Clot-Dissolving Drugs Could Be Key to Halting Heart Attacks
New drugs may soon make it possible to stop most heart attacks shortly after they begin, scientists believe. The drugs dissolve clots that prevent nutrients and oxygen from reaching heart muscles and have the potential to save a significant number of the 500,000 Americans who die from heart attacks each year.
A key feature of the drugs is that they may be able to destroy clots before any permanent damage is done to heart muscles.
The drugs may also be able to dissolve clots in the arms and legs. Such clots are not as serious as those in the heart, but are disabling nonetheless. Within the last two years, scientists have made impressive strides in improving the effectiveness of clot-dissolving drugs and in developing new techniques to locate and identify clots within the body. Many of those scientists gathered last month in San Diego to discuss some of their newest findings.
Before treatment of a clot is begun, it is important to know where the clot is located. If the clot is in the heart, its presence can be detected by an electrocardiogram. If it is elsewhere, less desirable techniques must be used. The most common technique is venography, in which a dye is injected into an artery through a thin tube.
The dye shows up on an X-ray. “If the X-ray shows that the dye has no access to a particular area, it is inferred that there is a blockage caused by a clot,” Gary Matsueda of the Harvard School of Medicine said after the meeting. “But there are other things that can prevent the dye from getting through, such as a spasm of the artery.
Cumbersome Procedure
“Furthermore, venography is a cumbersome and painful procedure that is potentially hazardous in the seriously ill and that can itself cause clots,” Matsueda added. What is needed, he said, is a technique that does not require invading the patient’s body with tubes or other devices.
Matsueda and Michael Ezekowitz of the Yale University School of Medicine have independently developed new procedures to locate clots. Ezekowitz uses platelets, a type of blood cell that helps form the bulk of the clot. He tags platelets with a small amount of a radioactive isotope and injects them into the patient.
The tagged platelets accumulate at the clot site and can be detected with an imaging device that permits precise location of the clot. “The test can be used in the sickest patients without harm,” Ezekowitz said by phone. “Since the platelets persist in the body for as long as seven days, the technique can also be used to monitor therapy.” The technique is now being tested at half a dozen major hospitals in this country and Europe.
Matsueda makes use of a new tool called monoclonal antibodies to locate clots. Antibodies are a component of the blood that bind to foreign cells or chemicals to mark them for destruction by the immune system.
Monoclonal antibodies are produced using new biotechnology techniques that allow investigators to produce large quantities of identical antibodies that will bind to specific materials in the blood.
Matsueda’s monoclonal antibodies bind to fibrin, a structural component of clots. Fibrin is produced at the clot site by enzymes that break up a larger protein molecule, called fibrinogen, which normally circulates freely in the blood.
Other scientists have attempted to produce monoclonal antibodies that bind to fibrin, but those antibodies also bound to fibrinogen in the blood. The antibodies thus did not accumulate in excess quantities at the clot.
Matsueda told the conference that he overcame this problem by creating monoclonal antibodies that bind to the free end of the fibrin molecule produced when fibrinogen is broken down. These antibodies do not bind to fibrinogen, and thus do accumulate at the clot site. Matsueda tags them with a radioactive isotope so they can be detected with an imaging device.
Degrading Clot With Enzyme
Once the clot is identified, the problem is to get rid of it. The best way is to degrade the clot with an enzyme known as plasmin. Plasmin can be produced from a blood protein called plasminogen in the same way that fibrin is produced from fibrinogen. Unfortunately, the patient with a clot has no way to convert plasminogen to plasmin.
That conversion can be accomplished with an enzyme, streptokinase, that is isolated from a bacterium. It is now used routinely to treat heart attacks caused by clots, but can dissolve only about half of the clots or less.
If the treatment is begun immediately after the heart attack, permanent damage to heart muscles can frequently be avoided. After about six hours, however, the muscle tissues will be dead even if circulation is then restored.
Streptokinase presents problems, however. The most important is that it converts plasminogen to plasmin--activates it--throughout the body. This activation produces undesirable bleeding, particularly at the injection site, and other side effects.
Scientists have thus been very excited about a potential new drug for dissolving clots called tissue plasminogen activator or TPA. TPA was originally isolated from tissues of the uterus. In 1982, Desire Collen of the University of Leuven in Belgium and investigators at Genentech, a biotechnology company in South San Francisco, announced that they had isolated the gene that codes for TPA and had inserted it into bacteria. Other companies have subsequently also produced TPA this way.
“Studies in animals quickly showed that TPA was at least as effective as streptokinase at dissolving clots,” M. Verstraete of the University of Leuven told the San Diego meeting. “More important, the activity of TPA seems to occur almost exclusively at the clot site, so there is little bleeding elsewhere in the body.”
A major study comparing TPA with streptokinase was quickly organized at 25 medical centers in the United States and Canada. “That study was ended prematurely earlier this year,” Eugene Passamani of the National Institutes of Health reported at the conference. “The results with TPA were so much better than those with streptokinase that we could no longer justify giving streptokinase to patients. TPA will now be used exclusively.”
One other potentially exciting agent was described at the conference by Vincent Marder of the University of Rochester. It is a combination of a chemically modified form of plasminogen and streptokinase, called APSAC, that is produced by Beecham Laboratories of Bristol, Tenn., and is undergoing trials at 15 U.S. hospitals.
Like TPA, APSAC restores circulation in about two-thirds of patients; it also has very few side effects. “Its principal advantage,” Marder said in an interview, “is that it could be given to the heart attack victim in a two-minute infusion before the patient is brought to the hospital.”
TPA, in contrast, must be given by a continuous infusion and treatment is normally not started until the patient is in the emergency room.
All of the new drugs are useful, according to Marder. “We’ve demonstrated that clots can be dissolved, there’s no question about it. What we’re doing now is simply trying to improve the efficiency so that we can help more patients.”
