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New platelet receptor identified
Gene may be potential target for anti-clotting drugs
By Bijal P. Trivedi

The gene for a platelet receptor has been identified, and scientists say the discovery may lead to new drugs that reduce blood clots in people with a history of stroke or arterial disease.

The receptor, P2Y12, has been the target of two drugs, clopidogrel and ticlopidine, which are used for treatment of stroke and arterial disease. Researchers found that the drugs permanently block the P2Y12 receptor on the surface of the platelets, hindering clotting for up to 10 days, or until new platelets are produced. This is a particular problem in surgical patients. The drugs also cause gastrointestinal problems and reduce white blood cell counts, requiring regular monitoring of patients.

"Physicians want drugs that work reversibly, affect platelets for 24 hours, and are fast acting," says Pamela Conley, whose team at COR Therapeutics, Inc., in San Francisco, California, discovered P2Y12. Now that Conley has identified the receptor, her goal is to design a drug with these specifications.

P2Y12 is the third receptor to be associated with platelet activation and clumping. P2Y12 is only found on platelets and in some parts of the brain. P2Y1, by contrast, is found on nearly every cell in the body, making it a poor drug target. The role of P2X1 has not been clearly defined.

Conley has evidence that a drug aimed at P2Y12 would have few side effects. French colleagues of Conley's identified an elderly Frenchman with a mild bleeding disorder whose platelets did not respond to a common activation signal. When Conley and her colleagues examined DNA and blood samples from the patient they discovered that one copy of the P2Y12 gene contained mutations and the other copy of the gene was inexplicably turned off.

"The elderly Frenchman is a human P2Y12 'gene knockout'," says Conley. He does not have a healthy copy of this receptor, and thus his wounds heal slowly. Otherwise he is very healthy and does not appear to have any obvious neurological problems. Based on these observations, we would not expect a drug that blocked P2Y12 to have many side effects, says Conley.

Platelets are the smallest human blood cell and are essential for wound healing. The cells circulate through the blood in an inactive form until they encounter a damaged blood vessel. An injury activates platelets and causes them to stick together and create a cellular bandage that plugs the wound. But platelets that easily form clumps are particularly dangerous to people with narrowed arteries, placing a premium on anti-platelet drugs.

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Hollopeter, G. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409, 202-207 (January 11, 2000).

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