Lab mouse
Researchers say they have synthesized low molecular weight heparin (LMWH) that may someday replace animal-sourced heparin.
The team created heparin dodecasaccharides (12-mers) using a manufacturing method that yielded gram quantities—roughly 1000-fold more than previous approaches used to synthesize LMWHs.
One of these dodecasaccharides, called 12-mer-1, demonstrated safety and efficacy in animals models.
Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in Troy, New York, and his colleagues detailed this research in Science Translational Medicine.
The researchers tested 12-mer-1 in a mouse model of venous thrombosis induced by stenosis of the inferior vena cava. Twenty-four hours after stenosis, 12-mer-1 had reduced clot weight by about 60% (P<0.05), when compared to phosphate-buffered saline.
The effects of 12-mer-1 were comparable to those achieved with enoxaparin. However, the dose of 12-mer-1 (1.5 mg/kg) was one-fifth the dose of enoxaparin (7.5 mg/kg). This suggests 12-mer-1 has “considerably higher antithrombotic potency” than enoxaparin, according to the researchers.
Dr Linhardt and his colleagues also tested 12-mer-1 in a mouse model of sickle cell disease. The team said the anticoagulant (given at 2.0 mg/kg every 8 hours for 7 days) “significantly attenuated the activation of coagulation” when compared to saline (P<0.05).
The researchers then tested the clearance of 12-mer-1 in mice with severe kidney failure.
The team observed significant impairment of clearance for both high-dose (1.5 mg/kg) and low-dose (0.3 mg/kg) 12-mer-1 (P<0.05). However, the impairment of 12-mer-1 clearance was dependent upon the severity of the kidney injury.
The researchers also performed toxicology studies of 12-mer-1 in rats. The animals received a single dose of 12-mer-1 at 3600 mg/kg per day for 7 consecutive days.
The rats experienced a decrease in white blood cell counts, but this was within the historical control data range. Two additional doses of 12-mer-1 (400 and 1200 mg/kg per day) produced similar results.
Therefore, Dr Linhardt and his colleagues concluded that 12-mer-1 was well-tolerated.
The researchers also noted that anticoagulation with 12-mer-1 was completely reversible via treatment with protamine, which could potentially reduce bleeding risk.
The team believes that, with substantial optimization, 12-mer-1 could be suitable for industrial-scale synthesis.
“This is at the cusp of clinical trials and commercial use,” Dr Linhardt said. “There is no question about the science. We have proven that this is a safer, more effective alternative to its natural counterpart, and what now determines its success or failure is the marketplace.”
