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Researchers Develop Cost-effective Method of Synthesizing Common Anticoagulant

Heparin, an anticoagulant medication, can now be made efficiently in the lab without the risks that come with animal-derived drugs

Meeri Kim, Contributor
Mon, 09/18/2017


Anticoagulant medications made from an animal-derived compound called heparin help to treat and prevent clotting disorders like arterial and venous thrombosis. However, heparin typically comes from the mucous membranes of porcine intestine, meaning it is vulnerable to risks associated with disease epidemics in animals and adulteration at one of the many steps from animal harvesting to final drug. Most notably, batches of contaminated heparin were recalled in 2008 and caused 81 deaths.

In an effort to replace animal-sourced heparin with a synthetic version, researchers from the University of North Carolina at Chapel Hill have designed a synthetic compound that could serve as a potential substitute. Their results were published Sept. 6 in Science Translational Medicine.

“Heparin is a carbohydrate-based drug. Traditional synthesis of such molecules is very difficult and costly, and also generates a large amount of chemical waste,” said senior author Jian Liu. “It is impossible to prepare synthetic heparin using the chemical approach at the cost that is competitive with animal-sourced heparin.”

Instead Liu and his colleagues invented a scalable, enzyme-based synthesis to prepare synthetic low-molecular weight heparin. Previously, the chemoenzymatic method could only be used to produce very small amounts of product on the milligram scale. The team first began the project about 15 years ago, gradually making improvement in the process. For instance, they discovered two heparin structures, called 12-mer-1 and 12-mer-2, that could be easily synthesized with this approach. The structures are examples of a type of carbohydrate called oligosaccharides, which consist of a relatively small number of simple sugars linked together. In comparison, animal-derived heparin is a mixture of various oligosaccharides. The scientists also employed engineered bacteria strains to synthesize chemicals, called cofactors, used by the enzymes to increase the efficiency of the reactions.

Their scalable method of making synthetic heparin is cost-effective, efficient, and does not generate chemical waste. The team tested 12-mer-1—the easier molecule to synthesize—in mouse models of venous thrombosis and sickle cell disease. One day after narrowing the inferior vena cava of mice, 12-mer-1 significantly reduced clot weight by 60 percent compared to a control group. Also, sickle cell mice injected with 12-mer-1 every eight hours for a week had lowered levels of circulating procoagulation markers. Lastly, 12-mer-1 was observed to leave the body at a similar rate as the FDA-approved heparin drug enoxaparin in a nonhuman primate model.

In vitro experiments also demonstrated that protamine—a cheap and widely available antidote for heparin—could reverse the anticoagulant activity of 12-mers. This means in a case of overdose or bleeding, protamine could be given to the patient.

“Replacing animal-sourced drugs with their synthetic counterparts is a trend to improve the safety and reliability for medicines,” said Liu. “One classic example is insulin, a drug used for diabetic patients.”

Insulin, originally isolated from the pancreas of pigs, is now almost completely synthesized rather than animal-sourced.

Andreas Greinacher, a professor of transfusion medicine at the Medical School and Hospital of the Ernst-Moritz-Arndt-University Greifswald in Germany, who was not involved in the project, believes the study is an important development in the field of anticoagulants. Synthesis of heparin could help meet increases in demand for anticoagulants as the world’s population grows and health care systems around the world improve.

“Heparins are the most frequently used anticoagulant in in-hospital patients and their consequent use has substantially reduced the risk for thrombosis and pulmonary embolism,” said Greinacher. “There is no risk of transmitting pathogens from animals with this synthetic heparin, and its production is not restricted by the availability of biological material.”