Pathophysiologic mechanisms in thrombosis and hemostasis

The primary interest of our laboratory is the investigation of the effects of antiphospholipid (aPL) antibodies on an anticoagulant protein, annexin A5 (previously known as annexin V). The antiphospholipid (aPL) syndrome is an enigmatic autoimmune disorder that is characterized by thrombosis and/or recurrent spontaneous pregnancy losses that occur in patients who have evidence for antibodies against phospholipid-binding proteins.

Annexin A5 (A5) is a phospholipid-binding protein with potent anticoagulant properties that are a consequence of its forming 2-dimensional crystals over membranes containing anionic phospholipids. A5 is highly expressed by cells with barrier functions, including endothelial cells and placental trophoblasts. It is presumed to play a thrombomodulatory role on the apical surfaces of placental syncytiotrophoblasts and on endothelial cells.

We were the first to propose and demonstrate that aPL antibodies disrupt the annexin A5 anticoagulant shield on artificial bilayers and on cell membranes. Our current projects in this area include:

1. Investigation of the effects of aPL antibodies on vascular and placental cells
2. Characterization of the effects of aPL antibodies and cofactors on AnxA5 crystallization over phospholipid bilayers with binding studies, coagulation studies and, in collaboration with the Imaginig Facility at the University of Vermont, with atomic force imaging
3. Characterization of the role of ß2-glycoprotein I in the aPL-mediated disruption of annexin A5
4. Development of translational tests for “AnxA5 resistance”
5. Development of novel treatments for the aPL syndrome that protect the AnxA5 bilayer from disruption

Additional research interests include:

1. The development, in collaboration with Prof. Augusto Federici of Milan, of a web-based registry for the acquired von Willebrand syndrome (AVWS) (intreavws.com)
2. The localization of vWF in vascular subendothelium and the biochemical and functional characterization of type VI collagen as a major binding site for the protein

Most Significant Research Contributions

• Discovery that von Willebrand Factor is an extracellular matrix protein present in vascular subendothelium where it is bound to  type VI collagen. Morphologic and functional characterization of the von Willebrand factor-type VI collagen complex.
• Proposal and evidence that annexin A5 plays a thrombomodulatory role in the placental circulation.
• Discovery of the "Disruption of the Annexin A5 Anticoagulant Crystal Shield" concept as a mechanism of thrombosis and pregnancy loss in the antiphospholipid syndrome.
• Proposal of genetic and acquired "Annexinopathies" as a new class of diseases.
• Contribution toward the development of, a web-based International Registry for the Acquired von Willebrand Syndrome, sponsored by the Scientific Standardization Committee of the International Society of Thrombosis and Haemostasis.
• Inventor of US Patent #6284475 and #7252959, "Assys for Diagnosis of Thrombophilic Disease" assigned to Mount Sinai School of Medicine

Awards

• 2006, Moses Research Award, Montefiore Medical Center
• 2004, Visiting Professor - Coney Island Hospital
• 2003, Visiting Professor and John Edson Lecturer, Long Island College Hospital
• 1999, Tisdale Lecturer - Department of Medicine, University of Vermont College of Medicine
• 1998, Newman Research Fellowship - Mount Sinai School of Medicine
• 1998, Lipsey Memorial Lecturer - Cornell University Medical College
• 1997, Martin C. Rosenthal Visiting Professor - Mount Sinai School of Medicine

1. Rand JH, Wu XX. Antibody-mediated interference with annexins in the antiphospholipid syndrome. Thromb Res. 2004;114(5-6):383-9
2. Wu XX, Pierangeli SS, Rand JH Resistance to annexin A5 binding and anticoagulant activity in plasmas from patients with the antiphospholipid syndrome but not with syphilis. J Thromb Haemost. 2006 Jan;4(1):271-3.
3. Rand JH, Arslan AA, Wu XX, Wein R, Mulholland J, Shah M, van Heerde WL, Reduction of circulating annexin A5 levels and resistance to annexin A5 anticoagulant activity in women with recurrent spontaneous pregnancy losses Am J Obstet Gynecol. 2006 Jan;194(1):182-8.
4. Rand JH, Wu XX, Lapinski R, van Heerde WL, Reutelingsperger CP, Chen PP, Ortel TL. Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome. Blood. 2004 Nov 1;104(9):2783-90. Epub 2004 Jul 8.
5. Federici AB, Budde U, Rand JH. Acquired von Willebrand syndrome 2004: International Registry--diagnosis and management from online to bedside. Hamostaseologie. 2004 Feb;24(1):50-5.
6. Warkentin TE, Aird WC, Rand JH. Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology (Am Soc Hematol Educ Program). 2003;:497-519.