BIOLOGY 2F03 Lecture Notes - Lecture 5: Alpha 2-Antiplasmin, Plasmin, Antifibrinolytic
19 May 2018
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Physiology of F13
• Circulates in plasma bound to the d-domain of fibrinogen
• thrombin cleaves the activation peptide of F13 on the surface of the fibrin clot
o this is much more efficient than thrombin-F13 in vitro
• F13a uses calcium ions to create covalent (isopeptide-gamma-glutaminyl-epsilon-lysyl) bonds
between adjacent fibrin polymers
o this cross linking usually occurs between lysine and glutamine residues (lysine acting as
an acid/ electron donor)
• cross linking between gamma chains occurs first, then alpha chains
1. One of the functions of fibrin it to provide the trigger for its own dissolution
Functions of fibrin
• provides mechanical meshwork/matrix for wound repair
• supports platelet adhesion/aggregation
• provides trigger for its own dissolution (fibrinolysis)
Initiation of Fibrinolysis is driven by fibrin by two major mechanisms
• Plasminogen is a zymogen synthesised in the liver.
• tPA is expressed by endothelial cells. It circulates as an active enzyme with low intrinsic activity.
o Both plasminogen and tPA bind to fibrin via lysine residues on fibrin kringle domains
o this brings plasminogen & tPA into close contact and thus reduces the (Km) minimum
concentration of plasminogen required for a reaction to occur
• Fibrin also directly enhances tPA (increased Vmax for reaction)
• Fibrin enhances tPA to cleave plasminogen on the surface of fibrin to produce plasmin
o Another plasminogen activator, uPA is involved extravascularly and is not influenced by
fibrin. uPA is involved in extraceullar matrix degradation (which contributes to cell
motility) and growth factor activation via plasmin
5. Plasmin is the key molecule in fibrinolysis. Its broad specificity highlights the need for antiplasmin
and other anti-fibrinolytic molecules
• Plasmin has broad substrate specificity and cleaves after lysine and arginine residues
• Plasi reaks firi ito D-diers; it has the aility to reak 50-60 bonds at once
• Plasmin generated by uPA can activate other proteases and cellular growth factors
• hence plasmin is implicated in a wide arrange of disease
o tPA plasmin – CVS disease, atherosclerosis
o uPA pasmin - cancer
Anti-fibrinolytic molecules
• Antiplasmin
• Plasimogen-activator-inhibitors 1 & 2 (tPA inhibitors)
o these are both serine proteases
• Thrombin-activated-fibrinolysis-inhibitor (TAFI)
o carboxypeptidase enzyme which removes lys or arg residues from C-termini of fibrin to
prevent it from stimulating tPA
find more resources at oneclass.com
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Document Summary
Functions of fibrin: provides mechanical meshwork/matrix for wound repair, provides trigger for its own dissolution (fibrinolysis) supports platelet adhesion/aggregation. Initiation of fibrinolysis is driven by fibrin by two major mechanisms: plasminogen is a zymogen synthesised in the liver. tpa is expressed by endothelial cells. Mi: desmodus rotundus pa (from bats which use it to keep sucked blood liquid) for stroke, upa used for mi/pe. 1. 3 antithrombin & heparin: antithrombin is the key anti-coagulant molecule in the termination of coagulation. Structure of antithrombin: 8kda serine protease, has 3 (cid:373)ai(cid:374) (cid:858)parts(cid:859) to the (cid:373)ole(cid:272)ule the main body, a bait loop, and a helical area for. Physiology of antithrombin: circulates in plasma at higher concentration than most coagulation factors, effectively inhibits free circulating serine proteases, but principally thrombin and f10a. Mechanism of action of heparin: heparin pentasaccharide binds to helical area and causes antithrombin to adopt active conformation this is enough to inhibit 10a.
