Document Detail


Selective factor Xa inhibition by recombinant antistasin prevents vascular graft thrombosis in baboons.
MedLine Citation:
PMID:  1637785     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A baboon model of high-shear, platelet-dependent vascular graft thrombosis was used to assess the antithrombotic effect of recombinant antistasin (rATS), a 119-amino acid protein with selective, subnanomolar inhibitory potency against coagulation factor Xa. In this model, a Dacron vascular graft segment of a femoral arteriovenous (AV) shunt provided the thrombogenic stimulus. Antithrombotic efficacy of rATS was assessed by continuous monitoring of 111In-labeled platelet and 125I-labeled fibrin(ogen) deposition onto the graft surface and blood flow through the vascular shunt. Systemic intravenous administration of rATS (2 or 4 micrograms/kg.min-1) dose dependently decreased both platelet and fibrin(ogen) deposition onto the graft. Vascular graft thrombus formation was completely inhibited at a systemic dose of rATS of 4 micrograms/kg.min-1. None of the AV shunts in animals receiving rATS at either dose occluded, and blood flow was maintained at 81 +/- 4% (2 micrograms/kg.min-1 rATS) or 96 +/- 3% (4 micrograms/kg.min-1 rATS) of basal flow. Systemic fibrinopeptide A elevations in response to exposure to the Dacron graft segment were completely suppressed by both doses of rATS. The ex vivo activated partial thromboplastin times were extended to greater than 150 seconds during infusion of both doses of rATS; however, even at fully antithrombotic doses, template bleeding times were not significantly increased. Thus, in this baboon model, rATS is a potent antithrombotic agent that inhibits both platelet and fibrin(ogen) deposition onto a Dacron vascular graft segment. Furthermore, these results demonstrate that selective inhibition of coagulation factor Xa by rATS can completely prevent vascular graft thrombus formation without significantly compromising primary hemostasis as measured by template bleeding time.
Authors:
L W Schaffer; J T Davidson; G P Vlasuk; C T Dunwiddie; P K Siegl
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Arteriosclerosis and thrombosis : a journal of vascular biology / American Heart Association     Volume:  12     ISSN:  1049-8834     ISO Abbreviation:  Arterioscler. Thromb.     Publication Date:  1992 Aug 
Date Detail:
Created Date:  1992-09-01     Completed Date:  1992-09-01     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  9101388     Medline TA:  Arterioscler Thromb     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  879-85     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pa. 19486.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticoagulants / therapeutic use*
Blood Vessels / transplantation*
Factor Xa / antagonists & inhibitors*
Hemostasis / drug effects
Invertebrate Hormones / therapeutic use*
Male
Papio
Postoperative Complications / prevention & control*
Recombinant Proteins / therapeutic use
Thrombin / physiology
Thrombosis / prevention & control*
Chemical
Reg. No./Substance:
0/Anticoagulants; 0/Invertebrate Hormones; 0/Recombinant Proteins; 110119-38-5/antistasin; EC 3.4.21.5/Thrombin; EC 3.4.21.6/Factor Xa

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