The results are shown in Table 1 and Figures 4, 5, and 6. Increasing doses of heparin did not influence the lysis of fibrin in either saline- or rt-PA-treated rabbits. Heparin efficiently inhibited thrombus growth in saline-treated rabbits. This effect was found only with high doses of heparin in rt-PA-treated rabbits. Thrombus weight values were in keeping with the results of the fibrinolysis and thrombus growth-inhi-bition experiments.
Our data confirm that the efficacy of heparin as an adjunct to rt-PA therapy is dose-dependent. They also provide a clue to explain the apparent discrepancy between the results of different experimental studies.- The difference in the results is likely to be due to the use of “therapeutic” doses in some studies (activated partial thromboplastin time [aPTT] prolonged 2-fold above the baseline values) and of larger doses in the others (aPTT prolonged 6- to 8-fold above the baseline values). Our study provides evidence that the level of anticoagulation may play a role in preventing thrombus extension after thrombolysis with rt-PA; thus, the efficacy of heparin could be improved by increasing the dose. Increasing the dosage of heparin is not safe in humans. Thus, there is a need for antithrombotic agents more effective than heparin when administered to the same prolongation ofaPTT.
Table 1—Effect of Heparin on rt-PA-lnduced Lysis
|Treatment||Fibrinolysis, %||Thrombus Growthf||Thrombolysis, %|
|Saline||40±3 (11 ±2)||67±7 (61 ±4)||43±4 (12±2)|
|30U||42±4 (11 ±2)||63±5 (46±4)||46±6 (13±2)|
|50U||41 ±3 (12±3)||61 ±6 (32±3)||54±5 (13±2)|
|100U||44±2 (14±2)||41 ±5 (23±4)||58±4 (14±2)|
|200U||46±3 (14±3)||29 ±3 (19 ±3)||63±6 (16±2)|
Figure 4. Effects of increasing doses of heparin (anti-Xa U/kg) infused over 3 h with rt-PA, 0.4 mg/kg, or with saline on lysis of preformed fibrin.
Figure 5. Effects of increasing doses of heparin (anti-Xa U/kg) infused over 3 h with rt-PA, 0.4 mg/kg, or with saline on fibrin accretion on preformed thrombi.
Figure 6.Thrombolytic effects of increasing doses of heparin (anti-Xa U/kg) infused over 3 h with rt-PA, 0.4 mg/kg, or with saline. Thrombolysis was assessed by wet weight of the residual thrombosis.