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Year 2 Collin > Haem 7 - Haemostasis > Flashcards

Haem 7 - Haemostasis Flashcards

1
Q

What is haemostasis

A

Cellular and biochemical processes that enable both specific and regulated cessation of bleeding in response to vascular insult

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2
Q

What is haemostasis for

A

Prevent blood loss from intact and injured vessels, enable tissue repair

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3
Q

What may tip the haemostatic balance towards bleeding

A

Increased fibrinolytic factors or anticoagulant proteins

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4
Q

What may tips the balance towards the thrombotic side

A

Increased coagulant factors, platelets

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5
Q

Haemostatic plug formation occurs in response to injury to endothelial cell lining

A
  1. Vessel constriction - VSMC contract locally —> limits blood flow to injured vessel
  2. Formation of unstable platelet plug - platelet adhesion + platelet aggregation —> limits blood loss + provides surface for coagulation
  3. Stabilisation of plug with fibrin - blood coagulation –> stops blood loss
  4. Vessel repair and clot dissolution - cell migration/proliferation and fibrinolysis –> restores vessel integrity
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6
Q

On vessel wall, the endothelial cell is (by definition) anticoagulant - e.g. EPCR. The Layers under the endothelial cell are procoagulant.

A

Y

Subendothelium = procoagulant - basement membrane contains elastin, collagen.

VSMC and fibroblasts also present, alongside Tissue factor (TF)

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7
Q

Describe platelets

A
  1. Small (2-4 um)
  2. Anuclear
  3. Lifespan = 10 daysish
  4. Platelet count = 150-350 x10^9/l
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8
Q

All platelets in our blood are derived from?

A

Megakaryocytes (4000 can be derived from just one MK)

Haematopoietic stem cell –> promegakaryocyte –> megakaryocytic —> platelet

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9
Q

What are the various roles that platelets have

A
  1. Haemostasis and thrombosis
  2. Cancer
  3. Atherosclerosis
  4. Infection
  5. Inflammation
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10
Q

Explain how VWF is involved in haemostasis (platelet adhesion)

A
  1. Multimeric VWF circulates in plasma in globular conformation. Platelet binding site hidden from GP1B on platelet
  2. Vascular injury - damages endothelium and exposes sub-endothelial collagen
  3. Various collagen binding sites that are exposed bind globular VWF
  4. VWF recruited and undergoes structural transformation - unravelled in response to shear forces of flowing blood
  5. VWF binds to GP1B of platelet - recruits platelets to site of vessel damage
  6. IF LOW SHEAR CONDITIONS (i.e. not arteries/capillaries) - platelets can also bind directly to collagen via GPVI and A2B1.
  7. Platelets activated - further recruit platelets
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11
Q

Explain platelet activation.

A
  1. Collagen and thrombin also activate platelets
  2. Platelets bound to collagen/VWF release ADP and thromboxane - activates/primes platelets
  3. Activated platelets (a2bB3) recruit additional platelets. a2bB3 also binds fibrinogen. Platelet plug develops. This helps slow bleeding and provides surface for coagulation
    4.
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12
Q

Upon adhesion, activation and aggregation, how does the platelet change?

A

It starts to spread (once it has become a spreading platelet then irreversible adhesion - but the stage before (hemisphere shaped platelet) is reversible adhesion)

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13
Q

What is the most common inherited bleeding disorder

A

VWD

Causes ineffective platelet recruitment as lack/dysfunctional VWF

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14
Q

What platelet disorders may contribute to abnormal haemostasis

A

Low platelet count (thrombocytopenia) or improperly behaving platelets

Tethered VWF may also get unravelled by shear forces of flowing blood

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15
Q

What is the key role of thrombin

A

To cleave fibrinogen into fibrin

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16
Q

Where do most of our clotting factors come from?

A

Liver

the factors are all serine proteases domain containing

17
Q

What are the cofactors involved in coagulation

A

TF
F5a
F8a

18
Q

Serine proteases contain a catalytic triad - which is?

A

His/Asp/Ser

The serine proteases cleave substrates after specific Arg and Lys residues

19
Q

How is coagulation initiated?

extrinsic pathway - TF

A

Tissue damage causes Tissue factor (TF - integral membrane protein) to come into contact with F7a (plasma protein) - they both bind and switches on F7a.

Hence, TF is a cellular receptor for F7/7a - TF is the only coagulation factor that doesn’t require an activation step

20
Q

Where is TF located?

A

At extravascular sites - expressed higher in certain organs

21
Q

Describe the domain structure that F7, F9, F10 and Protein C & S all share

A

Serine protease, EGF2, EGF1, Gla domain

(going closer to membrane)

Gla domain binds to phospholipid surfaces

EGF domain involved in protein-protein interactions

All the relevant factors circulate in zymogen form

22
Q

What is the formation of a Gla domain dependent on?

A

Vit K

Glutamic acid —- (Vit K carboxylase) —> adds on a carboxylic acid - so there are now 2 negatively charged carboxylic acid domains –> amino acids can now bind Ca very tightly

Binding of Ca causes the structural transition so it can bind phospholipids

THIS IS HOW WARFARIN works

23
Q

What 2 things does the TF-F7a complex do?

A

Proteolytically activated F10 and F9 by removing activation peptide - yields active enzyme

24
Q

What does F10a do?

A

Activates prothrombin - generates thrombin

However, this step is inefficient AF, as only little quantities of thrombin are generated.

But thrombin activates F8a, and F8a is a cofactor for F9a. (Thrombin also activates f5a)

This F8a/F9a complex can then activate F10a. Activation of f10a this way is way more efficient than activation of f10a by TF.

Also, F5a (also activated by thrombin) forms a complex with f10a and can convert prothrombin into thrombin much more efficiently)

25
Q

Haemophilia A is a deficiency in?

wb Haemophilia b?

A

A = F8

B = F9

They are both X-linked

26
Q

What are the 3 means of regulating coagulation

A
  1. TFPI - tissue factor pathway inhibitor
  2. APC and protein S
  3. Anti-thrombin
27
Q

How does TFPI work

usually v low conc in blood

A

TFPI-F10a complex can bind/inactivate TF-F7a active site via Kunitz domain.

Essentially docks the 4 mofos.

TFPI regulates the initiation of coagulation

28
Q

Describe the protein C pathway

Thrombin aka F2A

A

Protein C - plasma protein.

Activated by thrombin-thrombomodulin complex on endothelial cells (Protein C –> APC)

APC inhibits thrombin generation - proteolytically inactivates procoagulant cofactors F5A and F8A

Protein C pathway regulates propagation phase of coagulation - down regulates thrombin generation (doesn’t inhibit thrombin)

29
Q

What are the 2 cofactors

A

F5A and f8a

30
Q

What happens when thrombin binds to thrombomodulin

A

It turns from a procoagulant protease to an anticoagulant protease —> activates PC (by removing activation peptide)

Activation of protein C by definition occurs at the edge of a clot

31
Q

What is antithrombin (AT)

A

SERPIN (SERine Protease INhibitor).

AT inactivates many activated serine proteases (F10A, thrombin, F9A, F11A) - it mops up free serine proteases that escape the site of vessel damage

32
Q

How does heparin work?

A

Binds to thrombin and makes it much better at inhibiting thrombin or F10A

33
Q

Deficiencies of AT, protein C and protein S are important RFs for?

A

Thrombosis

34
Q

How is the clot dissolved?

A

tpa (tissue plasminogen activator) converts plasminogen into plasmin

Plasmin then helps to degraded the clot

tPA can be used therapeutically for thrombosis - promotes dissolution of the clot

35
Q

Name common anticoagulants

A

Heparin, warfarin, DOACs

36
Q

Name common anti platelet agents

A

Aspirin, P2Y12 blockers

37
Q

D-dimer can be used as a test to determine?

A

How much haemostasis has been going on

D-dimer is a fragment of fibrin that is produced when a clot gets degraded - gives snapshot of how much haemostasis has been occurring beforehand

Year 2 Collin (114 decks)

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