2007 Astute Clinician Topic: From the Rivers of Babylon to the Coronary Blood Stream

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. This defect was a result of deficiencies or abnormalities in the integrin (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.

Dr. Coller’s lab developed a monoclonal antibody that inhibits this platelet function. A derivative of that antibody (abciximab; ReoPro™ Centocor/Eli Lilly) was developed to prevent ischemic complications of percutaneous coronary interventions such as angioplasty and stent insertion. Abciximab 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. More than 2.0 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.