Improved understanding of the molecular mechanisms of fibrinolysis has led to major advances in fibrinolytic and antifibrinolytic therapy. Characterization of the genes for all the major fibrinolytic proteins has revealed the structure of the relevant serine proteases, their inhibitors, and their receptors. The development of genetically engineered animals deficient in one or more fibrinolytic protein(s) has revealed both expected and unexpected functions. In addition, we now have a catalog of acquired and inherited disorders reflective of either fibrinolytic deficiency with thrombosis or fibrinolytic excess with hemorrhage. These advances have led to development of more effective and safer protocols for both pro- and antifibrinolytic therapy in a variety of circumstances.
Acronyms and Abbreviations
α2-PI, alpha-2 plasmin inhibitor; APL, acute promyelocytic leukemia; IL, interleukin; MMP, matrix metalloproteinase; Plg, plasminogen; PAI, plasminogen activator inhibitor; TAFI, thrombin-activatable fibrinolysis inhibitor; TGF-β, transforming growth factor beta; t-PA, tissue-type plasminogen activator; u-PA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor.
BASIC CONCEPTS OF FIBRINOLYSIS
In response to vascular injury, fibrin, the insoluble end product of the action of thrombin on fibrinogen, is deposited in blood vessels, thus stemming the flow of blood. Once the vessel has healed, the fibrinolytic system is activated, converting fibrin to its soluble degradation products through the action of the serine protease, plasmin (Fig. 135–1A). Fibrinolysis is subject to precise control because of the actions of multiple activators, inhibitors, and cofactors.1 In addition, receptors expressed by endothelial, monocytoid, and myeloid cells provide specialized, protected environments where plasmin can be generated without compromise by circulating inhibitors (Fig. 135–1B).2,3 Beyond its more traditional role in fibrin degradation, the fibrinolytic system also supports a variety of tissue remodeling mechanisms. This chapter reviews the fundamental features of plasmin generation, considers the major clinical syndromes resulting from abnormalities in fibrinolysis, and discusses approaches to fibrinolytic and antifibrinolytic therapy.
Overview of the fibrinolytic system. A. Fibrin–based plasminogen activation. The zymogen plasminogen (Plg) is converted to the active serine protease, plasmin (PN), through the action of tissue plasminogen activator (t-PA) or urokinase (u-PA). The activity of t-PA is greatly enhanced by its assembly with Plg through lysine residues (K) on a fibrin–containing thrombus. u-PA acts independently of fibrin. Both t-PA and u-PA can be inhibited by plasminogen activator inhibitor–1 (PAI–1), the main physiologic regulator of plasminogen activator activity. By binding to fibrin, PN is protected from its major inhibitor, α2–plasmin inhibitor (α2–PI). Fibrin-bound plasmin degrades crosslinked fibrin, giving rise to soluble fibrin degradation products (FDPs). B. Cell surface plasminogen activation. Although many cell types express receptors for Plg, urokinase, and t-PA, only the endothelial cell is depicted here. The annexin A2 heterotetramer, consisting of two copies each of annexin A2 (A2) and protein p11 (p11), binds both t-PA and Plg, thereby augmenting the efficiency of plasmin generation on endothelial ...
Log In to View More
If your institution is currently a subscriber
of the HemOnc Collection please sign in below.
If your institution is not a subscriber
please click here
to learn more.
Want remote access to your institution's subscription?
Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.
If your institution subscribes to this resource, and you don't have a MyAccess profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus.
Pop-up div Successfully Displayed
This div only appears when the trigger link is hovered over.
Otherwise it is hidden from view.