Fibrin affinity of erythrocyte-coupled tissue-type plasminogen activators endures hemodynamic forces and enhances fibrinolysis in vivo.
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.
Ganguly
Kumkum
K
Institute for Environmental Medicine, University of Pennsylvania School of Medicine, One John Morgan Bldg., 3620 Hamilton Walk, Philadelphia, PA 19104-6068, USA.
Goel
Mukul S
MS
Krasik
Tatyana
T
Bdeir
Khalil
K
Diamond
Scott L
SL
Cines
Douglas B
DB
Muzykantov
Vladimir R
VR
Murciano
Juan-Carlos
JC
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
D005337:Fibrin; D010959:Tissue Plasminogen Activator