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Biochem 2 > Fibrinolysis > Flashcards

Fibrinolysis Flashcards

1
Q

Describe Plasminogen activation

A

plasminogen activators cleave the bond by Arg561

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2
Q

What is Plasminogen?

A

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

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3
Q

How to accelerate the plasminogen activation?

A
  • Glu-Plg → Lys-Plg cleavage, or
  • Conformational change, eg. by fibrin,
    -> N-terminal peptide removed or flipped, so Arg561-bond is accessible
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4
Q

What are Plasminogen activators?

A

endogeneous: tPA, uPA, FXII?

exogeneous: Streptokinase

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5
Q

What is The dual role of fibrin in fibrinolysis:?

A
  • Cofactor in the tPA-mediated plasminogen activation (600X faster)
  • Substrate of plasmin
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6
Q

What is single-chain tPA?

A

tissue-type plasminogen activator, released from endothelial cells

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7
Q

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

A

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

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8
Q

Urokinase (uPA) is synthesized by __

A

endothelial cells

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9
Q

Urokinase (uPA) is released into __

A

blood

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10
Q

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

A

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

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11
Q

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

A

NO!

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12
Q

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

A

the uPA-receptor is the cofactor

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13
Q

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

A

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

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14
Q

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

A

Factor XIIa

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15
Q

The role of Factor XIIa in Contact system that activates fibrinolysis

A

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

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16
Q

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

A

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

17
Q

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

A

tPA or uPA

18
Q

What is the role of Streptodornase?

A

Streptodornase cleaves DNA

19
Q

Is Streptokinase (SK) an active enzyme?

A

No

20
Q

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

A

SK-Plg- Complex functions as a plasminogen activator

21
Q

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

A

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

22
Q

The role of Fibrinolytic action of plasmin?

A

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

23
Q

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

A

Fibrin

24
Q

Characteristics of Fragment X?

A

Lower clottability FgDP

25
Q

Characteristics of Fragment D, E & Y?

A

Non-clottable FgDP

26
Q

Characteristics of Fragment X?

A

Lower clottability FgDP

27
Q

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

A

D-Dimer: laboratory marker of coagulation+fibrinolysis

28
Q

What is PAI-1?

A

Serpins against tPA, uPA

29
Q

Regulation of fibrinolysis
-> Identify the substances in red squares

A
30
Q

Regulation of fibrinolysis
-> Identify the substances in red squares

A
31
Q

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

A

TAFI is a Pro-Carboxypeptidase

32
Q

Definition and role of TAFIa?

A

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

33
Q

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

A

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

34
Q

The role of Serpins in the regulation of fibrinolysis

A

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

35
Q

Example of Serpins in the regulation of fibrinolysis

A

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

36
Q

Steps of FXIIIa and fibrin stabilization

A
  • Plasmin dissolves the XL- Fibrin slower
  • FXIIIa cross-links plasmin- inhibitor to fibrin (and PAI-1, TAFI, as well)
37
Q

The role of Anti-fibrinolytic drugs – Lysine-analogues

A
  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
38
Q

What are the 4 Thrombolytics : tPA and tPA-derivatives

A

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

Biochem 2 (38 decks)

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