Animal models for arterial thrombolysis and prevention of reocclusion. Erythrocyte-rich versus platelet-rich thrombus.
Experimental animal models for erythrocyte-rich (ER) and platelet-rich (PR) arterial thrombosis were developed in dogs and rabbits and used for the evaluation of the effect of antithrombin and antiplatelet agents on thrombolysis with recombinant tissue-type plasminogen activators (rt-PA). The canine models consist of a whole blood clot produced in the left anterior descending coronary artery (ER thrombus) or a 1-cm everted (inside-out) segment graft in the circumflex coronary artery that predisposes to occlusion with PR material (PR thrombus). The rabbit models consist of a femoral arterial whole blood clot (ER thrombus) or a femoral arterial eversion graft (PR thrombus). The whole blood clot models are sensitive to recanalization with rt-PA but are consistently associated with reocclusion, notwithstanding the concomitant use of heparin and/or aspirin. Clot lysis is accelerated and reocclusion is prevented by the administration of F(ab')2 fragments of a monoclonal antibody 7E3 directed against the platelet glycoprotein IIb/IIIa receptor; of Argatroban, a synthetic thrombin inhibitor; or of kistrin, a glycoprotein IIb/IIIa-blocking polypeptide from the Malayan pit viper venom. The PR thrombus models are very resistant to recanalization with rt-PA, but this resistance can be overcome by the concomitant use of the platelet glycoprotein IIb/IIIa-blocking antibody. Thus, selective platelet glycoprotein IIb/IIIa inhibitors are more effective than aspirin, heparin, or both in accelerating arterial thrombolysis with rt-PA; in preventing reocclusion after clot lysis; and in overcoming the resistance of PR thrombus to dispersion with rt-PA. These experimental animal models may be useful in the development of improved thrombolytic strategies using plasminogen activators in conjunction with specifically targeted antiplatelet and anticoagulant agents.
Gold
H K
HK
Cardiac Division, Massachusetts General Hospital, Boston 02114.
Yasuda
T
T
Jang
I K
IK
Guerrero
J L
JL
Fallon
J T
JT
Leinbach
R C
RC
Collen
D
D
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D001792:Blood Platelets / Q000473:pathology*; D004195:Disease Models, Animal; D004285:Dogs; D004912:Erythrocytes / Q000473:pathology*; D005263:Femoral Artery; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D011817:Rabbits; D012008:Recurrence; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control
D005343:Fibrinolytic Agents