy.

Methods Mol Biol. 2013;931:259-93.

Quinn AS, Rand JH, Wu XX, Taatjes DJ.

PMID: 23027007.

Annexin A5 binds to lipopolysaccharide and reduces its endotoxin activity.

March 13, 2012
Rand JH, Wu XX, Lin EY, Griffel A, Gialanella P, McKitrick JC.

Annexin A5 binds to lipopolysaccharide and reduces its endotoxin activity.

MBio. 2012 Mar 13;3(2).

Rand JH, Wu XX, Lin EY, Griffel A, Gialanella P, McKitrick JC.

PMID: 22415004; PMCID: PMC3312215

Dos and don'ts in diagnosing antiphospholipid syndrome.

January 1, 2012
Rand JH, Wolgast LR.

Dos and don'ts in diagnosing antiphospholipid syndrome.

Hematology Am Soc Hematol Educ Program.2012;2012:455-9.

Rand JH, Wolgast LR.

PMID: 23233619

Resistance to annexin A5 anticoagulant activity in women with histories for obstetric antiphospholipid syndrome.

November 1, 2011
Hunt BJ, Wu XX, de Laat B, Arslan AA, Stuart-Smith S, Rand JH.

Resistance to annexin A5 anticoagulant activity in women with histories for obstetric antiphospholipid syndrome.

Am J Obstet Gynecol. 2011 Nov;205(5):485.e17-23.

Hunt BJ, Wu XX, de Laat B, Arslan AA, Stuart-Smith S, Rand JH.

PMID: 21784397; PMCID: PMC3205287

How I treat the acquired von Willebrand syndrome

June 23, 2011
Tiede A, Rand JH, Budde U, Ganser A, Federici AB.

How I treat the acquired von Willebrand syndrome

Blood. 2011 Jun 23;117(25):6777-85.

Tiede A, Rand JH, Budde U, Ganser A, Federici AB.

PMID: 21540459

Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug.

March 18, 2010
Rand JH, Wu XX, Quinn AS, Ashton AW, Chen PP, Hathcock JJ, Andree HA, Taatjes DJ

Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug.

Blood. 2010 Mar 18;115(11):2292-9. 

Rand JH, Wu XX, Quinn AS, Ashton AW, Chen PP, Hathcock JJ, Andree HA, Taatjes DJ. 

PMID: 19965621; PMCID: PMC2844013

Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers.

September 1, 2008
Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ.

Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers.

Blood. 2008 Sep 1;112(5):1687-95.

Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ.

PMID: 18577708; PMCID: PMC2518879

General Contact

Tashauna Holley
Assistant to Dr. Jacob Rand
Department of Pathology and Laboratory Medicine
Weill Cornell Medical College
525 E. 68th Street
New York, NY 10065
T: 212 -746-3505
F: 212-746-8855
tah9062@nyp.org

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