Venous thrombotic disorders are a leading cause of mortality in the US. While anticoagulants are the primary treatment, their use is limited by bleeding risks. This highlights the critical need for safer alternatives. In this study, we investigated eight sulfonated polymers for anticoagulant potential using human plasma clotting assays. Nonacetylated lignosulfonate (NALS) emerged as the most promising candidate, doubling clotting times at 309-980 μg/mL concentrations. We also performed chromogenic assays targeting key coagulation factors (thrombin, factor Xa, and factor XIa) to elucidate its mechanism of action. NALS exhibited a potent and selective inhibition of factor XIa, with an IC50 of ~8 μg/mL, while showing minimal effects on thrombin or factor Xa. Factor XIa inhibition is particularly advantageous, as it may reduce thrombosis while preserving hemostasis, addressing a major drawback of current therapies. Our findings position NALS as a novel, targeted anticoagulant lead with a mechanistically improved safety profile. Future studies will explore its efficacy in vivo and structure-activity relationships to optimize therapeutic potential. This work opens new avenues for developing safer antithrombotic drugs.
Al-Horani et al. (Wed,) studied this question.