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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

Authors

  • 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
Weitere Informationen

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.