Myocardial infarction and the balance between fibrin deposition and removal.
When fibrin deposition and removal are properly balanced, the organism is protected from both a catastrophic loss of blood at the site of injury and the inappropriate loss of fluidity within the vascular system. When these activities are not properly balanced, however, severe bleeding or thromboses can occur. Myocardial infarction is a common and morbid consequence of the latter. The thrombin/thrombomodulin complex plays an essential role in regulating this balance because it generates both an anticoagulant substance, activated protein C, and an antifibrinolytic substance, activated TAFI (thrombin activatable fibrinolysis inhibitor, also known as plasma carboxypeptidase B or carboxypeptidase U). Thus, the coagulation and fibrinolytic cascades are explicitly linked by virtue of thrombin catalyzed activation of TAFI, either by the thrombin/thrombomodulin complex or, in the absence of thrombomodulin, by the massive amounts of thrombin generated through the factor XI-dependent pathway after clotting. Some potential targets for diagnosis, prognosis and therapy related to the balance between fibrin formation and removal include: development of a convenient global assay for plasma fibrinolytic potential; an assay for plasma or urine thrombomodulin that had been oxidized at methionine 388 and thereby has lost its capacity to stimulate activation of protein C but not TAFI; an assay for activated TAFI; discovery of a means for tapping the tremendous potential of the vasculature to acutely release tissue-type plasminogen activator; and an assessment of the potential role of polymorphisms in the TAFI gene which might influence TAFI levels or the properties TAFIa. In addition, a much fuller and quantitative understanding of the properties of the coagulation and tibrinolytic cascades is needed in order to optimize diagnosis, prognosis and therapy in disorders such as myocardial infarction that are related to the balance between fibrin formation and removal.
Nesheim
M
M
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada. nesheimm@post.queensu.ca
D001777:Blood Coagulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005337:Fibrin / Q000096:biosynthesis* / Q000378:metabolism*; D005342:Fibrinolysis / Q000502:physiology; D006801:Humans; D009203:Myocardial Infarction / Q000097:blood* / Q000175:diagnosis / Q000628:therapy; D011379:Prognosis; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000378:metabolism
D018180:Thrombomodulin; D005337:Fibrin; D013917:Thrombin