Dermatan sulfate inhibition of fibrin-rich thrombus formation in nonhuman primates.
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 111In-platelets by imaging analysis and by the accumulation of 125I-fibrin. Intravenous infusion of DS at 0.83, 8.3, and 42 mg/kg maintained plasma levels at approximately 7, 70, and 400 micrograms/mL, 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.
Cadroy
Y
Y
Laboratoire d'Hémostase, Centre de Transfusion Sanguine, Hôpital Purpan, Toulouse, France.
Hanson
S R
SR
Harker
L A
LA
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D003871:Dermatan Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000378:metabolism*; D006487:Hemostasis / Q000187:drug effects; D008297:Male; D010215:Papio; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism* / Q000517:prevention & control*
D003871:Dermatan Sulfate; D005337:Fibrin; D013917:Thrombin