Platelets, the blood cells that help a cut finger stop bleeding, can also take a deadly turn as they course through veins and arteries. When platelets in the bloodstream clump together as a clot, they can trigger a heart attack or a stroke. When platelets stick to a moving cancer cell, they may hide it from the body's natural defenses.
A Hopkins scientist is working on ways to disable platelets' unhealthy habits while preserving their ability to halt blood loss. The goal, says Konstantinos Konstantopoulos, is to unlock the secrets of the tacky molecules that platelets use to cling to each other and to the walls of blood vessels.
To do this, Konstantopoulos, an assistant professor of chemical engineering, has set up equipment that simulates the flow of human blood beneath a microscope. A video camera attached to the microscope lets him record and study cells that are moving as they would through blood vessels. With this equipment, he has begun testing medications that could keep platelets from using their stickiness in ways that jeopardize human health.
Under normal conditions, platelets simply circulate through the body along with red and white blood cells, posing no threat. "If you look inside the blood vessels of a healthy person, you'll see the platelets moving passively without interacting with each other or with the walls of the blood vessel," Konstantopoulos explains.
If the skin is cut, sticky molecules appear on the surface of the platelets, which rush to the site and adhere to the broken vessel wall to prevent blood loss. But sometimes, damage inside a blood vessel or a medical disorder can set off the sticky response. If the platelets stick to each other and form a clot that stops critical blood flow to the heart or the brain, cardiac arrest or a stroke may occur. This leaves researchers with a challenge: Can platelets continue to control bleeding without forming lethal blood clots?
Fortunately, two different molecules appear to be involved in these processes. Generally, a molecule called glycoprotein Ib assists the platelets in adhering to a blood vessel wall, which is critical to controlling blood loss. But a molecule called glycoprotein IIb-IIIa usually allows platelets to stick to one another. "So what the drug companies want to do," Konstantopoulos explains, "is to block the receptor for IIb-IIIa without affecting Ib. That way, you can reduce the risk of clots while continuing to limit blood loss."
In related research, the Hopkins scientist is trying to understand how platelets manage to stick to cancer cells that have broken off from a primary tumor and entered the bloodstream. "There is some evidence that these loose tumor cells can interact with platelets," Konstantopoulos says. "We think the platelets mask the cancer cells so that the body's defense mechanisms don't recognize that something foreign has invaded the bloodstream. As a result, the cancer cells are free to move anywhere, stick someplace and form another colony."
This life-threatening process is called cancer metastasis. The Hopkins researcher wants to block metastasis so that a surgeon can cut away the primary tumor without worrying that the disease will spread elsewhere. "I want to identify the molecules on the platelets and the tumor cells that allow them to stick together," he says. "Then, presumably, if you inject agents that prevent this adhesion, the body's natural defenses will recognize the cancer and fight it."
With these aims in mind, Konstantopoulos has obtained funding from the Whitaker Foundation to begin testing pharmacological agents that may keep platelets from sticking to each other or to cancer cells. He brings to this line of research the tools and techniques of both a chemical engineer and a biologist. Instead of simply looking at cells that remain still beneath a microscope, he studies them as they flow through tubes under pressure.
"The focus of all this research is to learn how cells stick to other cells or to vessel walls under flow conditions," Konstantopoulos explains. "In the lab, I can simulate the conditions that occur inside the blood vessels, inside the body. In the past, biologists mainly looked at how cells interact under static conditions. We are interested in these biological processes, but we are also interested in how the flow of blood can affect these processes. We have found differences."