© 2000 American Heart Association, Inc.
Thrombosis |
Influence of Fibrin Network Conformation and Fibrin Fiber Diameter on Fibrinolysis Speed
Dynamic and Structural Approaches by Confocal Microscopy
Presented in part as an abstract at the meeting of the International Society of Thrombosis and Haemostasis, August 16 to 20, Washington, DC, 1999.
From the Department of Cardiology (J.P.C., G.M.) and the Hemostasis Laboratory (C.L.), Pitié-Salpétrière Hospital, and the Research Laboratory Sainte Marie (J.S., C.S.), Hotel Dieu Hospital, Paris, France, and the Department of Cell and Developmental Biology (J.P.C., D.P., J.W.W.), University of Pennsylvania, Philadelphia.
Correspondence to J.P. Collet, MD, PhD, Department of Cardiology, Centre Hospitalier Universitaire Pitié-Salpétrière, 47, boulevard de l’Hôpital, 75013 Paris, France. E-mail jean-philippe.collet{at}psl.ap-hop-paris.fr
Abstract—Abnormal fibrin architecture is thought to be a determinant factor of hypofibrinolysis. However, because of the lack of structural knowledge of the process of fibrin digestion, relationships between fibrin architecture and hypofibrinolysis remain controversial. To elucidate further structural and dynamic changes occurring during fibrinolysis, cross-linked plasma fibrin was labeled with colloidal gold particles, and fibrinolysis was followed by confocal microscopy. Morphological changes were characterized at fibrin network and fiber levels. The observation of a progressive disaggregation of the fibrin fibers emphasizes that fibrinolysis proceeds by transverse cutting rather than by progressive cleavage uniformly around the fiber. Plasma fibrin clots with a tight fibrin conformation made of thin fibers were dissolved at a slower rate than those with a loose fibrin conformation made of thicker (coarse) fibers, although the overall fibrin content remained constant. Unexpectedly, thin fibers were cleaved at a faster rate than thick ones. A dynamic study of FITC–recombinant tissue plasminogen activator distribution within the fibrin matrix during the course of fibrinolysis showed that the binding front was broader in coarse fibrin clots and moved more rapidly than that of fine plasma fibrin clots. These dynamic and structural approaches to fibrin digestion at the network and the fiber levels reveal aspects of the physical process of clot lysis. Furthermore, these results provide a clear explanation for the hypofibrinolysis related to a defective fibrin architecture as described in venous thromboembolism and in premature coronary artery disease.
Key Words: fibrin • fibrinolysis • confocal microscopy
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