Fibrinolysis

Question 1

Describe Plasminogen activation

Answer 1

plasminogen activators cleave the bond by Arg561

Question 2

What is Plasminogen?

Answer 2

Glu/or Lys (N-terminal AA, Lys-Plg is shorter), Glu-Plg compact structure, hard to activate (Arg561 is hidden)

Question 3

How to accelerate the plasminogen activation?

Answer 3

• Glu-Plg → Lys-Plg cleavage, or
• Conformational change, eg. by fibrin,
  -> N-terminal peptide removed or flipped, so Arg561-bond is accessible

Question 4

What are Plasminogen activators?

Answer 4

endogeneous: tPA, uPA, FXII?

exogeneous: Streptokinase

Question 5

What is The dual role of fibrin in fibrinolysis:?

Answer 5

• Cofactor in the tPA-mediated plasminogen activation (600X faster)
• Substrate of plasmin

Question 6

What is single-chain tPA?

Answer 6

tissue-type plasminogen activator, released from endothelial cells

Question 7

What is Urokinase (uPA)? How is it isolated?

Answer 7

uPA: urokinase-type plasminogen activator, first isolated from urine

Question 8

Urokinase (uPA) is synthesized by __

Answer 8

endothelial cells

Question 9

Urokinase (uPA) is released into __

Answer 9

blood

Question 10

What is the role of Urokinase (uPA) in ECM?

Answer 10

„extravascular” fibrinolysis, Neu, Mono, cancer cells, etc also express uPA

Question 11

Is Fibrin a cofactor in the uPA-Plg-activation?

Answer 11

NO!

Question 12

In the uPA-Plg-activation, which one is the cofactor?

Answer 12

the uPA-receptor is the cofactor

Question 13

In the uPA-Plg-activation the uPA-receptor is the cofactor
-> What are the consequences?

Answer 13

1/ Pericellular proteolysis around cells expressing uPA-receptor
2/ Plasmin promotes the activation of MMPs– ECM degradation
3/ Role in inflammation, cancer metastasis, etc

Question 14

Contact system activates fibrinolysis
-> What activates Plg to plasmin?

Answer 14

Factor XIIa

Question 15

The role of Factor XIIa in Contact system that activates fibrinolysis

Answer 15

Factor XIIa activates prekallikrein to kallikrein and kallikrein activates scuPA to tcuPA

Question 16

Contact system activates fibrinolysis
-> Factor XIIa activates prekallikrein to kallikrein and kallikrein activates scuPA to tcuPA
-> What is the role of Kallikrein?

Answer 16

Kallikrein makes bradikinin, and bradikinin stimulates tPA-secretion from endothelial cells

Question 17

FXIIa is a poor plasminogen activation, but its plasma concentration is much higher than that of __ or ___

Answer 17

tPA or uPA

Question 18

What is the role of Streptodornase?

Answer 18

Streptodornase cleaves DNA

Question 19

Is Streptokinase (SK) an active enzyme?

Answer 19

No

Question 20

Exogeneous, bacterial plasminogen activators, (Streptokinase)
-> What is the role of SK-Plg- Complex?

Answer 20

SK-Plg- Complex functions as a plasminogen activator

Question 21

Exogeneous, bacterial plasminogen activators, (Streptokinase)
-> What is the role of DNS?

Answer 21

DNS released from leukocytes can inhibit fibrinolysis, bacteria are packed into fibrin
-> Fibrinolysis enables their spreading

Question 22

The role of Fibrinolytic action of plasmin?

Answer 22

Degrades the fibrin network to smaller, water soluble degradation products (FDPs)

Question 23

What is a better substrate for plasmin? Fibrin or Fibrinogen?

Answer 23

Fibrin

Question 24

Characteristics of Fragment X?

Answer 24

Lower clottability FgDP

Question 25

Characteristics of Fragment D, E & Y?

Answer 25

Non-clottable FgDP

Question 26

Characteristics of Fragment X?

Answer 26

Lower clottability FgDP

Question 27

What are characteristics of D-dimer: E-complex?

Answer 27

D-Dimer: laboratory marker of coagulation+fibrinolysis

Question 28

What is PAI-1?

Answer 28

Serpins against tPA, uPA

Question 29

Regulation of fibrinolysis -> Identify the substances in red squares

Answer 29

Question 30

Regulation of fibrinolysis -> Identify the substances in red squares

Answer 30

Question 31

What type of enzyme is Thrombin activatable fibrinolysis inhibitor (TAFI)?

Answer 31

TAFI is a Pro-Carboxypeptidase

Question 32

Definition and role of TAFIa?

Answer 32

an active carboxypeptidase, which removes the C-terminal Lys-rests from fibrin– these were generated by plasmin-cleavage

Question 33

Thrombin activatable fibrinolysis inhibitor (TAFI) -> What is the consequence of Removal of C-terminal Lys-rests

Answer 33

decreases the cofactor activity of the partially cleaved fibrin, and hence, slows down plasminogen activation

Question 34

The role of Serpins in the regulation of fibrinolysis

Answer 34

The enzymes recognize serpins as their substrates, cleave them, but the covalent acyl-enzyme intermediate is stabile, which blocks the active site Ser.

Question 35

Example of Serpins in the regulation of fibrinolysis

Answer 35

Plasmin - Plasmin inhibitor (a2-Antiplasmin) Plasminogen activator - PAI-1, 2... Activated protein C inactivates PAI-1 – a pro-fibrinolytic action

Question 36

Steps of FXIIIa and fibrin stabilization

Answer 36

- Plasmin dissolves the XL- Fibrin slower - FXIIIa cross-links plasmin- inhibitor to fibrin (and PAI-1, TAFI, as well)

Question 37

The role of Anti-fibrinolytic drugs – Lysine-analogues

Answer 37

1. Tranexamic acid and e-aminocaproic acid binds to the kringle domains of plasminogen, diminished fibrin-binding, slower plasminogen activation 2. Helpful in bleeding patients after tooth extraction, fibrinolysis is induced in the mouth

Question 38

What are the 4 Thrombolytics : tPA and tPA-derivatives

Answer 38

1/ Alteplase 2/ Lanoteplase 3/ Tenecteplase 4/ Reteplase