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Research

Blood platelets are required to arrest bleeding at sites of vascular injury. They accomplish this by adhering to damaged blood vessels, aggregating one with another, and facilitating the generation of thrombin and the deposition of fibrin. Abnormalities in platelet numbers or function can, therefore, result in excessive bleeding. On the other hand, platelets play a key role in ischemic cardiovascular and cerebrovascular disease, the most common cause of death worldwide, since platelet aggregation can close off a blood vessel that is narrowed by atherosclerosis. This can result in the development of a myocardial infarction or a stroke.

By studying the receptors responsible for platelet aggregation and patients who lack the receptors on a genetic basis (Glanzmann thrombasthenia), we and others were able to identify the platelet GPIIb/IIIa (αIIbβ3) receptor as being important in the aggregation process, and thus a potential target for antithrombotic therapy. We made monoclonal antibodies that inhibit platelet aggregation by blocking the binding to this receptor of plasma glycoproteins (fibrinogen and von Willebrand factor) that can bind to two different platelets simultaneously to initiate platelet aggregation. One of these antibodies has been developed into a drug (abciximab) to prevent ischemic complications of percutaneous coronary interventions (angioplasty and stent placement) in patients with myocardial infarction and other conditions. More than 2 million patients have been treated worldwide with abciximab since its approval by the FDA in 1994. This agent is also currently under investigation for the treatment of stroke.

The crystal structure of the αVβ3 receptor, which is very similar to GPIIb/IIIa, was recently reported and we are analyzing the structure-function relationships by studying mutant proteins and the epitopes of monoclonal antibodies. This now provides exciting opportunities to understand better the conformational changes that occur when platelets are activated that convert the GPIIb/IIIa receptors into a high affinity ligand binding state.

Most recently, we have studied the mechanisms involved in the vascular disease associated with sickle cell disease, which results in painful crises and other serious complications. In particular, we have studied the adhesion of sickle cells to blood vessels and identified the αVβ3 receptor and adherent leukocytes as important in this process. Our recent discovery that sickle cells occlude blood vessels in mice with sickle cell disease by binding to adherent leukocytes rather than directly to the blood vessel wall, opens new opportunities for therapeutic interventions targeted at the leukocyte-blood vessel wall and/or the red blood cell-leukocyte interactions.