title: Fibrin affinity of erythrocyte-coupled tissue-type plasminogen activators endures hemodynamic forces and enhances fibrinolysis in vivo.
abstract: Plasminogen activators (PAs; e.g., tissue-type, tPA) coupled to red blood cells (RBCs) display in vivo features useful for thromboprophylaxis: prolonged circulation, minimal extravasation, and preferential lysis of nascent versus preexisting clots. Yet, factors controlling the activity of RBC-bound PAs in vivo are not defined and may not mirror the profile of soluble PAs. We tested the role of RBC/PA binding to fibrin in fibrinolysis. RBC/tPA and RBC/tPA variant with low fibrin affinity (rPA) bound to and lysed plasminogen-containing fibrin clots in vitro comparably. In contrast, when coinjected in mice with fibrin emboli lodging in pulmonary vasculature, only RBC/tPA accumulated in lungs, which resulted in a more extensive fibrinolysis versus RBC/rPA (p < 0.01). Reconciling this apparent divergence between in vitro and in vivo behaviors, RBC/tPA, but not RBC/rPA perfused over fibrin in vitro at physiological shear stress bound to fibrin clots and caused greater fibrinolysis versus RBC/rPA (p < 0.001). These results indicate that because of high fibrin affinity, RBC/tPA binding to clots endures hemodynamic stress, which enhances fibrinolysis. Behavior of RBC/PAs under hemodynamic pressure is an important predictor of their performance in vivo.
authors.affiliation: Institute for Environmental Medicine, University of Pennsylvania School of Medicine, One John Morgan Bldg., 3620 Hamilton Walk, Philadelphia, PA 19104-6068, USA.
authors.forename: Kumkum
authors.initials: K
authors.lastname: Ganguly
authors.forename: Mukul S
authors.initials: MS
authors.lastname: Goel
authors.forename: Tatyana
authors.initials: T
authors.lastname: Krasik
authors.forename: Khalil
authors.initials: K
authors.lastname: Bdeir
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Murciano
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects*; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011655:Pulmonary Embolism / Q000188:drug therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D005337:Fibrin; D010959:Tissue Plasminogen Activator