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Pumps, Pipes and Electrics > Regulation of Fibrin Clot Structure and its Role in Thrombosis > Flashcards

Regulation of Fibrin Clot Structure and its Role in Thrombosis Flashcards

1
Q

What is fibrinogen?

A

It is the precursor to Fibrin

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2
Q

How is Fibrinogen converted into Fibrin?

A
  1. When a blood vessel wall is compromised by injury, tissue factor is exposed which activates FVII(7)
  2. FVII then activates FX(10)
  3. FX then activates Thrombin, and simultaneously activates FVIII(8) and FIX(9) needed to boost thrombin amplitude
  4. Thrombin is then used to cleave Fibrinogen and produce Fibrin
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3
Q

What is the pathway that converts Fibrinogen to Fibrin by Thrombin called?

A

The Fibrin Pathway

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4
Q

How does Tissue Factor activate FVII?

A

This is currently unknown.
An enzyme is needed to cleave it, but this enzymes identity remains elusive.
It is possible that FVII may under-go autoactivation, or small quantities of FVII may be in permanent circulation that then become active once bound to Tissue Factor

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5
Q

By what other name is Fibrinogen known?

A

Factor 1

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6
Q

How much fibrinogen is in the body?

A

It is a VERY abundant protein

Approximately 3mg of Fibrinogen per ml of blood

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7
Q

Is fibrinogen Soluble?

A

Yes, but fibrin is NOT

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8
Q

What is Fibrin used for?

A

It is an insoluble protein that forms polymers to make blood clots

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9
Q

What is so good about fibrin?

A

It is one of the most elastic polymers known to nature-it can be stretched to 2.5 times its original length-a quality that makes it as extensible as spider silk

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10
Q

What is a fibrinogen molecule made up of?

A

6 Polypeptide chains:

  • 2 Alpha chains
  • 2 Beta chains
  • 2 Gamma chains
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11
Q

What is meant by a tri-nodular protein?

A

Fibrinogen has 3 main parts:

  • 2 ‘D’ Regions (Distal)
  • 1 ‘E’ Region (central)
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12
Q

What joins the ‘D’ regions to the ‘E’ region?

A

a Coiled-Coil of alpha helices (this is made up of the alpha chains) and provides fibrinogen with its elastic properties

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13
Q

What are fibrinopeptides?

A

Fibrinopeptides are 4 short terminal chains of alpha and beta chains that protrude from the ‘E’ region.
They are about 14-16 amino acid residues long and they are all very flexible

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14
Q

What is an Alpha-C Domain?

A

The other ends of the alpha chains are a LOT longer than the beta and gamma chains (approximately 400 residues longer) and so these protrude from the ‘D’ regions to meet in the central region called the ‘Alpha C Domain’

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15
Q

What is the first step in the Fibrinogen cleaving process?

A
  1. Thrombin binds to Fibrinopeptide Alpha (FpA)
  2. Thrombin then cleaves off this 16-residue FpA sequence to reveal a binding sequence called ‘GPRP’
  3. GPRP then binds with high affinity to an area on the ‘D’ region called the gamma nodule of an ADJACENT fibrinogen molecule which starts the polymerisation process
    THIS MARKS THE PRODUCTION OF FIBRIN I
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16
Q

What sort of bonds form between GPRP and the gamma nodule on an adjacent fibrinogen molecule?

A

Hydrogen Bonds-these are relatively weak

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17
Q

What is the second step in the Fibrinogen Cleaving Process?

A
  1. Fibrinopeptide Beta (FpB) is then also cleaved by Thrombin
  2. This cleaving reveals a binding site called GHRP
  3. GHRP binds with high affinity to the beta nodule on ADJACENT ‘D’ regions
    THIS MARKS THE PRODUCTION OF FIBRIN II
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18
Q

What type of bonds form between GHRP and beta nodule?

A

Hydrogen Bonds-Still weak but they consolidate binding

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19
Q

What is the third step in the Fibrinogen Cleaving Process?

A
  1. Following FpB cleaving, the Alpha C Domains are triggered to unfold and become sticky
  2. Alpha C then too binds to the beta nodules on adjacent fibrinogen molecules along with GHRP
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20
Q

What process does the binding of Alpha C Domains to beta nodules initiate?

A

Lateral Aggregation of Fibrin Protofibrils

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21
Q

How many protofibrils are contained within each Fibrin fibre?

A

Hundreds of protofibrils and aggregations

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22
Q

What is Factor XIII also known as?

A

Fibrin-Stabilising Factor

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23
Q

How is FXIII activated?

A

Cleavage by Thrombin

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24
Q

What type of protein is FXIII?

A

A Transglutaminase - i.e it makes bonds

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25
Q

Where does FXIII come from?

A

It is present in small concentrations in the plasma, but is mainly released from platelets trapped in the Fibrin network of a clot

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26
Q

What does activated FXIII do?

A

It forms Covalent bonds between Fibrin Protofibrils to strengthen the mesh network

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27
Q

Where do the covalent bonds made by FXIII occur?

A

The covalent bonds form across the D-D Interface i.e between the D regions of adjacent protofibrils

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28
Q

Where else does FXIII make covalent bonds?

A

FXIII makes 4 covalent bonds between adjacent Alpha C Domains which stabilises lateral aggregation

29
Q

What is the purpose of these extra covalent bonds made by FXIII?

A

The extra covalent bonds add a tremendous amount of 3D strength to the Fibrin mesh network

30
Q

What happens if we lack/have faulty fibrinogen?

A
  • 40% of patients have an unusually normal phenotype
  • 30% of patients will have a bleeding disorder
  • 30% of patients see thrombosis (thought to form because dysfunctional fibrin means clots aren’t held together as well so emboli break off and form thrombotic disorders)
31
Q

How are fibrinogen levels associated with Coronary Artery Disease and Venous Thrombosis?

A

Patients with CAD and VTE often show high levels of Fibrinogen which may be making them more vulnerable to clot formation

32
Q

What is meant by the statement: ‘Fibrinogen is an Acute Phase Protein’?

A

Fibrinogen’s levels are massively increased during inflammatory states-concentrations can be as much as double normal blood quantities i.e 6mg per ml of blood rather than 3mg

33
Q

What did ‘Machlus, Blood, 2011’ say?

A

Murine In Vivo studies have shown that inflammation plays a causal role in elevating levels of fibrinogen and so inflammation increases thrombosis risk

34
Q

What type of clot are thrombotic disorders associated with?

A

dense clots that are resistant to fibrinolysis, and that occur when fibrinogen levels are high

35
Q

What is a normal clot like in comparison to abnormal?

A

They degrade quicker, less rigid and more elastic

36
Q

How are clots associated with Abdominal Aortic Aneurysm?

A

Blood flow in an AAA is very turbulent, so a laminal thrombus forms around the lining/walls of the vessel

37
Q

What is the problem with thrombus formation in a AAA?

A

The wall thrombus contributes to wall degradation:

  1. Plasmin is released to breakdown the clot which damages the vessel wall
  2. The clot attracts leukocytes such as neutrophils which release elastase which also damages the wall
  3. Leukocytes release further damaging proteases, all of which contribute to the increased risk of vessel rupture
38
Q

What have studies of clots in AAA shown?

A

The larger the aneurysm, the denser the clot.

Even after aneurysm repair surgery, patients are still at very high risk of thrombotic events

39
Q

How are abnormal clots associated with liver disease?

A

Fibrinogen is made in the liver, so previously liver disease has been associated with bleeding disorders. However, it is now apparent that liver disease can also produce denser clots that are less permeable and is thought to occur because cirrhosis renders patients unable to maintain the delicate balance of clotting and so can be pushed in either direction-clotting or bleeding

40
Q

What is a splice variant of a protein?

A

mRNA needs to be spliced before translation to remove non-coding Introns so that only Exons are left behind
When this process occurs in an unusual fashion, an intron may not be spliced out where it ought to be and so a ‘Splice Variant’ of the protein is produced

41
Q

What is Fibrinogen Y(Gamma)’(Prime)?

A

Fibrinogen Y’ is a Splice Variant of Fibrinogen

42
Q

Where does the splice variation in Y’ occur?

A

At the C-terminus of the Gamma Chain

43
Q

Which intron is not spliced out?

A

Intron 9

44
Q

How many extra amino acid residues are left behind that ought to have been removed?

A

~20 residues

45
Q

What is the effect of these extra 20 residues?

A

The 20 residues are mainly negative,meaning that the overall charge on the fibrinogen molecule becomes more negative which affects folding.
The 20 residues also make the fibrinogen molecule longer which too affects folding

46
Q

How and why are there combinations of Y’?

A

There are 2 gamma chains in fibrinogen, so there are 3 combinations of Y’:

  1. YA/YA (Normal) = 80/85%
  2. YA/Y’ (Heterozygous) = 10/15%
  3. Y’/Y’ (Homozygous) = <1%
47
Q

What did Allan,2012 say about Y’ clots?

A

Y’ clots are less dense and weaker because the fibrin fibres are thinner and smaller

48
Q

How did Allan,2012 prove that the effects on clot structure were because of Y’?

A

They used Reptilase (a snake venom that converts Fibrinogen to Fibrin) to assess how fast Y’ clots were made in comparison to YA. The Y’ clot formed much quicker and required much less absorbance of Reptilase

49
Q

How does Y’ Affect protofibril growth? (Allan, 2012)

A

Atomic Force Microscopy has shown that Y’ inhibits protofibril growth.
Normal YA produce protofibrils 327nm long
Y’ protofibrils are 231nm
This is a 30% reduction!

50
Q

What do Allan,2012’s findings prove?

A

It proves that the bulky, 20 residue Y’ extension interferes with D-E-D attraction and bonding between adjacent fibrinogen molecules so protofibril growth is inhibited

51
Q

What did Domingues,2016 discover?

A

Y’ makes no difference to protofibril radius.
But, with Y’ protofibrils, there is a lot LESS packing of Protofibrils in to Fibrin fibres
This may be because the Y’ protofibrils are more negative and so will not be compressed together tightly

52
Q

How many Protofibrils do YA and Y’ fibrin fibres contain?

A

YA= 400 protofibrils
Y’= 150 protofibrils
(this can be visualised using an electron microscope)

53
Q

What does the reduced protofibril packing of Y’ mean for clot structure?

A

Reduced protofibril packing in Y’ decreases clot stiffness.
Y’ fibres are 3 fold less stiff and less elastic
Even cross-linking by FXIII cannot adequately improve the stiffness and elasticity of Y’ protofibrils

54
Q

How does Y’ affect fibrinolysis?

A

You would expect that less packing of protofibrils i.e a less dense clot would result in quicker fibrinolysis, but this is not the case.
Y’ protofibrils are resistant to fibrinolysis by Plasmin
Y’ seems to bind Plasmin and tPA much less effectively (this has implications for the use of thrombolysis in stroke-Kim,2014)
So y’ makes clots less strong but simultaneously more resistant to fibrinolysis

55
Q

Which residues cause the change in properties with Y’?

A

The end of YA shows: AGDV
Y’ replaces the AGDV with 20 different amino acid residues.
To assess which residues cause the change in Y’ function, researchers eliminated the residues in different combinations (unpublished data)
YA + Y’(0 residues) = normal function
Y’(12), Y’(16) + Y’(20) all showed progressive stunted growth with Y’(20) showing the greatest growth restriction
So the more residues there are, the more that protofibril growth is stunted.

56
Q

What studies have looked at physiological concentrations of Y’?

A

Pieters, blood, 2013 collaborated with the PURE epidemiological study
Investigated 2010 subjects in south africa, found that Y’ to YA ratio was 12.1% which further confirms that physiological concentrations of Y’ are generally 10-15%
The study showed that even at physiological concentrations, Y’ was able to exert an effect on clot structure

57
Q

How else has the increased Y’/YA ratio been demonstrated?

A

Light scattering is reduced because of reduced protofibril packing
There is increased resistance to fibrinolysis

58
Q

Pieters,Blood, 2013 aimed to investigate the determinants of increased plasma Y’ levels:

A

They used stepwise forward regression models:
They showed that:
-Cardiovascular risk factors such as smoking, obesity, hypertension and diabetes accounted for 19.9% of increased Y’ (so cardiovascular risk factors cause Y’ levels to increase-don’t know how)
-Total fibrinogen 16% (y’ levels are independently regulated in comparison to YA)
-Other unknown factors account for >60% of Y’ so there is still a lot of research to be done

59
Q

How is FXIII structured?

A

It is composed of 4 subunits:

  • 2 alpha chains that contain the active site
  • 2 beta chains that are the carrier unit
60
Q

What does FXIII bind to?

A

There is a specific FXIII binding site on the Alpha C Domain of the Fibrinogen molecule

61
Q

How is FXIII used?

A
  1. FXIII is activated by thrombin which causes the ‘carrier’ beta subunits to dissociate
  2. The active alpha subunit binds to the gamma nodule on ‘D’ region of fibrinogen and forms covalent bonds
  3. Following FXIII binding to gamma nodule, the Alpha C Domain on fibrinogen opens up and the FXIII moves from the gamma nodule to the Alpha C Domain
  4. 4 covalent bonds are formed between the Alpha C Domains of adjacent fibrinogen molecules
62
Q

How is FXIII related to altered clot structure?

A

FXIII polymorphisms have been linked to cardiovascular disease and may affect clot structure as it changes the way clots are stabilised (Smith, Blood, 2013)

63
Q

What is an SNP?

A

A single Nucleotide Polymorphism - when a nucleotide is swapped for another

64
Q

How do SNPs affect FXIII?

A

FXIII is very polymorphic and the mutations generally occur in the active alpha subunit

65
Q

What is Val34Leu?

A

Valine is swapped for Leucine at position 34

  • This increases FXIII activity and has increased activation by thrombin (Duval, ATVB, 2016)
  • Increased risk of aneurysm and TIA
  • BUT REDUCES MI, VTE, CAD, PE and DVT
  • This mutation is very functional because it sits very close to FXIII’s active site
  • Val34Leu produces stronger fibres as demonstrated by cross-linking in vivo (Duval, ATVB, 2016)
66
Q

What is Tyr204Phe?

A

Tyrosine is swapped for Phenylalanine at position 204

  • It causes a reduced plasma concentration and activity of FXIII
  • it is related to an increased risk of ischaemic stroke (maybe because clot is not stabilised anymore so clot can embolise and cause stroke)
67
Q

What is Pro564Leu?

A

Proline is swapped for Leucine at position 506

  • it causes reduced plasma concentrations but increased FXIII activity
  • it produces an increased susceptibility to M.I
68
Q

Who has investigated the most Polymorphisms and should be used as the reference?

A

Bagoly, Thromb Res, 2012

69
Q

Who should be used as a reference for Val34Leu and its altered thrombin activation rate and increased cross-linking in vivo?

A

Duval, ATVB, 2016

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