HEPARINLESS CARDIOPULMONARY BYPASS WITH ACTIVE-SITE BLOCKED FACTOR IXA - A PRELIMINARY-STUDY ON THE DOG

Objective: Cardiopulmonary bypass is a potent stimulus for activation of procoagulant pathways. Heparin, the traditional antithrombotic agen t, however, is often associated with increased perioperative blood los s because of its multiple sites of action in the coagulation cascade a nd its antiplatelet and profibrinolytic effects. Furthermore, heparin- mediated immunologic reactions (that is, heparin-induced thrombocytope nia) may contraindicate its use. Cardiopulmonary bypass with a selecti ve factor IXa inhibitor was tested to see whether it could effectively limit bypass circuit/intravascular space thrombosis while decreasing extravascular bleeding, thereby providing an alternative anticoagulant strategy when heparin may not be safely administered. Methods: Active site-blocked factor IXa, a competitive inhibitor of the assembly of f actor IXa into the factor X activation complex, was prepared by modifi cation of the enzyme's active site by the use of dansyl glutamic acid- glycine-arginine-chlormethylketone. Twenty mongrel dogs (five were giv en standard heparin/protamine; 15 were given activated site-blocked fa ctor IXa doses ranging from 300 to 600 mu g/kg) underwent 1 hour of hy pothermic cardiopulmonary bypass, and blood loss was monitored for 3 h ours after the procedure. Results: Use of activated site-blocked facto r IXa as an anticoagulant in cardiopulmonary bypass limited fibrin dep osition within the extracorporeal circuit as assessed by scanning elec tron microscopy, comparable with the antithrombotic effect seen with h eparin, In contrast to heparin, effective antithrombotic doses of acti vated site-blocked factor IXa significantly diminished blood loss in t he thoracic cavity and in an abdominal incisional bleeding model. Conc lusion: These initial studies on the dog suggest that administration o f activated site-blocked factor IXa may be an effective alternative an ticoagulant strategy in cardiopulmonary bypass when heparin is contrai ndicated, affording inhibition of intravascular/extracorporeal circuit thrombosis with enhanced hemostasis in the surgical wound.