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Thromb Haemost 1993; 70(04): 631-635
DOI: 10.1055/s-0038-1649640
Original Article
Coagulation
Schattauer GmbH Stuttgart

Antithrombotic Effects of Synthetic Pentasaccharide with High Affinity for Plasma Antithrombin III in Non-Human Primates

Yves Cadroy
1   Laboratoire d’Hémostase, Centre de Transfusion Sanquine, Hôpital Purpan, Toulouse, France
,
Stephen R Hanson
Division of Hematology and Oncology, Department of Medicine, and Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, GA, USA
,
Laurence A Harker
Division of Hematology and Oncology, Department of Medicine, and Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, GA, USA
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Publikationsverlauf

Received 08. Februar 1993

Accepted after revision 18. Mai 1993

Publikationsdatum:
05. Juli 2018 (online)

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Summary

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 × 109 platelets and 0.62 ± 0.04 mg fibrin deposited on the collagen segments, and 1.9 ±0.4 × 109 platelets and 3.3 ± 0.4 mg fibrin accumulated in the chambers. PS at HD abolished the formation of fibrin-rich thrombus in the chambers and decreased platelet-rich thrombus on collagen by half (p <0.01), while the ID reduced fibrin-rich thrombus in the chambers by about half (p <0.01) but had no effect on platelet-rich thrombus forming on the segments of collagen-coated tubing (p >0.5). Despite its lack of antithrombin activity, PS also decreased plasma fibrinopeptide A levels in a dose-response manner. However, PS had no effect on platelet hemostatic function in vivo, as measured by template bleeding time (BT) determinations (p >0.5). Despite the ability of PS-ATIII complex to inactivate soluble fXa, the complex lacked significant inhibitory activity for fXa immobilized to thrombus formed in vivo. Thus, PS-dependent inactivation of soluble fXa produces antithrombotic effects, primarily for venous-type thrombosis, that are equipotent to Standard heparin on a gravimetric basis, but more sparing of platelet hemostatic function.

 

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