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Yr 2 MCD - Haem > 7 - Haemostasis > Flashcards

7 - Haemostasis Flashcards

1
Q

What is haemostasis?

A

The cellular and biochemical processes that enables both the specific and regulated cessation of bleeding in response to vascular insult

Protects us from bleeding out

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2
Q

What is the purpose of haemostasis?

A

To prevent blood loss from intact and injured vessels, enable tissue repair

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3
Q

What normal haemostasis a balance between?

A

Bleeding and Thrombosis

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4
Q

How does a haemostatic plug form?

A

Response to injury to endothelial cell lining

  • Vessel constriction
  • Vascular smooth muscle cells contract locally
  • Limits blood flow to injured vessel
  • Formation of an unstable platelet plug
  • Platelet adhesion
  • Platelet aggregation
  • Limits blood loss + provides surface for coagulation
  • Stabilisation of the plug with fibrin
  • Blood coagulation
  • Stops blood loss
  • Vessel repair and dissolution of clot
  • Cell migration/proliferation & fibrinolysis
  • Restores vessel integrity
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5
Q

Increase in what factors disrupt the normal haemostatic balance towards bleeding and further from thrombosis?

A

Decrease coagulant factors

Decrease platelets

Increase fibrinolytic factors

Increase anticoagulant factors

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6
Q

Increase in what factors disrupt the normal haemostatic balance towards thrombosis and further from bleeding?

A

Increase coagulant factors

Increase platelets

Decrease fibrinolytic factors

Decrease anticoagulant factors

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7
Q

What functions do platelets serve in haemostatic plug formation?

A

Physical barrier

  • fill gap in injured endothelial cell lining
  • although, still need fibrin to stop bleeding completely

Surface
- provide surface for upon which many coagulation reaction occur

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8
Q

What is Primary Haemostasis?

A

PLATELET RECRUITMENT

A platelet plug is formed to rapidly stop the initial bleeding after injury

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9
Q

What is Secondary Haemostasis?

A

STABILISATION OF PLUG

The formation of insoluble, cross-linked fibrin by activated coagulation factors, specifically thrombin.

Fibrin stabilises the primary platelet plug.

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10
Q

What cell layer lines all blood vessels?

A

Endothelial cell layer

It is, by definition, an anticoagulant layer. It allows blood to flow over it without clotting.

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11
Q

What protein is the primary ignitor of the coagulation cascade?

A

Tissue Factor (on smooth muscle cells)

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12
Q

What are the constituents of the endothelial cell lining?

A

ANTICOAGULANT BARRIER

  • TM
  • EPCR
  • TRFI
  • GAG
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13
Q

What are the constituents of the subendothelium?

A

PROCOAGULANT TISSUE

Basement membrane
- elastin, collagen

VSMC
- tissue factor

Fibroblasts
- tissue factor

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14
Q

Why does vessel constriction occur during haemostatic plug formation?

A

Mainly important in small blood vessels

Local contractile response to injury

Reduces amount of blood flowing to the injured region

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15
Q

What are platelets?

A

A small colourless disc-shaped cell fragment without a nucleus (anuclear)

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16
Q

How big are platelets?

A

Small

2-4µm

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17
Q

What is the normal circulating lifespan of a platelet?

A

Approximately 10 days

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18
Q

What is the normal platelet count in humans?

A

150-350 x 10^9/L

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19
Q

What cells are platelets derived from?

A

Megakaryocytes

  • large lobular nuclei
  • granular cytoplasm
  • found within bone marrow
  • there is also a source in the lungs
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20
Q

Outline the development of stem cells to platelets

A

Haematopoietic Stem Cell
- in bone marrow

Promegakaryocyte
- then proliferation

Megakaryocyte

  • then maturation
  • looses its ability to divide
  • become polyploidy
  • 2n to 16n
  • cytoplasm enlarges
  • start to form proplatelets (pseudopodia-like extensions)
  • these extend into the lumen of blood vessel
  • platelets come off the end of these projections into lumen

Platelet

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21
Q

Define polyploidy

A

The state of a cell or organism having more than two paired (homologous) sets of chromosomes

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22
Q

How many platelets does each megakaryocyte produce?

A

Approximately 4000 platelets

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23
Q

How many platelets are produced by a person on average per day?

A

10^11 platelets per day

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24
Q

What is the ultrastructure of a platelet?

A

No nucleus

Receptors on surface

  • α2β1
  • αIIbβ3
  • GPVI
  • GPIb/V/IX
  • P2Y1/12
  • PAR (responsive to thrombin)
  • TP (response to thromboxane)

Granules inside cytoplasm

  • α granules
  • dense granules
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25
Q

What do α granules contain?

A

Contain:

  • growth factors
  • fibrinogen
  • FV
  • Von Willebrand Factor
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26
Q

What do dense granules contain?

A

Contain:

  • ADP
  • ATP
  • Serotonin
  • Ca2+

Secreted on platelet activation

Help augment the action of surrounding platelets

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27
Q

What is the function of microtubules and actomyosin in platelets?

A

Part of the cytoskeleton

Give ability to change shape very dramatically

Important for:

  • platelet morphology
  • shape change
  • pseudopods
  • contraction
  • clot retraction
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28
Q

Why do platelets get flatter and larger as they become active?

A

This gives the a greater surface area of which they can then use to carry out their function

Goes from flowing, disc-shaped platelet to spreading platelet

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29
Q

What are the general roles of platelets in the body?

A

Hameostasis & Thrombosis

Inflammation

Infection

Atherosclerosis

Cancer

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30
Q

Outline platelet plug formation (primary haemostasis) at the cellular level

A

PLATELET ADHESION

Injury to blood vessel endothelium

Several component of sub endothelium become exposed

  • collagen
  • fibronectin
  • laminin

Platelets get recruited to these components via binding domain

Exposed sub-endothelial collagen binds globular VWF via its A3 domain

Tethered VWF is unravelled by rheological shear forces of flowing blood into extended, linear form

This unravelling exposes platelet binding site (Gplb) on VWF

Platelets get tethered

Binding VWF to platelet GpIb (glycoprotein) recruits platelets to site of vessel damage

Platelets can also bind directly to collagen via GPVI and α2β1 receptors on their surface (only at low shear)

PLATELET ACTIVATION

Platelets become activated by collagen and thrombin (signals sent into platelets)

Platelets

  • change shape
  • release granule contents
  • change composition of phospholipid surface

Platelets bound to collagen/VWF release ADP and thromboxane

These released products activate and recruitment further platelets

These platelets recruit other platelets (αIIbβ3)
- cross-linking

αIIbβ3 also binds fibrinogen

Platelets bind to each other via fibrinogen on activated αIIbβ3 integrin

PLATELET AGGREGATION

Platelets aggregate

Platelet plug begins to develop (primary plug)

Helps slow bleeding and provides a surface of coagulation

COAGULATION CASCADE

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31
Q

What protein is important to platelet plug formation circulates in the plasma?

A

Von Willebrand Factor

  • multimeric
  • global formation
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32
Q

What is rheology?

A

The branch of physics that deals with the deformation and flow of matter, especially the non-Newtonian flow of liquids and the plastic flow of solids.

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33
Q

Other than binding via GpIb on their surface, how else can platelets bind to site of damage on endothelium?

A

They can bind via GPVI and α2β1 receptors on their surface

They can only do this at low shear force i.e. not in arteries/capillaries

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34
Q

What form of platelet can carry out firm, but reversible adhesion?

A

Hemisphere-shaped platelet (one step from activated spreading platelet)

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35
Q

What form of platelet carries out irreversible adhesion?

A

Spreading platelet

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36
Q

What are the 4 forms of platelets as they become activated?

A

Flowing, Disc-Shaped Platelet
- form that flows in blood before activation

Rolling, Ball-Shaped Platelet

  • activated
  • starts to have protruding filopodia which make it more sticky and adhesive

Hemisphere-Shaped Platelet
- reversibly adhesive

Spreading Platelet
- irreversible adhesive

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37
Q

What occurs in Von Willebrand’s Disease?

A

Inherited gene

Either reduced VWF levels
OR
Altered VWF protein function

No effective platelet recruitment

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38
Q

What is the most common inherited bleeding disorder?

A

Von Willebrand’s Disease

Affects approximately 1 in 100 people

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39
Q

What is thrombocytopenia?

A

Low levels of platelets

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40
Q

How would a person with a <100x10^9/L platelet level present?

A

No spontaneous bleeding

But may have issues with bleeding during trauma/surgery

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41
Q

How would a person with a <40x10^9/L platelet level present?

A

Common spontaneous bleeding

e.g. In Immune Thromobocytopenia (ITP)

42
Q

What are some of the signs/symptoms of ITP?

A

Immune Thrombocytopenia (ITP)

  • Purpura
  • Multiple Bruises
  • Ecchymoses
43
Q

What is an ecchymosis?

A

An ecchymosis is a subcutaneous spot of bleeding with diameter larger than 1 centimetre

44
Q

What is purpura?

A

Purpura is a condition of red or purple discolored spots on the skin that do not blanch on applying pressure.

45
Q

How would a person with a <10x10^9/L platelet level present?

A

Severe spontaneous bleeding

e.g. In a person having treatment for leukaemia due to myeloablation

46
Q

What is myeloablation?

A

A severe form of myelosuppression.

Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets.

It is a side effect of some cancer treatments.

47
Q

What bleeding disorder signs/symptoms would a person with myeloablation and severely low plaletes have?

A

Purpura

Petechiae

Due to platelets continually fixing our blood vessels

48
Q

What is a petechia?

A

A petechia is a small (1–2 mm) red or purple spot on the skin, caused by a minor bleed from broken capillary blood vessels

49
Q

What is the purpose of the coagulation cascade?

A

To form thrombin

Thrombin can then act as an enzyme which causes fibrinogen to become fibrin

50
Q

What fibres hold the platelet plug together?

A

Fibrin fibres

As the platelet plug forms, fibrin fibres stabilise it

51
Q

What is the primary source of most clotting factors and where are they secreted into?

A

The liver

Secreted into the blood, which is where they circulate

52
Q

In what form do clotting factors circulate?

A

They circulate in an inactive precursor form

- either serine protease zymogens or cofactors

53
Q

How are clotting factors activated?

A

By specific proteolysis

54
Q

What is a zymogen?

A

An inactive substance which is converted into an enzyme when activated by another enzyme

55
Q

What zymogens are part of the clotting cascade and what active enzymes do they become?

A

Prothrombin (Factor 2) –> Thrombin

F7 –> F7a

F9 –> F9a

F10 –> F10a

F11 –> F11a

F12 –> F12a

F13

56
Q

Which zymogens in the clotting cascade contain a GIa domain?

A

F7

F9

F10

57
Q

What cofactors are involved in the clotting cascade?

A

TF (Tissue Factor)

FVa

FVIIIa

58
Q

What inhibitors are involved in the clotting cascade?

A

TFPI

Protein C

Protein S

Antithrombin

59
Q

Which of the components of the clotting cascade become/are serine proteases?

A

F7

F10

Prothrombin

F9

F11

Protein C

60
Q

How do serine proteases function?

A

Once activated, serine protease domain catalyses proteolysis of target substrate

Serine protease contains a catalytic triad
= His/Asp/Ser

These serine proteases cleave substrate after a specific Arg (and Lys residues)

61
Q

Explain how the coagulation cascade occurs

A

Vessel damage exposes subendothelial layer and cells that express TF on their surface

F7 from the blood binds to TF on these cells via GIa domain and forms a complex. This binding activates the enzyme, becomes F7a

TF-F7a complex proteolytically activates F10 and F9 by removing the activation peptide to yield the active enzyme.

F10a converts prothrombin to thrombin. Thrombin is the central protease in the coagulation cascade.

Thrombin converts F8 to F8a

F8a is a cofactor for F9a, which was previously activated three steps before

F8a-F9a complex activates more F10a, which allows more efficient conversion of thrombin

F5 is also activated by thrombin

F5a and F10a form a complex, which can form thrombin up to 3000x more efficiently

Produce enormous amounts of thrombin

Thrombin converts fibrinogen to fibrin

Fibrin gets laid down at the site of vessel damage

62
Q

How is coagulation classically initiated?

A

It is initiated when the blood gains access to cells that have TF on their surface

63
Q

How much more active does TF make FVIIa upon their forming of a complex?

A

TF makes F7a 2x10^6 times more active

64
Q

Which is the only procoagulant factor that does not require proteolytic activation?

A

Tissue Factor (TF)

65
Q

What does TF acts as for FVIIa?

A

Has a cellular receptor for F7a

Cofactor

66
Q

What is a difference between TF protein and FVIIa protein?

A

TF is an integral membrane protein

F7a is a plasma protein

67
Q

What molecule is the primary initiator of coagulation?

A

Tissue Factor (TF)

68
Q

What is the size of TF in kDa?

A

47kDa

69
Q

Where is TF normally located?

A

At extravascular sites

- it is not usually exposed to the blood (VSMC, fibroblasts etc)

70
Q

Is TF present in the same amounts throughout all organs?

A

No, TF is expressed more in certain organs

- i.e. lungs, brain, heart, testes, uterus and placenta

71
Q

What does a higher amount of TF in certain organs suggest?

A

That these organs need further haemostatic protection

72
Q

How big is Factor VII in kDa?

A

48 kDa

73
Q

Where is Factor VII made?

A

Expressed and secreted in the liver

74
Q

What percentage of plasma Factor VII circulates in its activated form?

A

Approximately 1% of Factor 7 circulates in its activated form (F7a)

75
Q

Describe the domain structure of Factor VII

A

GIa domain

2x EGF-like domains

Serine protease domain

IN TOTAL, IT HAS 4 DOMAINS
A HOMOLOGOUS, MODULAR STRUCTURE

76
Q

Which serine proteases have the same domain organisation as Factor VII

A

Factor 9

Factor 10

Protein C

77
Q

Explain the function of each of the domains of Factor VII

A

Gla domain
- binding to negatively charged phospholipid surfaces

EGF domains
- involved in protein-protein interactions

Serine protease domain
- for its enzymatic function

78
Q

Why are Gla domains important in the coagulation cascade?

A

When platelets become activated and become negatively charged on their surface, Gla domain proteins from the circulating blood can bind to the platelets

79
Q

How are Gla domains formed?

A

Characteristic to haemostatic proteins

They are Vitamin K Dependent Proteins

In their end-terminals, they have glutamic acid residues that get modified when the proteins are being synthesised. They are modified in a vitamin K dependent fashion, by having an extra carboxylic acid added onto the glutamic acid residue

End up with two negatively charged carboxylic acid groups attached to these glutamic acids

With this extra charge, gives ability of these amino acids to bind calcium very tightly

All Gla domains have 6 or 7 calcium ions which allow the domains to fold up into their functional, phospholipid binding conformation

80
Q

How does warfarin have anti-coagulant properties?

A

Warfarin itself does not affect haemostasis

Instead, it is an antagonist of vitamin K

Therefore, Gla domains cannot be formed

As such, clotting factors are made that don’t have functional Gla domains and so can’t bind to phospholipid surfaces.

Haemostasis cannot occur correctly as a result

81
Q

What is the issue surrounding the conversion of prothrombin to thrombin via Factor 10a?

A

It is a very inefficient step

Factor 10a by itself can only generate a very small amount of thrombin by itself

82
Q

What can improve the efficiency of the conversion of prothrombin to thrombin via Factor 10a?

A

The Factor 7a-Factor 8a complex

83
Q

What condition can occur in patients deficient in procoagulant factors?

A

Haemophilia

84
Q

What is deficient in Haemophilia A and Haemophilia B?

A

Haemophilia A = Factor 8 deficiency

Haemophilia B = Factor 9 deficiency

85
Q

What is the inheritance of Haemophilia A and B?

A

They are X-linked

Primarily effects boys

86
Q

What inhibitory systems exist to keep the coagulation cascade in check?

A

3 natural anticoagulant pathways

  • TFPI (Tissue Factor Pathway Inhibitor)
  • AT (Antithrombin)
  • APC (Activated Protein C and its cofactor Protein S)
87
Q

How does the TFPI pathway work?

A

Targets initiation process

  • binding of TF
  • binding of F7
  • activation of F10 to F10a

TFPI K2 domain can bind and inhibit the active site of Factor 5a

A complex forms between TFPI and Factor 5a

This complex docks back onto Factor 7a

Therefore, four way complex of TFPI, Factor 10a, Factor VIIa and TF forms which means initiation cannot continue

88
Q

Why doesn’t TFPI completely stop coagulation?

A

There are only small amounts of TFPI in the blood and so this inhibitory pathway can be overwhelmed relatively easily

89
Q

How does the APC pathway work?

A

Activated Protein C Pathway

  • Thrombin binds to TM
  • TM is thrombomodulin
  • TM converts thrombin from a procoagulant to an anticoagulant but it is still an active protease
  • Protein C is activated by thrombin-TM complex on endothelial cells at the edge of a clot
  • APC proteolytically cleaves and inactivates cofactor F5a and F8a
  • Therefore, APC down-regulates (but does not inhibit) thrombin generation
  • This signals that homeostasis can slow down/stop

NOTE: Protein S is the cofactor of Protein C

90
Q

What part of the coagulation cascade does TFPI inhibit?

A

Initiation Phase

91
Q

What part of the coagulation cascade does Protein C inhibit?

A

Propagation Phase

92
Q

As the APC pathway does not inhibit thrombin production, just down-regulates it, what happens to all the excess thrombin and what prevents coagulation from occurring elsewhere?

A

As thrombin is a soluble molecule, it could get transported to other areas of the body. However, we do not want coagulation to occur in random places in the body.

AT inactivates many activated coagulation serine proteases (F10a, F9a, F11a, Thrombin)

AT “mops up” any free serine proteases that escape the site of vessel damage

Therefore, the AT pathway confines thrombin to the site of vessel damage

93
Q

What is AT?

A

Antithrombin (AT)

  • 58kDa serine protease inhibitor (SERPIN)
94
Q

How does heparin work?

A

Heparin itself is not an anticoagulant molecule

Heparin binds to Antithrombin (AT) and makes AT much more effective at mopping up and inhibiting free serine proteases

95
Q

What deficiencies can be risk factors for thrombosis?

A

Deficiencies of:

  • antithrombin (AT)
  • protein S
  • protein C
96
Q

How is the platelet plug eventually degraded?

A

Fibrinolytic System

tPA (tissue plasminogen activator) binds to fibrin in fibrin clot

tPA converts plasminogen to plasmin (activate enzyme)

Plasmin starts to degrade the clot

97
Q

What are the products of fibrin degradation?

A

Fibrin Degradation Product (FDP)
d-dimer

FDP is elevated in Disseminated Intravascular Coagulation (DIC)

98
Q

How can tPA be used therapeutically?

A

It degrades fibrin clots

Therefore, can be used in therapeutic thrombolysis for myocardial infarction, ischaemic stroke etc.

Restores blood flow

99
Q

What drugs can acts as anticoagulants?

A
  • Heparin
  • Wafarin
  • DOACs (Direct-Acting Oral Anticoagulants)
100
Q

What drugs can acts as antiplatelet agents?

A
  • Aspirin

- P2Y12 blockers

101
Q

What tests can be used to investigate why patients have certain clotting abnormalities?

A

Coagulation (PT, APTT)

Platelet Function Tests

d-dimer Test

102
Q

What is the d-dimer test used for?

A

Marker of how much haemostasis has been occurring

d-dimer is a fragment of fibrin which is created when a clot is degraded

Yr 2 MCD - Haem (12 decks)

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