Researchers at the UNC Eshelman School of Pharmacy, UNC School of Medicine, and Rensselaer Polytechnic Institute have created a synthetic form of low-molecular-weight heparin, the effects of which can be quickly reversed in cases of emergency. The clinicians involved in the study believe this form of heparin will be safer for patients, especially those with poor kidney function.
“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” says Jian Liu, PhD, co-inventor of the drug and the John A. and Deborah S. McNeill Jr. Distinguished Professor in the UNC Eshelman School of Pharmacy.
While unfractionated heparin is the type commonly used in procedures such as dialysis, the more-refined low-molecular-weight heparins are the drugs of choice for preventing dangerous blood clots in hospitalized patients. A team led by Liu and RPI’s Robert Lindhardt, PhD, created a synthetic version of LMW heparin that can be counteracted by an existing drug. Their creation is described in an article published online February 23 by Nature Chemical Biology.
Up to 5 percent of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because the existing FDA-approved antidote protamine is available. But protamine is not as effective in reversing low-molecular-weight (LMW) heparin, so Liu and Lindhardt tweaked their drug’s molecular structure so that protamine is able to deactivate it.
LMW heparin is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system, a relatively common condition among hospitalized patients.
“If a person’s kidneys aren’t effectively clearing heparin from the blood, the drug stays active in the body for longer than expected,” says Nigel Key, MD, a hematologist with UNC Health Care and the UNC School of Medicine and one of the paper’s coauthors. “That can represent a potentially dangerous situation for the physician, pharmacist, and patient.”
Heparin is a naturally occurring polysaccharide that prevents blood clotting, or coagulation, and has been in use since the late 1930s. A polysaccharide is a long chain of carbohydrate molecules. There are three main types of heparin: unfractionated, the more highly processed low molecular weight heparin, and the synthetic fondaparinux. Natural heparin is most commonly extracted from the linings of pig intestines.
Heparin prevents blood clots from forming and is most often used during and after procedures, such as kidney dialysis, heart bypass surgery, stent implantation, indwelling catheters, and knee and hip replacement. Its side effects can include uncontrolled bleeding and thrombocytopenia – too few platelets in the blood.
The worldwide sales of heparin are estimated at $4 billion annually.
The natural form of the drug was in the spotlight in spring 2008 when more than 80 people died and hundreds of others suffered adverse reactions to it, leading to recalls of heparin in countries around the world. Authorities linked the problems to a contaminant in raw natural heparin from China.
“The pig stuff has served us well for 50 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Liu says. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”
Other study authors from UNC include associate Professor Rafal Pawlinski, PhD, and postdoctoral fellow Erica Sparkenbaugh, PhD, both in the UNC School of Medicine; assistant professor Yongmei Xu, PhD, graduate students Kasemsiri Chandarajoti and Po-Hung Hsieh; and research technician Truong Pham all from the UNC Eshelman School of Pharmacy.