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Modified from: Phipps R. Proc Natl Acad Sci. 2000;97:6930-6932. Macrophage Platelets T Cell Adventitia SMC EC = CD40 = CD40 Ligand SMC = Smooth Muscle Cell EC = Endothelial Cell CD40/CD40 Ligand André P, et al. Circulation. 2002;106:896-899. Shedding of CD40 Ligand CD40 ligand ADP Thrombin Collagen PDGF TGF? PF4 TSP GP IIb/IIIa Antagonists CD40 ligand sCD40L PDGF=platelet-derived growth factor. TGFβ=transforming growth factor-β. PF4=platelet factor 4. TSP=thrombospondin. WT CD40-/-Treatment Platelets Platelets Untreated 0.06 ± 0.05 0.02 ± 0.05 sCD40L 12.8 ± 2.2 13.02 ± 0.6 (D117E)-sCD40L 0.41 ± 0.28 0.41 ± 0.10 The Effect of CD40 Ligand on Washed Mouse Platelets D117E=?KGD Prasad K, et al. Proc Natl Acad Sci. 2003; 100:12367-12371. Soluble CD40 Induces ?3 Integrin Tyrosine Phosphorylation and Triggers Platelet Activation by Outside-in Signaling Conclusion: sCD40L functions as a primary platelet agonist, that αIIb/β3 is a primary agonist receptor, and that sCD40L functions in autocrine loop to regulate platelet biology. Unstim.=unstimulated. Inwald DP, et al. Circ Res. 2003;92:1041-1048. +CD40 ligand CD62P+ Platelets (%) sCD40LT (mcg/mL) CD40 Is Constitutively Expressed on Platelets and Provides a Novel Mechanism for Platelet Activation 0 10 0.01 0.1 1.0 Unstim. 70 60 50 40 30 20 10 Endpoints Primary Endpoint Incidence of major bleeding Cerebrovascular, retroperitoneal, GI bleed, or need for a transfusion Rate of site-access complications Arteriovenous fistula, pseudoaneurysm, major hematoma, need for surgical repair Secondary Endpoint 30-day MACE Danzi GB, et al. Catheter Cardiovasc Interv. 2004;61:179-184. Results Tirofiban Abciximab P n=274 n=280 Major Bleeding 0% 1.4% 0.12 Site-access Complications 3.3% 3.6% 0.96 30-day MACE 5.8% 7.1% 0.65 Death 0.3% 2.1% MI 4.3% 3.2% Repeat PCI 0.7% 0.7% CABG 0.4% 1.1% Danzi GB, et al. Catheter Cardiovasc Interv. 2004;61:179-184. Comparison in Patients Having Primary Coronary Angioplasty of Abciximab ver