New York University School of Medicine researchers have found, for the first time, an antibody that destroys an essential component of the blood called platelets. The novel finding may open new therapeutic avenues to treating a blood platelet disorder associated with HIV infection, and other types of vascular disease, including blood clots in arteries.
Platelets, blood cells that look like oval plates, are needed for the blood to clot. When a blood vessel breaks, the platelets usually rush to the scene of the injury to begin the process of filling in the damaged area and providing a surface for coagulation factors. When the platelet count is low, a medical condition called thrombocytopenia, the blood cannot clot properly and bleeding can occur. People with this condition may bruise easily. There also is a risk of life-threatening bleeding into the brain even though no injury has occurred.
Thrombocytopenia is associated with a number of diseases and can also be caused by some drugs. People with early HIV infection often develop a form of the condition called immunologic thrombocytopenia, which appears to be caused by antibodies that attack platelets. Other types of thrombocytopenia are not caused by antibodies, although the cause of some forms remains unknown.
In a new study, Simon Karpatkin, M.D., Professor of Medicine at NYU School of Medicine, and his colleagues prove that an antibody that binds to a specific protein on the surface of platelets causes platelets to self-destruct. Moreover, they show that the antibody carries out its mission by triggering a particular biochemical pathway in the platelets.
The new study is published in the September 7 issue of the journal Cell. It is the first report of an antibody, by itself, destroying a platelet, and the first description of an antibody triggering a reactive-oxygen biochemical pathway to destroy a cell, says Dr. Karpatkin.
"This was an unexpected finding because antibodies had never been shown to act in this fashion," says Dr. Karpatkin. "We believe that this discovery could be of use in the clinic. It is conceivable that this antibody could be used to dissolve clots in the arteries, which can cause myocardial infarction, stroke, and other conditions."
Activation of serum proteins called complement by antibody-antigen complexes is a major pathway for the immune system to get rid of foreign invaders. Antibodies are the immune system's sentinels. They usually alert the body to a foreign invader by binding to it and forming a complex, which recruits complement.
The new report now describes another pathway that is used by antibodies to destroy cells in the absence of complement. This pathway generates highly unstable hydrogen peroxide (a water molecule with extra oxygen attached), which blows apart the platelet. Such a pathway is used by white blood cells to destroy foreign invaders like bacteria, but no one had expected that antibodies would use this same pathway. In the study, the NYU School of Medicine researchers injected the antibody into mice that lacked the complement system, and showed that the antibody still destroyed platelets.
Dr. Karpatkin's group has developed compounds that can block or inhibit the new antibody, which could potentially prevent the destruction of platelets in patients with HIV. The group is also devising monoclonal antibodies that could be used clinically to destroy platelets. Such a therapy might be useful in breaking up blood clots in arteries that contain an abundance of platelets.
In addition to Dr. Karpatkin, the authors of the study are Michael Nardi, Stephen Tomlinson, and M. Alba Greco. The study was supported by the National Institutes of Health, the Dorothy and Seymour Weinstein Platelet Research Fund and the American Heart Association.