Enhanced antithrombotic effects of unfractionated heparin in rats after repeated oral doses and its relationship to endothelial heparin concentration

Background and purpose: An oral, single dose of 7.5 mg kg −1 of unfractionated heparin (UFH) reduces thrombosis by 50% in a rat model of venous thrombosis. As long‐term use is required clinically, our objectives were to study the antithrombotic effects following repeated oral UFH administration. Experimental approach: Bovine lung UFH was administered by oral gavage to rats in 3 doses of 7.5 mg kg −1 each 12, 24, 48, and 72 h apart; and in 3 or 15 doses of 1 mg kg −1 every 48 h. The last dose was given immediately after thrombus initiation where 10% formalin in methanol was applied to the jugular vein. The vessel was examined for thrombosis 4 h later. Amounts of heparin in tissue and endothelium, and plasma anticoagulant activity were measured. Key results: When 3 × 7.5 mg kg −1 heparin was given, thrombotic incidence was most reduced at 48 h dose‐intervals and was significantly less than single dose treatment. There was a negative correlation between endothelial heparin content and thrombotic incidence, but not anticoagulant activity. When 3 doses of 1 mg kg −1 every 48 h were given, thrombotic incidence was similar to single dose treatment. When 15 doses were given, total thrombotic incidence was less than for 3 doses and was similar to that after s.c. administration. Conclusions and implications: Antithrombotic activity increased with repeated doses of oral UFH, with antithrombotic effects similar to s.c. administration. Antithrombotic activity was related to heparin on endothelium. British Journal of Pharmacology (2008) 153 , 1177–1184; doi: 10.1038/bjp.2008.14 ; published online 11 February 2008