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BSc module 3 > Thrombin Generation and regulation > Flashcards

Thrombin Generation and regulation Flashcards

1
Q

Stages of coagulation

A

Initiation and proagation

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2
Q

Haemostasis in this context

A

fine balance between pro- and anti- coagulant activities

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3
Q

Excessive procoagulant and/or inadequate anticoagulant function →

A

Thrombosis

e.g. atherosclerosis, genetic risk factors, etc.

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4
Q

Inadequate procoagulant and/or excessive anticoagulant function →

A

Bleeding

E.g. genetic deficiency such as haemophilia, drugs

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5
Q

Necessities of clotting system

A

Rapid response
Localised to site of damage
Once bleeding stopped, must shut down system

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6
Q

Haemostatic plug formation. Step 1

A
  1. Formation of unstable platelet plug: adhesion and aggregation of platelets - limits blood loss and provides surface for coagulation
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7
Q

Haemostatic plug formation. Step 2

A
  1. Stabilisation of plug with fibrin: Blood coagulation - Stops blood loss
    Note: temporary like plaster
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8
Q

Haemostatic plug formation. Step 3

A
  1. Vessel repair and dissolution of clot: Cell migration/proliferation and fibrinolysis - Restores vessel integrity
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9
Q

Platelet activation in step 1 of haemostatic plug formation

A

Platlets also become activated and change their membrane composition - get negatively lipid surface and becomes a mean of attracting platelets

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10
Q

Clot composition

A

Mainly platelet aggregates and all held together by fibrin protein meshwork

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11
Q

Where are proteins for coagulation cascade produced

A

MOSTLY LIVER - produces and secretes into plasma

b. Endothelial cells – VWF, TM, TFPI
c. Megakaryocytes – VWF, FV

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12
Q

What are the clotting factors called when inactive precursors in circulation and why are they inactive

A

Zymogen

- Need them ready to respond to injury but not active else too much clotting

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13
Q

What are active forms of clotting factors calls

A

Serine protease

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14
Q

What are the cofactors

A

TF, FVa, FVIIIa

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15
Q

What are the zymogens

A 
Prothrombin (FII)
FVII
FIX
FX
FXI
FXII
FXIII
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16
Q

What are the serine proteases

A 
thrombin (FIIa)
FVIIa
FIXa
FXa
FXIa
FXIIa
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17
Q

Haemophilia a

A

Definiciency in FVIII

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18
Q

Haemophilia b

A

Deficient in FIX

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19
Q

What are the inhibitors

A

TFPI
Protein C
Protein S
Antithrombin

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20
Q

Haemostasis - sequence of events

A
  1. Coagulation is initiated upon vessel damage, which leads to the exposure of TF to plasma clotting factors
  2. TF-FVIIa can activate FX and FIX.
  3. FXa activates prothrombin (ProT) inefficiently leading to the generation of trace amounts of thrombin.
  4. Thrombin can then activate FVIII and FV, which function as non-enzymatic cofactors for FIXa and FXa, respectively.
  5. FIXa-FVIIIa catalyses the conversion of increased quantities of FXa
  6. FXa-FVa catalyses enhanced generation of thrombin.
  7. Thrombin at the site of vessel damage converts fibrinogen (Fbg) to fibrin (Fbn), which is the molecular scaffold of a clot.
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21
Q

What do majority of reactions in cascade require?

A

↘ Most reactions here require Ca2+ ions and phospholipid membrane
↘ Hence most take place primarily upon activated platelet surfaces

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22
Q

What is FVIIIa a cofactor for?

A

FIXa

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23
Q

What is FVa a cofactor for?

A

FXa

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24
Q

What are coagulation factors made up of

A 
4 common discrete domains:
1. Gla domain
2/3. EGF (2 of these)
4. Serine protease
FIX, FX, FVII, Protein C
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25
Q

What is prothrombin made up of

A
  1. Gla domain
    2/3. Kringle domain (2 of these)
  2. Serine protease
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26
Q

Which factors share same domain organization

A

FVII, FIX, FX and PC
• A homologous modular structure (4 domains)
• All circulate in plasma in zymogen form
• Hence they require activation to become proteolytically competent → activated by proteolysis (removal of activation peptide)

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27
Q

What does EGF domain do?

A

involved in protein-protein interactions

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28
Q

What does Gla domain do

A

binding to phospholipid surfaces

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29
Q

What does Serine protease domain do

A

cleave substrates after specific Arg (and Lys residues)

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30
Q

What are the serine protease domains

A

Homologous family of proteases

Serine protease contain a catalytic triad His/Asp/Ser

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31
Q

How are serine proteases present in plasma

A

precursor zymogens – activated specifically upon demand

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32
Q

Serine protease domain-containing proteins

A
  • FVII
  • FX
  • Prothrombin
  • FIX
  • FXI
  • Protein C
    Note:
    Similar module structure Diverse roles
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33
Q

Gla domain containing proteins:

A

FVII

  • FX
  • FIX
  • Prothrombin
  • Protein C
  • Protein S
34
Q

What does Gla domain do

A

binding to phospholipid surfaces

- Defines vit K dependent protein

35
Q

Effect of Gla on Vit K dependent proteins

A
  1. At the N-terminus of the Gla domain containing protein there are glutamic acid residues
  2. These get post-translationally modified by vitamin K dependant carboxylase
  3. This causes the domain to greatly elevate the binding of Ca2+ to the Gla domains
36
Q

Gla domain structure

A

9 Gla residues with Ca2+ ions sandwiched in
If Gla domain does not have Gla residues → it does not bind to Ca2+
If it does not bind Ca2+ then it cannot fold up into required confirmation (as above) and therefore cannot bind phospholipid surfaces

37
Q

Warfarin action

A

Vit K antagonist: Prevents gama carboxylation - messes up the synthesis of Gla domain containing proteins. Coagulation proteins still produced (no effect on expression levels) but cannot bind to phospholipid surfaces
Hence are not recruited to site of blood vessel damage

38
Q

Omega loop part of hydrophobic residue

A

sually insert into the phospholipid membrane (where water is excluded)

39
Q

What are the requirements for the initiation of coagulation?

A
  1. Fast (to rapidly prevent bleeding)
  2. Specific (must only be activated upon requirement)
  3. Regulated (must be controlled to prevent thrombosis)
40
Q

Property of epithelial cell subface vs subendothelial environent

A

Epithelial cell surface is anticoagulant Blood can flow over with no problem
- Underneath the endothelium the environment is procoagulant (various matrix proteins, collagens, etc.)
Plus other cell types that do not normally come into contact with blood (e.g. VSMCs, fibroblasts)
→ They contain tissue factor (the main initiator of the coagulation cascade)

41
Q

What is TF

A

Integral membrane protein

Cellular receptor and cofactor for FVII and FVIIIa

42
Q

Location of TF

A

located at extravascular sites (usually not exposed to blood)

43
Q

Distinction of TF from other procoagulant factors

A

Only procoagulant factor that does not required an activation event – it is ‘ready to go’
↘ Tissue factor as the primary initiator of coagulation

44
Q

Organs where TF expressed higher and why

A

lungs, brain, heart, testis, uterus, and placenta

→ TF in these locations provide extra haemostatic protection in these organs

45
Q

Ligand for TF

A

Factor VII

46
Q

FVIIa presence in blood at all time

A

1% in blood circulates in active form
This is essential for clotting system
Although we still don’t know where this comes form

47
Q

What does TF-FVII complex do

A

a. Activate FIX to FIXa

b. Activate Factor X to FXa

48
Q

FXa action

A

can activate prothrombin to generate thrombin
Activation is inefficient
Very small quantities of thrombin are generated

49
Q

What does small amount of thrombin do

A

This small amount is able to feedback and amplify its own production
• Via activation of cofactor FVIII and FV

50
Q

Effect of FVIII → FVIIa

A

Provides a cofactor for FIXa

The complex formed then converts more FX → FXa Leads to ↑FXa

51
Q

Effect of FVIIIa vs TF-FVIIa complex

A

much more efficient

Hence a new way of producing more FXa

52
Q

Effect of FV → FVa

A

Makes FXa a super activator of prothrombin → thrombin

Enhances FXa function by ~300,000 times

53
Q

Key thrombin action apart from co-factors

A

convert fibrinogen into fibrin

Spontaneously polymerises into a 3D network

54
Q

Regulation of initiation phase of coagulation (before thrombin produces)

A

Regulation of this part by TFPI

Tissue factor pathway inhibitor

55
Q

Structure of TFPI

A

43kDa Kunitz-type inhibitor TFPI has 3x Kunitz domains

56
Q

What does TFPI inhibit

A

TF-FVIIa in a FXa-dependent manner
• Kunitz domain 2 binds and inhibits FXa
• Kunitz domain 1 binds and inhibits TF-FVIIa
Formation of a complex between these four proteins
Inactive quaternary complex (TF-FVIIa/FXa-TFPI) Has no more procoagulant or enzymatic function

57
Q

Primary influence of TFPI

A

TFPI primarily influences the initiation of coagulation
So if there is only a very small amount of TF exposed, probably don’t need the coagulation cascade and thrombin generation
Hence TFPI will stop the system triggering and the system initiating to any extent - TFPI threshold must be breached before coagulation can proceed efficiently

58
Q

TFPI pathway sequence of events

A
  1. TF (transmembrane) bound to FVIIIa
  2. Complex binds FX (converts it to FXa)
  3. FXa dissociates from complex and moves on
  4. TFPI binds to inhibit FXa via 2nd Kunitz domain
  5. This complex can then dock back to the TF-FVIIa complex
  6. And inhibit the FVIIa via its 1st Kunitz domain
  7. Shuts down the initiation phase
59
Q

Breaching of TFPI threshold

A

Thrombin feedback to activate FVIII and FV cofactors
Once FVIII is activated and forms a complex with FIXa
FXa can be produced via thrombin generation
This is the huge amplification effect
At this point we no longer need TF-FVIIIa complex
Hence TFPI is now of no use

60
Q

Regulation when site of injury ‘plugged’

A

Protein C

61
Q

How is protein C activated

A

activated by thrombin-thrombomodulin

complex on the surface of endothelial cells

62
Q

Action of activated protein C

A

inhibits thrombin generation by proteolytically inactivating procoagulant cofactors FVa and FVIIIa

63
Q

Which phase does protein C act on

A

APC acts primarily upon the propagation phase of coagulation

No effect on initiation phase

64
Q

Factor 5 Leiden

A

Procoagulant genetic trait (5% of population)

Impairs function of Proetein C pathway and get activated protein C resistance

65
Q

Domain organisation of Protein C

A

Gla domain, 2 EGF domains and Serine protease

66
Q

How is protein C pathway switched on

A

When site of injury is filled

→ Thrombin then encounters the endothelial surface and binds to TM

67
Q

What happens when thrombin reaches the endothelium and binds to thrombomodulin

A

If encountering endothelium - means that gap has been plugged so no longer need coagulation.
→ Modulates the action of thrombin
→ Causes it to become an anti-coagulation enzyme

Thrombin can then activate protein C

68
Q

Activation of protein C by…

A

Thrombin–thrombomodulin complex

69
Q

What does activated protein C do

A

(with cofactor protein S) then cleaves FVa (at 3 different sites) and FVIIIa - so they can no longer function as cofactors
Does not inhibit thrombin but downregulates production

70
Q

Cofactor of protein C

A

Protein S.

helps APC assemble on phospholipid surfaces

71
Q

Where does protein C activation take place

A

Perimeter of site of vessel damage

72
Q

What is antithrombin?

A

a 58kDa serine protease inhibitor (SERPIN)

73
Q

Concentration of antithrombin in plasma

A

AT circulates in plasma at high concentration (2.5μM)

74
Q

Action of antithrombin

A
  • inactivates many activated coagulation serine
    proteases (FXa, thrombin, FIXa, FXIa and FXIIa)
  • mops up any free serine proteases that escape the
    site of vessel damage
75
Q

Effect of antithrombin on factors when bound or in comples

A

Does not inhibit factors when bound on a phospholipid surface or in complex.
Only those that escape the site of vessel damage
It is only FREE enzymes

76
Q

What enhances antithrombin?

A

AT is enhanced by GAGs/heparin

Heparin is not in itself an anticoagulant

77
Q

Action of heparin

A
  • Makes anti-thrombin more effective

* It is a cofactor for anti-thrombin

78
Q

Mechanism of antithrombin

A
  1. AT presents a bait loop to target proteases (like mousetrap)
  2. Bait loop contains a ‘mock substrate’
  3. Bait loop binds active site of target protease Thrombin binds in an attempt to cleave the bait loop
  4. AT undergoes a massive conformational change that locks the target protease in a covalent, inactive complex that can no longer function
  5. AT inhibits FREE proteases.
  6. AT cannot inhibit proteases in complexes
79
Q

What is TAT level

A

(Thrombin anti-thrombin levels) Measure of thrombin generation in an individual

80
Q

Use of TAT levels

A

Used in the clinic to look at whether pts have increased amounts of basal clotting
If people have a thrombotic event, ↑clotting
The TAT levels will go up

BSc module 3 (10 decks)

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