Dermatan sulfate (DS), a factor that amplifies plasma heparin cofactor II antithrombin (HCII) activity, has been evaluated in baboons for its relative antithrombotic and antihemostatic effects by use of a model that combines both platelet-rich and fibrin-rich thrombus formation. Thrombus was generated in a two-component thrombogenic device incorporated into exteriorized femoral arteriovenous shunts, in which a proximal segment of collagen-coated tubing induces platelet-rich arterial-type thrombus and distal expanded chambers with disturbed and static flow produce fibrin-rich venous-type thrombus. Thrombus formation was measured as the deposition of autologous '"In-platelets by imaging analysis and by the accumulation of '"I-fibrin. Intravenous infusion of DS at 0.83, 8.3, and 42 mg/kg maintained plasma levels at approximately 7, 70, and 400 ftg/mh, respectively, throughout the period of study. By enhancing HCII-dependent inactivation of soluble thrombin, DS prolonged the coagulation times, reduced plasma fibrinopeptide A levels, and decreased fibrin-rich thrombus formation in the chamber portion of the device in a dose-dependent manner, ie, the intermediate dose reduced fibrin accumulation by approximately 70% (p<.05). By contrast, neither platelet deposition on collagen nor platelet hemostatic function, assessed with bleeding time determinations, was significantly affected by DS at any dose studied (P>.2 and P>.1, respectively, for the high dose), a finding presumably explained by the resistance of immobilized thrombin to inactivation by DS.