New antithrombotic strategies for resistant thrombotic processes

Life-threatening thrombo-occlusive events producing heart attacks and strokes develop in patients at sites of atherosclerotic arterial stenoses when plaques rupture, a process resistant to both aspirin and heparin. Resistant thrombotic complications are also troublesome during therapeutic thrombolytic or mechanical interventions for symptomatic atherosclerotic vascular disease, including angioplasty, various types of atherectomies, endarterectomy, endovascular stent deployment, or implanted small caliber vascular grafts. In this review therapeutic strategies for more effective management of these resistant, platelet-dependent, occlusive thrombi are discussed, including: a) inhibition of platelet recruitment by anti-GPIIb/IIIa monoclonal antibodies, naturally occurring peptides containing RGD sequences, or synthetic competitive analogs; b) direct inactivation of thrombin bound to thrombus by natural or synthetic antithrombin peptides; c) interruption of thrombin's production by natural or synthetic antagonists of Factor Xa or extrinsic and intrinsic coagulation pathways; and d) elimination of thrombogenicity at sites of vascular injury by immediately restoring confluent endothelium or prior therapy with dietary n-3 fatty acids. However, antagonists of both GPIIb/IIIa- and thrombin-dependent platelet recruitment produce equivalent inhibition of thrombus formation and platelet hemostatic function. Interestingly, hemostasis is spared by therapies that inhibit thrombin's production. Recommendations for development strategies are related to the relative hemostatic risks and antithrombotic benefits.