Antidote can deactivate new form of heparin

February 26, 2014

Low-molecular-weight heparin is commonly used in surgeries to prevent dangerous blood clots. But when patients experience the other extreme - uncontrolled bleeding - in response to low-molecular-weight heparin, there is no antidote.

Now researchers at the University of North Carolina at Chapel Hill and Rensselaer Polytechnic Institute have created a synthetic form of low-molecular-weight heparin that can be reversed if things go wrong and would be safer for patients 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," said Jian Liu, the John A. and Deborah S. McNeill Jr. Distinguished Professor in the UNC Eshelman School of Pharmacy, and one of the inventors of the new drug.

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. However, low-molecular-weight heparin doesn't have an antidote and it is also cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened kidney function, a relatively common condition among hospitalized patients.

Liu and RPI's Robert Lindhardt and their teams created a synthetic version of low-molecular-weight heparin that can be counteracted by an existing drug and can be cleared by the liver, not the kidneys. Their creation is described in Nature Chemical Biology this week.

Up to 5 percent of patients receiving heparin experience some form of uncontrolled bleeding, explained Liu. Patients receiving unfractionated heparin are in less danger because there is an existing FDA-approved antidote available. The antidote, called protamine, is not as effective in reversing low-molecular-weight heparin so Liu and Lindhardt tweaked the drug's molecular structure so that protamine is able to deactivate it.

"If a person's kidneys aren't effectively clearing heparin from the blood, the drug stays active in the body for longer than expected," said Nigel Key, 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 prevents blood clots from forming and is most often used during and after such procedures 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 eighty 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. Natural heparin is most commonly extracted from the linings of pig intestines.

"The pig stuff has served us well for fifty years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug," Liu said. "I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost."
-end-
School of Pharmacy contact: David Etchison, (919) 966-7744, david_etchison@unc.edu
News Services contact: Thania Benios, (919) 962-8596, thania_benios@unc.edu

University of North Carolina at Chapel Hill

Related Heparin Articles from Brightsurf:

UC San Diego researchers move closer to producing heparin in the lab
In a new study published in PNAS, UC San Diego researchers moved one step closer to the ability to make heparin in cultured cells.

Rivaroxaban superior to heparin in preventing blood clots after common orthopedic surgeries
The direct oral anticoagulant rivaroxaban dramatically cut the likelihood of serious venous thromboembolism (VTE) in people recovering from lower limb orthopedic surgery requiring immobilization in comparison with enoxaparin, another anticoagulant agent, according to research presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

Hitting HIT: Heparin therapy
Heparin is widely used as an anticoagulant, but evokes in some patients a potentially life-threatening condition called HIT.

URI chemistry professor develops contaminant detection technique for heparin
In 2008, a contaminant eluded the quality safeguards in the pharmaceutical industry and infiltrated a large portion of the supply of the popular blood thinner heparin, sickening hundreds and killing about 100 in the US.

Synthetic version of popular anticoagulant poised for clinical trials
A synthetic version of low molecular weight heparin is poised for clinical trials and development as a drug for patients with clotting disorders, and those undergoing procedures such as kidney dialysis, heart bypass surgery, stent implantation, and knee and hip replacement.

Heparin stimulates food intake and body weight gain in mice
Research shows that heparin, which is well known for its role as an anticoagulant, can also promote food intake and body weight increase in animal models.

Apixaban lowers stroke risk in AF patients undergoing cardioversion (EMANATE)
Apixaban lowers the risk of stroke compared to warfarin in anticoagulation-naïve patients with atrial fibrillation scheduled for elective cardioversion, according to late-breaking results from the EMANATE trial presented today in a Hot Line LBCT Session at ESC Congress.

No difference in rate of adverse cardiovascular events when comparing anticoagulants
In patients undergoing transradial primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI), there was no significant difference in the rate of a composite of death, myocardial infarction and stroke whether they were anticoagulated with bivalirudin or unfractioned heparin, according to a study today in JACC: Cardiovascular Interventions.

Smart patch releases blood thinners as needed
An interdisciplinary team of researchers has developed a smart patch designed to monitor a patient's blood and release blood-thinning drugs as needed to prevent the occurrence of dangerous blood clots.

Two differing medications used during heart procedure are both safe and effective, study finds
Two differing blood clot prevention medications are just as safe and effective for patients undergoing percutaneous coronary intervention, a non-surgical procedure to open blood vessels narrowed by plaque buildup, according to a new study.

Read More: Heparin News and Heparin Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.