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A Practical Guide to Laboratory Haemostasis

 

Fibrinolysis: Introduction



Introduction

Fibrinolysis is the process by which fibrin is removed from damaged blood vessels. Fibrinolysis is also important in tissue remodelling and repair after injury.

Key: t-PA - tissue plasminoge activator; u-PA - urinary plasminogen activator; XL-Fibrin - cross-linked fibrin; TAFI - Thrombin Activatable Fibrinolytic Inhibitor.


The components of the fibrinolytic pathway comprise:

Protein Function Half-Life Gene
Plasminogen [PLG] -
is the precursor of plasmin, the active active serine protease that is involved in the breakdown of fibrin. 
Plasmin can also interact with other molecules e.g fibrinogen, factor V, VIII,
PLG contains an active site serine that constitutes the active site serine protease of plasmin but in addition 5 kringle modules [so called because of their resemblance to a Scandinavian pastry, a Nordic variety of pretzel], 4 of which have lysine binding sites and it through these that plasminogen interacts with its substrates; its activators and its inhibitors.
Cleavage of the Arg561-Val562 bond in PLG either by t-PA or u-PA converts the protein from an inactive zymogen to the active serine protease.
50 hours 6q27
t-PA A serine protease secreted constitutively by vascular endothelial cells. 
T-PA is the principal activator of PLG.
T-PA has a shortly half-life of 2-3 minutes in plasma due to the presence of a potent inhibitor termed PAI-1.
The affinity of t-PA for PLG increases significantly in the presence of a fibrin clot.
Cleavage of t-PA from a single chain molecular to a two chain molecule is also associated with an increase in its enzymatic activity.
2-3 minutes 8p11.1
u-PA U-PA was first isolated from urine and from which it obtains it name.
U-PA is an activator of PLG to plasmin and primarily involvd in extra-vascular remodelling and repair after tissue injury.
2-3 minutes 10q22
PAI-1 Major inhibitor of t-PA and u-PA.  Secreted constitutively by vascular endothelial cells.
Member of the SERPIN [serine protease inhibitor] superfamily of proteins.
T-PA:PAI-1 complexes are removed by the liver.
T-PA bound to a fibrin clot is relatively protected from inactivation by PAI-1
4-5 minutes 7q22
α2-antiplasmin
2-Plasmin Inhibitor]
The major inhibitor of Plasmin. 
Member of the SERPIN [serine protease inhibitor] superfamily of proteins.
Cross-linked in the fibrin clot by FXIIIa and so renders the clot resistant to fibrinolysis
72 hours 17p13
Fibrinogen Converted by thrombin to fibrin and cross-linked to form an insoluble polymer by FXIIIa 90 hours 4q32 for all 3 chains
TAFI TAFI removes the C-terminal lysines from plasmin and so removes the binding sites for both PLG and t-PA, 10 minutes 13q14


Data Interpretation

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