Researchers say they’ve developed a synthetic molecule that can reverse the effects of all heparin products, both in vitro and in vivo.
Finding a drug to reverse the anticoagulant effect of heparin is complicated because there are about a dozen approved heparin products on the market.
None of the available, synthetically made reversal drugs work with all varieties of heparins, and they are relatively toxic, with toxicity varying from person to person.
With all this in mind, Jayachandran Kizhakkedathu, PhD, of the University of British Columbia in Vancouver, and his colleagues set out to create a safe, synthetic antidote that works with all heparins used in clinics today.
They described their results in Science Translational Medicine.
The team created a range of fully synthetic dendritic polymer-based universal heparin reversal agents (UHRAs). These UHRA molecules completely neutralized the activity of unfractionated heparin, tinzaparin, semuloparin, and fondaparinux in vitro.
In comparison, the agent protamine was able to reverse the effects of unfractionated heparin but could only partially reverse the activity of tinzaparin, fondaparinux, and semuloparin.
The UHRA lead molecule, UHRA-7, completely and rapidly neutralized the effects of unfractionated heparin and enoxaparin in rats. Protamine reversed the effects of unfractionated heparin completely but could only reverse 60% of enoxaparin activity.
In mice, UHRA-7 arrested bleeding induced by all the heparins. Mice that received 10 mg/kg of UHRA-7 five minutes after unfractionated or low-molecular-weight heparins had significantly reduced bleeding times and hemoglobin loss compared to mice that received heparin alone (P<0.0001). UHRA-7 at 20 mg/kg arrested the bleeding induced by fondaparinux.
The researchers also assessed the safety of UHRA-7 in mice, monitoring them for 29 days after administration. The team saw no changes in body weight and no signs of acute toxicity in these mice.
Aditionally, there were no changes in lactate dehydrogenase levels in serum and no abnormalities detected by necropsy analysis of the organs.
These results suggest UHRA-7 could benefit patients undergoing high-risk surgical procedures and those requiring treatment for bleeding complications, Dr Kizhakkedathu said.
He noted that a synthetic drug offers consistency in health effects and performance. It also avoids possible immunological reactions sometimes associated with antidotes of biological origin.
Dr Kizhakkedathu and his colleagues plan to continue investigating UHRA-7 in the lab, with the goal of conducting human testing in 3 to 5 years.
