HOW DOES HYPERFIBRINOGENEMIA LEAD TO THROMBOSIS

Authors
Citation
J. Mcdonagh et Mh. Lee, HOW DOES HYPERFIBRINOGENEMIA LEAD TO THROMBOSIS, Fibrinolysis & proteolysis, 11, 1997, pp. 13-17
Citations number
15
Categorie Soggetti
Hematology,"Medicine, Research & Experimental
Journal title
ISSN journal
13690191
Volume
11
Year of publication
1997
Supplement
1
Pages
13 - 17
Database
ISI
SICI code
0268-9499(1997)11:<13:HDHLTT>2.0.ZU;2-A
Abstract
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.