Sensor helps doctors monitor heparin levels in whole blood

By Sally Pobojewski
News and Information Services

U-M researchers have developed the first sensor that can directly measure the amount of heparin in whole blood and alert physicians to the dangerous bleeding heparin produces in some patients. Heparin is a drug commonly used in surgery to prevent the formation of blood clots that can cause strokes.

The U-M sensor will allow physicians to monitor heparin levels faster and more precisely than is possible with current methods and help warn physicians of drug-related side effects, according to Victor C. Yang, associate professor of pharmaceutics.

Yang is presenting preliminary test results on the sensor at the meeting of the American Association of Pharmaceutical Scientists this week in San Antonio, Texas.

Yang explained that physicians currently measure heparin levels indirectly by testing how long it takes for a patient’s blood to coagulate or form a clot. Normal clotting time is about two minutes, although it varies from patient to patient. During heparin therapy, physicians try to maintain clotting times that are about three times longer than the patient’s normal time.

“Between 8 percent and 30 percent of all patients who receive this level of heparin develop bleeding complications during or following surgery,” Yang said. To prevent these complications, physicians routinely give another drug called protamine to neutralize heparin’s anticoagulant effects. Protamine has dangerous side effects of its own, however, including allergic reactions, drops in blood pressure and possibly fatal cardiac arrest.

“If physicians could monitor heparin levels in the bloodstream frequently, they could take measures to make heparin therapy safer, administer appropriate dosages of protamine, and reduce side effects of both drugs in their patients,” Yang said.

“The heparin sensor is not a substitute for a clotting time test,” said Mark E. Meyerhoff, professor of chemistry, who helped design the sensor’s polymer membrane electrode technology. “But it does provide a valuable additional piece of information. If a patient with bleeding complications has no free heparin left in his blood, then bleeding is probably a result of something other than heparin. Instead of giving more protamine and increasing the risk of side effects, physicians can look for the underlying cause of the problem.”

Yang and Meyerhoff are developing two applications for the heparin sensor. One is an inexpensive, disposable, semiconducting chip covered with a heparin-sensitive membrane. Designed for use during surgery or as a bedside screening test, the microelectronic sensor can detect heparin levels in a drop of blood within two minutes.

In the second application, the heparin sensor will be used in conjunction with a multiple protamine filter system developed by Yang to remove heparin from the bloodstream of patients undergoing circulatory bypass procedures during open-heart surgery and organ transplants. A feedback system will automatically switch to a regenerated protamine filter whenever the sensor indicates that the original filter is saturated and heparin levels are too high.

According to Meyerhoff, the heparin sensor’s accuracy and reliability has been verified in an initial study of 10 patients undergoing open-heart surgery. Additional clinical studies are planned.

The heparin sensor membranes are cast from a specific polymer solution mixed with a quaternary ammonium compound that reacts with heparin, producing an electrical signal. The polymer membrane technique has been used to create sensors for potassium, sodium and calcium ions, but this is the first time it has been used for large ionic molecules like heparin, according to Meyerhoff.

The U-M has applied for a patent on the heparin sensor and is seeking licensees to develop the technology. U-M post-doctoral researcher Shu-Ching Ma and graduate student Bin Fu assisted with the sensor’s development. The research is funded in part by the National Institutes of Health.


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