Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy.
Fibrin II monomer has a dramatic inhibitory effect on the rate of heparin-catalyzed inactivation of human alpha-thrombin by antithrombin III. At 6 microM fibrin II monomer, equivalent to the concentration of fibrinogen in plasma, the second-order rate constant was reduced by a factor of 308--from 2.05 x 10(8) M-1.s-1 to 6.65 x 10(5) M-1.s-1. Fibrin II monomer minimally affected the uncatalyzed rate of thrombin inactivation showing a reduction in the second-order rate constant by a factor of only 1.6. Fibrinogen and the product of plasmin degradation of fibrinogen, fragment E, at 6 microM concentrations also decreased the second-order rate constant for heparin-catalyzed thrombin inactivation, but by factors of only 2.7 and 1.9, respectively. On the basis of these observations it is proposed that protection of thrombin from inactivation by heparin-antithrombin III by fibrin II monomer can explain the limited efficacy of heparin in preventing coronary reocclusion in patients treated with tissue plasminogen activator and other fibrinolytic agents.
Hogg
P J
PJ
American Red Cross Blood Services, Southeastern Michigan Region, Detroit, 48232.
Jackson
C M
CM
D000990:Antithrombin III / Q000502:physiology*; D005337:Fibrin / Q000502:physiology*; D005340:Fibrinogen / Q000378:metabolism; D006493:Heparin / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D011485:Protein Binding; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000990:Antithrombin III; D005337:Fibrin; D005340:Fibrinogen; D006493:Heparin; D013917:Thrombin