Effects of therapeutic doses of heparin on thrombolysis with tissue-type plasminogen activator in rabbits.
The objective of the study was to evaluate the ability of heparin to enhance the thrombolytic effect of recombinant tissue type plasminogen activator (rt-PA) and to prevent thrombus growth during and after thrombolysis with rt-PA. In the thrombolysis studies, three groups of rabbits were infused with rt-PA at a dose of 0.5 mg, 1 mg, or 2.5 mg over 3 hours, respectively. Rabbits in each group were randomized to receive, in addition to rt-PA, heparin, 20 or 60 antifactor Xa U/kg/h, or saline over 6 hours. The three doses of rt-PA produced the same extent of thrombolysis both in the two groups treated with heparin (34% +/- 6%, 52% +/- 7%, and 79% +/- 8% in the lower dose group; 39% +/- 6%, 49% +/- 4%, and 81% +/- 6% in the higher dose group) and in the group treated with saline (37% +/- 4%, 47% +/- 5%, and 84% +/- 7%). In the thrombus growth inhibition studies 0.5 mg of rt-PA was infused over 3 hours in each rabbit. In addition, the rt-PA-treated rabbits were randomized to receive heparin, 20 or 60 antifactor Xa U/kg/h over 6 hours, or saline. At the end of infusion, no statistically significant differences in thrombus growth were found in three groups of rabbits (54.8 +/- 7.4 micrograms and 52.4 +/- 12.1 micrograms in the low and high dose of heparin groups, respectively, and 59.4 +/- 10.4 micrograms in the saline group). In different experiments rabbits were randomized to receive heparin, 60 antifactor Xa U/kg/h, or saline at the end of the rt-PA infusion. In these experiments heparin inhibited thrombus growth more efficiently than saline (41.1 +/- 6.5 micrograms and 58.7 +/- 12.9 micrograms, respectively, P less than .05). In vitro experiments confirmed that heparin is unable to prevent fibrin accretion on the clots during lysis with rt-PA while both D-Phe-Pro-Arg-CH2-Cl (PPACK) and hirudin are able to prevent the accretion of fibrin. We conclude that the data obtained in these animal models do not support the concomitant use of heparin and rt-PA. However, heparin could be used successfully after rt-PA to inhibit thrombus growth.
Agnelli
G
G
Istituto di Semeiotica Medica, Università di Perugia, Italy.
Pascucci
C
C
Cosmi
B
B
Nenci
G G
GG
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000378:metabolism / Q000627:therapeutic use; D005337:Fibrin / Q000378:metabolism; D006493:Heparin / Q000627:therapeutic use*; D006629:Hirudins / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D000590:Amino Acid Chloromethyl Ketones; D006629:Hirudins; D011994:Recombinant Proteins; D005337:Fibrin; D006493:Heparin; D015951:Factor Xa; D010959:Tissue Plasminogen Activator; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone