SEARCHING FOR SYNTHETIC HEPARIN: Rensselaer Polytechnic Institute's Robert Linhardt has been searching for a way to make heparin in the lab and decrease the drug industry's dependence on China. Image: Image courtesy of Rensselaer Polytechnic Institute
Blood thinners made from the complex carbohydrate heparin have been routinely used in the U.S. since the 1930s to keep veins, arteries and lungs clear of potentially fatal clots and to reduce the amount of time that kidney failure patients spend on dialysis machines. These drugs are so popular that there is not enough heparin—the active pharmaceutical ingredient (primarily derived from pig intestines) that enables these blood thinners to stop or prevent blood from clotting during medical procedures and treatments—to meet the daily U.S. demand of 300,000-plus doses. To make up the difference, U.S. drug makers purchase the majority of the heparin used in their products from China.
It's unlikely that many patients considered the source of the drug until earlier this year, when doctors began reporting hundreds cases of severe side effects (including dangerously low blood pressure) attributed to contaminated batches at U.S. hospitals and clinics around the country. The U.S. Food and Drug Administration (FDA) has cited 81 deaths as a result of the contamination and continues to investigate whether the tainted meds were responsible for others.
In the wake of the deaths, the FDA launched an investigation to pinpoint the source of contamination, which it traced to Changzhou SPL Company, Ltd., based in China that supplied Wisconsin-based Scientific Protein Laboratories, LLC, (SPL) with the heparin it sold to companies such as Baxter International, Inc., in Deerfield, Ill., for that company to use in its blood-thinner products.
The incident added to fear about the safety of products made in China first raised last year when the industrial poison melamine was found in pet food that sickened and killed hundreds of U.S. cats and dogs. Melamine was also later found in dairy products, including baby formula made in China, blamed for sickening thousands of infants and killing four.
The heparin contamination was particularly disturbing, because the contaminated blood thinners passed through several layers of supposed screening. When the tainted drugs were discovered, Baxter, the supplier of 50 percent of heparin in the U.S. market, recalled nearly all of its doses (purchased from SPL). The FDA, which had since December been investigating complaints related to heparin products, tapped the expertise of several groups of scientists to find the nature and the source of the contamination by March and has since been working to tighten its screening of heparin imports from China, which supplies 70 percent of the heparin used in blood thinners worldwide. (The European Union, the U.S., Canada and Brazil supply nearly all of the rest.) The agency's investigation and efforts to find more effective ways of detecting contaminants is ongoing.
In an effort to prevent future scares, scientists are trying to develop a safer, more effective synthetic form of heparin that could be made in U.S. labs, thereby negating the need for purchasing possibly contaminated ingredients from China or other countries lacking stiff safety regs. Robert Linhardt, a professor of biology, chemistry and chemical engineering at Rensselaer Polytechnic Institute in Troy, N.Y., in February received a phone call that validated his five-year quest to develop heparin in the lab. Linhardt says he listened intently as a Baxter researcher told him about a report of severe allergic reactions to heparin-based blood thinners in dialysis patients, including children. "I was then asked if I was available to help with discovering the cause of this contamination," he says. "I responded affirmatively and then asked if it were not simply a bacterial contamination in the [heparin] vial-filling process. When I was assured that this was one of the first things tested for and ruled out, I realized that this would be a very interesting investigation, and I was hooked."
The crisis begins
The Missouri Department of Health and Senior Services first notified the U.S. Centers for Disease Control and Prevention (CDC) of a potential heparin problem in early January. Alexis Elward, an internist specializing in infectious disease at Saint Louis Children's Hospital, had alerted the department that some of her pediatric dialysis patients had suffered serious allergic reactions (including angioedema, shortness of breath, nausea, vomiting, diarrhea and abdominal pain) and, in some cases, dangerously low blood pressure after they took heparin-based blood thinners (used to prevent clots when waste is being filtered from the blood of patients whose own kidneys are too damaged to perform the function).