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A Practical Guide to Haemostasis


Fibrinolysis: Introduction


Introduction

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

Schematic of Fibrinolysis

Key: t-PA - Tissue Plasminogen Activator; u-PA - Urokinase-type Plasminogen Activator; XL-Fibrin - cross-linked fibrin; TAFI - Thrombin Activatable Fibrinolytic Inhibitor; TAFIa - Activated Thrombin Activatable Fibrinolytic Inhibitor; α2-AP - Alpha-2-antiplasmin [Alpha2-Plasmin Inhibitor]; scu-PA - single chain Urokinase-type Plasminogen Activator.  A red line indicates an inhibitory pathway.


The components of the fibrinolytic pathway comprise:

Protein Function Half-Life Gene
Plasminogen [PLG] - is synthesised as a zymogen and
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 - Plasmin,
Glu-Plasminogen has a T½ of ~50hr
Lys-Plasminogen has a T½ of ~20hr.
PLG
Maps to the long arm of Chromosome 6: 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 PLAT
Maps to the short arm of Chromosome 8. 8p11.1

u-PA U-PA was first isolated from urine and from which it obtains its name.
U-PA is an activator of PLG to Plasmin and primarily involved in extra-vascular remodelling and repair after tissue injury.  It also has a role in mediating different types of immune response and in tumour metastasis.
2-3 minutes PLAU
Maps to the long arm of Chromosome 10: 10q22.2
PAI-1 Major inhibitor of t-PA and u-PA.  Secreted constitutively by vascular endothelial cells. Also stored in the platelet.
Member of the SERPIN [serine protease inhibitor] super-family 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 SERPINE1
Maps to the long arm of Chromosome 7: 7q22
PAI-2 Member of the SERPIN [serine protease inhibitor] super-family of proteins. 
Inhibitor of t-PA and u-PA.
Present in many cells and is upregulated during pregnancy as it is synthesised by the placenta.  Significant levels of PAI-2 in plasma are found only in pregnancy.
10-11 minutes SERPINB2
Maps to long arm of Chromosome 18: 18q21.33-q22.1
α2-antiplasmin
2-Plasmin Inhibitor]
The major inhibitor of Plasmin. 
Member of the SERPIN [serine protease inhibitor] super-family of proteins.
Cross-linked in the fibrin clot by FXIIIa and so renders the clot resistant to fibrinolysis
72 hours SERPINF2
Maps to the short arm of chromosome 17: 17p13
Fibrinogen Converted by Thrombin to fibrin and cross-linked to form an insoluble polymer by FXIIIa 90 hours FGA, FGBFGG
Map to long arm of Chromosome 4: 4q31.3
TAFI TAFI is activated by Thrombin to TAFIa and this removes the C-terminal lysines from Plasmin and therefore, the binding sites for both PLG and t-PA.  10 minutes CPB2
Maps to the long arm of Chromosome 13: 13q14.11


The individual assays are convered in detail elsewhere on Practical-Haemostasis.com