Improved Coagulation in Bleeding Disorders by NASP Treatment.

Abstract

Additional therapeutic options are needed for patients with bleeding disorders such as hemophilia A, hemophilia B, and severe von Willebrand disease. A novel treatment approach which may benefit such clotting disorders has been identified that, parodoxically, involves heparin-like sulfated polysaccharides. Select molecules of this broad class are largely devoid of anticoagulant activity and are here denoted Non-Anticoagulant Sulfated Polysaccharides (NASPs). Candidate NASPs were shown in clotting assays to demonstrate at least ten-fold lower anticoagulant activity as compared to heparin. Moreover, a subset of NASPs, including pentosan polysulfate (PPS) and fucoidan, improved (i.e. accelerated) the clotting time of human hemophilia A and hemophilia B plasmas or plasma with reduced FVII levels when tested at concentrations ranging from 4–500 nM in dilute prothrombin time (dPT) assays. A broad window of efficacy was evident with both PPS and fucoidan. A mechanism involving potent blockade of the extrinsic pathway downregulator, Tissue Factor Pathway Inhibitor (TFPI), was implicated from modified dPT clotting tests. Improved hemostasis in vivo was observed in mice with hemophilias A or B following low dose subcutaneous administration of PPS or fucoidan, or a combination of NASP plus factor supplement. Studies in hemophilic dogs are in progress. Accordingly, administration of select NASPs may represent a unique approach for treating multiple bleeding disorders.