dissolution of pre-existing platelet thrombus by synergistic administration of low concentrations of bifunctional antibodies against β3 integrin协同政府解散现有的血小板血栓的低浓度的双功能抗体β3整合素.pdfVIP

Dissolution of Pre-Existing Platelet Thrombus by Synergistic Administration of Low Concentrations of Bifunctional Antibodies against b3 Integrin 1,2 2 3 2,3 Suying Dang , Tao Hong , Thomas Wisniewski *, Wei Zhang * 1 Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, 2 Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, People’s Republic of China, 3 Departments of Neurology, Pathology and Psychiatry, New York University School of Medicine, New York, New York, United States of America Abstract Most antithrombotic approaches target prevention rather than the more clinically relevant issue of resolution of an existing thrombus. In this study, we describe a novel and effective therapeutic strategy for ex vivo clearance of pre-existing platelet thrombus by the combination of two bifunctional platelet GPIIIa49-66 ligands that target different parts of the arterial thrombus. We produced an additional GPIIIa49-66 agent (named APAC), which homes to activated platelets. Like our previously described SLK (which targets newly deposited fibrin strands surrounding the platelet thrombus), APAC destroys platelet aggregates ex vivo in an identical fashion with 85% destruction of platelet aggregates at 2 hours. The combined application of APAC and SLK demonstrated a ,2 fold greater platelet thrombus dissolution than either agent alone at a low concentration (0.025 mM). Platelet-rich clot lysis experiments demonstrated the time required for 50% platelet-rich fibrin clot lysis (T50%) by APAC (95 66.1 min) or SLK (145 67.1 min) was much longer than that by combined APAC+SLK (6567.6 min) at the final concentration of 0.025 mM (APAC