Fibrinolysis Flashcards
Describe Plasminogen activation
plasminogen activators cleave the bond by Arg561
What is Plasminogen?
Glu/or Lys (N-terminal AA, Lys-Plg is shorter), Glu-Plg compact structure, hard to activate (Arg561 is hidden)
How to accelerate the plasminogen activation?
- Glu-Plg → Lys-Plg cleavage, or
- Conformational change, eg. by fibrin,
-> N-terminal peptide removed or flipped, so Arg561-bond is accessible
What are Plasminogen activators?
endogeneous: tPA, uPA, FXII?
exogeneous: Streptokinase
What is The dual role of fibrin in fibrinolysis:?
- Cofactor in the tPA-mediated plasminogen activation (600X faster)
- Substrate of plasmin
What is single-chain tPA?
tissue-type plasminogen activator, released from endothelial cells
What is Urokinase (uPA)? How is it isolated?
uPA: urokinase-type plasminogen activator, first isolated from urine
Urokinase (uPA) is synthesized by __
endothelial cells
Urokinase (uPA) is released into __
blood
What is the role of Urokinase (uPA) in ECM?
„extravascular” fibrinolysis, Neu, Mono, cancer cells, etc also express uPA
Is Fibrin a cofactor in the uPA-Plg-activation?
NO!
In the uPA-Plg-activation, which one is the cofactor?
the uPA-receptor is the cofactor
In the uPA-Plg-activation the uPA-receptor is the cofactor
-> What are the consequences?
1/ Pericellular proteolysis around cells expressing uPA-receptor
2/ Plasmin promotes the activation of MMPs– ECM degradation
3/ Role in inflammation, cancer metastasis, etc
Contact system activates fibrinolysis
-> What activates Plg to plasmin?
Factor XIIa
The role of Factor XIIa in Contact system that activates fibrinolysis
Factor XIIa activates prekallikrein to kallikrein and kallikrein activates scuPA to tcuPA
Contact system activates fibrinolysis
-> Factor XIIa activates prekallikrein to kallikrein and kallikrein activates scuPA to tcuPA
-> What is the role of Kallikrein?
Kallikrein makes bradikinin, and bradikinin stimulates tPA-secretion from endothelial cells
FXIIa is a poor plasminogen activation, but its plasma concentration is much higher than that of __ or ___
tPA or uPA
What is the role of Streptodornase?
Streptodornase cleaves DNA
Is Streptokinase (SK) an active enzyme?
No
Exogeneous, bacterial plasminogen activators, (Streptokinase)
-> What is the role of SK-Plg- Complex?
SK-Plg- Complex functions as a plasminogen activator
Exogeneous, bacterial plasminogen activators, (Streptokinase)
-> What is the role of DNS?
DNS released from leukocytes can inhibit fibrinolysis, bacteria are packed into fibrin
-> Fibrinolysis enables their spreading
The role of Fibrinolytic action of plasmin?
Degrades the fibrin network to smaller, water soluble degradation products (FDPs)
What is a better substrate for plasmin? Fibrin or Fibrinogen?
Fibrin
Characteristics of Fragment X?
Lower clottability FgDP
Characteristics of Fragment D, E & Y?
Non-clottable FgDP
Characteristics of Fragment X?
Lower clottability FgDP
What are characteristics of D-dimer: E-complex?
D-Dimer: laboratory marker of coagulation+fibrinolysis
What is PAI-1?
Serpins against tPA, uPA
Regulation of fibrinolysis
-> Identify the substances in red squares
Regulation of fibrinolysis
-> Identify the substances in red squares
What type of enzyme is Thrombin activatable fibrinolysis inhibitor (TAFI)?
TAFI is a Pro-Carboxypeptidase
Definition and role of TAFIa?
an active carboxypeptidase, which removes the C-terminal Lys-rests from fibrin– these were generated by plasmin-cleavage
Thrombin activatable fibrinolysis inhibitor
(TAFI)
-> What is the consequence of Removal of C-terminal Lys-rests
decreases the cofactor activity of the partially cleaved fibrin, and hence, slows down plasminogen activation
The role of Serpins in the regulation of fibrinolysis
The enzymes recognize serpins as their substrates, cleave them, but the covalent acyl-enzyme intermediate is stabile, which blocks the active site Ser.
Example of Serpins in the regulation of fibrinolysis
Plasmin - Plasmin inhibitor (a2-Antiplasmin)
Plasminogen activator - PAI-1, 2…
Activated protein C inactivates PAI-1 – a pro-fibrinolytic action
Steps of FXIIIa and fibrin stabilization
- Plasmin dissolves the XL- Fibrin slower
- FXIIIa cross-links plasmin- inhibitor to fibrin (and PAI-1, TAFI, as well)
The role of Anti-fibrinolytic drugs – Lysine-analogues
- Tranexamic acid and e-aminocaproic acid binds to the kringle domains of plasminogen, diminished fibrin-binding, slower plasminogen activation
- Helpful in bleeding patients after tooth extraction, fibrinolysis is induced in the mouth
What are the 4 Thrombolytics : tPA and tPA-derivatives
1/ Alteplase
2/ Lanoteplase
3/ Tenecteplase
4/ Reteplase
