Antithrombotic effects of synthetic pentasaccharide with high affinity for plasma antithrombin III in non-human primates.
The pentasaccharide (PS) comprising the minimal heparin structure capable of binding with antithrombin III (ATIII) and exhibiting anti-factor Xa (anti-fXa) activity in plasma without producing detectable antithrombin activity, has been evaluated for its relative antithrombotic and antihemostatic effects in a baboon model combining both platelet-rich and fibrin-rich thrombosis. Thrombosis was produced in a two-component thrombogenic device incorporated into an exteriorized femoral arteriovenous (AV) shunt in baboons; the proximal component constituted a segment of collagen-coated tubing and induced platelet-rich arterial-type thrombus, while the distal component consisted of an expanded chamber producing static and disturbed flow and initiated fibrin-rich venous-type thrombosis. Thrombus formation was measured as the deposition of 111In-platelets and the accumulation of 125I-fibrin. PS was administered intravenously to maintain plasma anti-fXa activity at three different levels: a) low dose (LD) 0.3 +/- 0.1 U/ml; b) intermediate dose (ID) 0.6 +/- 0.1 U/ml; and c) high dose (HD) 5.6 +/- 0.4 U/ml. In untreated controls, thrombus formed rapidly, reaching a plateau by 40 min of 2.3 +/- 0.2 x 10(9) platelets and 0.62 +/- 0.04 mg fibrin deposited on the collagen segments, and 1.9 +/- 0.4 x 10(9) platelets and 3.3 +/- 0.4 mg fibrin accumulated in the chambers.(ABSTRACT TRUNCATED AT 250 WORDS)
Cadroy
Y
Y
Laboratoire d'Hémostase, Hôpital Purpan, Toulouse, France.
Hanson
S R
SR
Harker
L A
LA
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects; D004800:Enzymes, Immobilized; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D008297:Male; D009844:Oligosaccharides / Q000494:pharmacology*; D010215:Papio; D011485:Protein Binding; D013927:Thrombosis / Q000517:prevention & control
D004800:Enzymes, Immobilized; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009844:Oligosaccharides; C064764:PENTA; D000990:Antithrombin III