Mucopolysaccharide polysulfate (MPS) represents a mammalian-derived sulfated polysaccharide. Because the origin and structure of heparins is similar to MPS, this study was conducted to compare 2 ointment formulations containing MPS or heparin with a placebo ointment on tissue factor pathway inhibitor (TFPI) released in nonhuman primates (Macaca mulatta). A primate colony composed of 18 animals, housed at Loyola University Medical Center, was used in compliance with an Institutional Animal Care and Use Committee (IACUC)-approved protocol. Mucopolysaccharide polysulfate (4.5%), heparin (4.5%), and a placebo ointment were topically applied to individual groups of primates in a crossover study for periods of up to 2 weeks. Blood samples were drawn on days 1, 2, 5, 7, and 10. The anticoagulant effects (activated partial thromboplastin time [APTT], Heptest, thrombin time [TT]), TFPI antigen and functional levels, thrombin activatable fibrinolytic inhibitor (TAFI), and antiheparin platelet factor 4 antibodies (AHPF4 abs) were measured in citrated plasma. All data were compiled as mean +/- 1 standard deviation and compared in groups. Topical administration of both the MPS and heparin ointments resulted in no measurable anticoagulant effects in the primate model; however, MPS produced a concentration-dependent release of TFPI antigen and a functional activity that was stronger than the effects observed with heparin. A decrease in TAFI activation was also observed in the MPS-treated primates. In addition, in the heparin-treated group, a slight increase in AHPF4 abs was observed. In conclusion, MPS showed a stronger release of TFPI than heparin that was not associated with a strong anticoagulant effect. Moreover, MPS downregulated TAFI, resulting in an enhanced fibrinolytic effect.