Improved coagulation in bleeding disorders by Non-Anticoagulant Sulfated Polysaccharides (NASP)

Abstract

SummaryAdditional therapeutic options are needed for patients with bleeding disorders such as hemophilia A, hemophilia B, severe von Willebrand disease, and other rare factor deficiencies. A novel approach to improve coagulation in such clotting disorders has been identified that, parodoxically, involves heparinlike sulfated polysaccharides.Select molecules of this broad class are largely devoid of anticoagulant activity and are here denoted Non-Anticoagulant Sulfated Polysaccharides (NASPs).A mechanism involving blockade of the extrinsic pathway downregulator,Tissue Factor Pathway Inhibitor (TFPI) by NASPs, was conceived as an approach for improving procoagulant behavior in hemophilic settings.A subset of NASPs, including pentosan polysulfate (PPS) and fucoidan inhibited both full-length and Kunitz 1 and 2 (K1K2) TFPI and, at concentrations from 4-500 nM, improved (i.e. accelerated) the clotting time of human hemophilia A and hemophilia B plasmas or plasma with reduced factor VII levels when tested in dilute prothrombin time (dPT) assays. Fucoidan did not reduce normal plasma APTT times implying specificity for extrinsic pathway control. Improved hemostasis in vivo was observed in mice with hemophilias A orB following low dose subcutaneous administration of PPS or fucoidan, or a combination of NASP plus factor supplement. Increased survival of factor deficient mice following a bleeding challenge was observed. Accordingly, administration of select NASP(s), via mechanism(s) not fully understood, represents a unique means of improving coagulation in bleeding disorders.

Fucoidan Is a Novel Platelet Agonist for the C-type Lectin-like Receptor 2 (CLEC-2)

“…Fucoidan, a sulfated polysaccharide from a brown seaweed, decreases bleeding time and clotting time in hemophilia (8,9). Decreased bleeding times in the hemophilia animal models by in vivo administration of fucoidan highlights the beneficial FIGURE 4.…”

“…Furthermore, in vitro studies by using platelet poor plasma from hemophilia animal models and human patients have showed that fucoidan inhibits tissue factor pathway inhibitor, thereby contributing to an increase in the extrinsic coagulation pathway activity (8). The effect of fucoidan on platelets, however, has not been studied.…”

“…These polysaccharides are composed of a broad range of subclasses similar to heparins, glycoaminoglycans, fucoidan, dermatan, or dextran sulfates (7). Notably, compounds of natural origin exhibit different biological activities depending on the concentration or dose (8,9). Fucoidan, a nonanticoagulatory sulfated polysaccharide, is derived from the brown seaweed Fucus vesiculosus.…”

“…In humans, in vitro experiments with fucoidan demonstrated several beneficial effects on ulcers and bleeding disorders (11,12). Non-anticoagulatory sulfated polysaccharides were originally considered as a novel approach to improve coagulation because of their inhibitory effect on physiological anticoagulation, especially fucoidan, which inhibits tissue factor pathway inhibitor and accelerates clotting in hemophilia A and B patients (8). Therefore, fucoidan is in clinical trials as a new candidate drug for hemophilia patients.…”

Present and Future of Pediatric Hemophilia Treatment

“…They are believed to act through blockade of tissue factor pathway inhibitor, effectively removing the brakes from coagulation. NASP can accelerate the clotting times of plasma from hemophilia patients [11]. Finally, missense mutations leading to premature stop codons in FVIII or FIX occur in approximately 10% to 15% of persons with hemophilia A or B, respectively.…”