Introduction
Much is known about the fibrinolytic system that converts fibrin-bound plasminogen
to the active protease, plasmin, using plasminogen activators, such as tissue-type
plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plasmin then
cleaves fibrin at specific sites and generates soluble fragments, many of which have
been characterized, providing the basis for a molecular model of the polypeptide chain
degradation.1-3 Soluble degradation products of fibrin have also been characterized by transmission
electron microscopy, yielding a model for their structure.4 Moreover, high resolution, three-dimensional structures of certain fibrinogen fragments
has provided a wealth of information that may be useful in understanding how various
proteins bind to fibrin and the overall process of fibrinolysis (Doolittle, this volume).5,6
Both the rate of fibrinolysis and the structures of soluble derivatives are determined
in part by the fibrin network structure itself. Furthermore, the activation of plasminogen
by t-PA is accelerated by the conversion of fibrinogen to fibrin, and this reaction
is also affected by the structure of the fibrin. For example, clots made of thin fibers
have a decreased rate of conversion of plasminogen to plasmin by t-PA, and they generally
are lysed more slowly than clots composed of thick fibers.7-9 Under other conditions, however, clots made of thin fibers may be lysed more rapidly.10 In addition, fibrin clots composed of abnormally thin fibers formed from certain
dysfibrinogens display decreased plasminogen binding and a lower rate of fibrinolysis.11-13 Therefore, our increasing knowledge of various dysfibrinogenemias will aid our understanding
of mechanisms of fibrinolysis (Matsuda, this volume).14,15
To account for these diverse observations and more fully understand the molecular
basis of fibrinolysis, more knowledge of the physical changes in the fibrin matrix
that precede solubilization is required. In this report, we summarize recent experiments
utilizing transmission and scanning electron microscopy and confocal light microscopy
to provide information about the structural changes occurring in polymerized fibrin
during fibrinolysis. Many of the results of these experiments were unexpected and
suggest some aspects of potential molecular mechanisms of fibrinolysis, which will
also be described here.
