Two widely accepted tenants are relevant to consideration of this ques
tion. (1) The structure of a plasma clot is determined by the rate at
which it forms. The rate of formation is determined primarily by the c
oncentration of active thrombin and also the circulating fibrinogen co
ncentration in plasma. High levels of fibrinogen and a low concentrati
on of thrombin result in slow clot formation. (2) Biologically active
molecules bind to fibrin and the stiochometry of their binding may eff
ect the balance between thrombosis and fibrinolysis. These include thr
ombin, plasmin and tissue plasminogen activator (t-PA), and plasminoge
n. Previously there was no definitive mechanism to explain why elevate
d plasma fibrinogen is a risk factor for thrombosis and the answer may
be multifactorial. Some of our experiments will be discussed, from wh
ich a specific mechanism emerges: high plasma levels of fibrinogen res
ult in impaired plasminogen binding to the fibrin gel and thus suppres
sion of fibrinolysis. Direct binding studies showed that t-PA binding
to various forms of fibrin gels did not vary substantially (60-70% of
the total), but plasminogen binding decreased significantly (35-43%) a
s fibrinogen concentration increased and thrombin concentration decrea
sed. The gel composition also varied. With long clotting times the gel
consisted of fibrin II, fibrin I, and fibrinogen in various proportio
n. These studies show that when the clotting time is long, the fibrils
in the gel are long and plasminogen binding is critically suppressed.
Thus, fibrin clots formed with high fibrinogen and approximately phys
iological thrombin concentration have impaired fibrinolysis due to low
plasminogen binding to fibrin and the balance between coagulation and
fibrinolysis is shifted in favour of thrombosis.