Low–molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12-mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs.

低分子量肝素（LMWH）在临床上用于治疗凝血障碍。作为动物源性产品，LMWH是高度异质的混合物，其抗凝活性不能被鱼精蛋白完全逆转。此外，LMWH供应链的可靠性也是监管机构关注的问题。我们在克规模上证明了肝素十二糖（12-聚体）的合成。体外实验表明，使用鱼精蛋白可以逆转12-mer的抗凝活性。其中之一，标记为12-mer-1，可减少深静脉血栓形成的小鼠模型中血块的大小，并减弱镰状细胞疾病小鼠模型中的循环促凝血标记物。体外实验表明，鱼精蛋白可以逆转12-mer-1的抗凝活性。还在非人灵长类动物模型中检查了12-mer-1，以确定其药效学参数。在大鼠模型中进行的7天毒性研究表明，没有毒性作用。数据表明，合成的均质低聚糖可以替代动物来源的LMWH。