NIH VideoCast - From the Rivers of Babylon to the Coronary Blood Stream

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From the Rivers of Babylon to the Coronary Blood Stream

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Air date:	Wednesday, November 7, 2007, 3:00:00 PM Time displayed is Eastern Time, Washington DC Local
Views:	Total views: 132 * This only includes stats from October 2011 and forward.
Category:	WALS - Wednesday Afternoon Lectures
Runtime:	01:05:05
Closed captioning:	Check box to display CC outside of the video Note: You can drag the captioning window around and resize it
Description:	Patients with the rare platelet disorder, Glanzmann thrombasthenia, have a lifelong bleeding disorder characterized primarily as excessive mucocutaneous hemorrhage, including easy bruising, gum bleeding, heavy menstrual periods, bleeding with surgery and childbirth, and intermittent gastrointestinal bleeding. Studies of their platelets identified a profound defect in the ability of their platelets to aggregate one with another due to deficiencies or abnormalities in the integrin AlphaIIbBeta3 (GPIIb/IIIa) receptor. This receptor is the prime mediator of platelet aggregation. When platelets are activated, the receptor undergoes conformational changes that result in it being able to bind multivalent plasma ligands, including fibrinogen and von Willebrand factor, that crosslink platelets into aggregates. Monoclonal antibodies to the receptor are able to block ligand binding and thus prevent platelet aggregation. Our lab produced some of the first monoclonal antibodies to the receptor and used them to help diagnose the disorder. We later went on to develop a mouse/human chimeric Fab fragment derivative of one of the antibodies (7E3) into the drug abciximab in conjunction with the scientists at Centocor. Abciximab was approved for human use in 1994 to prevent ischemic complications of percutaneous coronary interventions in patients at high risk of developing such complications and has now been administered to more than 2 million people worldwide. In conjunction with the scientists at Accumetrics, we have also used the assay we employed to screen for the antibodies (inhibition of platelet agglutination of fibrinogen-coated beads) to develop a whole blood, cartridge based series of automated assays to monitor antiplatelet therapy by aspirin, clopidogrel and AlphaIIbBeta3 antagonists. We have also used a similar assay to screen more than 33,000 compounds for new inhibitors of AlphaIIbBeta3 and found one of novel structure that we are currently characterizing. We have also employed one of the antibodies (10E5) that stabilizes the AlphaIIbBeta3 complex to assist in the preparation of crystals of the AlphaIIbBeta3 headpiece for x-ray diffraction analysis in collaboration with Dr. Timothy Springer's laboratory at Harvard. Thus, careful clinical observations of patients with a platelet disorder that affects only approximately one person in a million provided the lead for the development of therapeutic and diagnostic strategies for coronary artery disease, one of the most common causes of death in the world. Dr. Coller is a member of Phi Beta Kappa, Alpha Omega Alpha, the American Society for Clinical Investigation, the Association of American Physicians, the Institute of Medicine of the National Academies and the National Academy of Sciences. He is a Fellow of the New York Academy of Medicine, the American Association for the Advancement of Science and the American Academy of Arts & Sciences and a Master of the American College of Physicians. Dr. Coller's research interests have focused on hemostasis and thrombosis, in particular platelet physiology. He developed a monoclonal antibody that inhibits platelet function and a derivative of that antibody (abciximab; ReoPro; Centocor Eli Lilly) was approved for human use by the FDA in 1994. It is now in clinical use throughout the United States, Europe, Scandinavia, Australia and portions of Asia, to prevent ischemic complications of percutaneous coronary interventions such as angioplasty and stent insertion. More than 2 million patients have been treated with abciximab. He also developed an assay to assess platelet function, and automated derivatives of that assay to monitor therapy with abciximab, aspirin and clopidogrel (Plavix) have been approved for human use by the FDA. Dr. Coller is the recipient or a co-recipient of thirteen U.S. patents. http://www.rockefeller.edu/research/abstract.php?id=226 WALS

NLM Title:	From the rivers of Babylon to the coronary blood stream / Barry S. Coller.
Author:	Coller, Barry S. National Institutes of Health (U.S.).
Publisher:
Subjects:	Biomedical Research Fibrinogen Integrin beta3 Platelet Activation Platelet Glycoprotein GPIIb-IIIa Complex Thrombasthenia
Publication Types:	Lecture Webcast
NLM Classification:	WH 300
NLM ID:	101322952
CIT Live ID:	6199
Permanent link:	https://videocast.nih.gov/watch=6199

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