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Cardiovascular system > Haemosatasis 1 > Flashcards

Haemosatasis 1 Flashcards

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1
Q

What are the two potential outcomes of the haemostatic system

A

May stop you bleeding to death.

May kill you with thrombosis

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2
Q

What is the ultimate aim of clinical haemostasis

A

A balance between thrombosis and bleeding

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3
Q

What happens in an intact blood vessel

A

coagulation factors (denoted by roman numerals) help form plug, regulatory proteins stop premature firing to prevent thrombosis

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4
Q

Describe the platelets

A

fragments of cells made from megakaryocytes in bone marrow, containing granules and receptors

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5
Q

Where are the triggers for coagulation found though

A

Found outside the circulation- expressed on fibroblasts (collagen and tissue factors).

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6
Q

What is separated at rest in haemostasis

A

factors and cofactors separated

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7
Q

What is the von Wileband Factor

A

VWF is a giant adhesive plasma protein
with many binding sites for platelets (GP1b, GP2b3a), collagen, factor VIII; assembled to multimers (20-50 monomers); usually rolled up in blood so binding sites hidden
Biggest soluble protein in the blood.

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8
Q

Describe what the von Willeband Factor does in response to shear stress

A

The collagen binding sites are normally hidden- but the shear stress of blood stretches collagen and when it binds to collagen- it becomes long and thin-exposing binding sites
Must be bound to collagen first
Bumps and gaps represent monomer

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9
Q

Describe the key features of platelet structure

A

Adhesive receptors on surface can bind to vWF (GP1b complex/Integrin alpha-II-b-beta3) and collagen (P1a-Iia/GPVI complex)
Stimulatory receptors on surface can be activated by ADP (purine receptors e.g. P2Y1/12), thromboxane and PGI2

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10
Q

What can stimulate platelet activation

A

ADP, Thromboxane and PGI2.

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11
Q

Describe the histology of platelets

A

Much smaller than erythrocytes

Granular (ADP, fibrinogen, vWF).

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12
Q

What granules are present inside the platelet

A

Lysosome
Alpha granule
Dense granule

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13
Q

Describe the formation of the platelet plug

A 
Endothelium damaged
Blood meets collagen and tissue factor
VWF in rolled up form
VWF binds to collagen- stretched out
Binding sites exposed for platelets
Platelet Activation
Degranulation- more VWF- more platelets trapped
Fibrinogen links the platelets together
Formation of primary platelet plug
Coagulation system not used.
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14
Q

What is not required for primary haemostasis

A

Tissue factor

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15
Q

What happens in platelet activation

A

Conversion from a passive to an interactive cell

Activated platelets:

Change shape
Expose phospholipid- negatively charged phospholipid.
Present new or activated proteins on their surface (i.e. GpIIb/IIIa)

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16
Q

What can cause platelets to change shape

A

Shape changes during adhesion, activation and aggregation

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17
Q

What happens when platelets bind to the VWF

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A

Platelets bind to VWF via GpIb
This slows down the platelet- allowing it to bind to collagen via Gp I- II alpha or the GPV1 complex. Platelets link together via fibrinogen via GPIIB-IIIa.
This binding activates the platelet and signals the activation of the platelet:
Dense granules release ADP
Alpha granules release Fibrinogen and VWF
Phospholipid exposed- TXA2 produced- which can act on the platelet
Brought about by Ca2+ influx.

18
Q

What does primary haemostasis require

Study These Flashcards
A

Requires
Collagen
Platelets
Von Willebrand Factor

19
Q

Where is primary haemostasis sufficient

Study These Flashcards
A

Sufficient for small vessels

In larger vessels requires stabilisation (fibrin)

20
Q

How do we stabilise the plug formed in primary haemostasis

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A

Coagulation:
Formation of a fibrin mesh
(secondary haemostasis)

21
Q

Where are Clotting Factors, Fibrinolytic

Factors and Inhibitors synthesised

Study These Flashcards
A
  1. The liver
  2. Endothelial cells (VIII and VWF)
  3. Megakaryocytes ( differentiate to platelets) (VWF ± FV)

Most synthesis is in the liver

22
Q

What does ‘a’ mean after VIIa

Study These Flashcards
A

Activated

Circulates in its active form- but useless until it meets its cofactor (tissue factor).

23
Q

Describe secondary haemostasis

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A

Endothelium damaged
Blood meets collagen and tissue factors (normally outside the vessel)
In 2o haemostasis, collagen not important, factor VIIa (activated factor VII - circulates in active form; useless unless tissue factor co-factor present) binds to co-factor
Tissue factor-VIIa complex forms, converting inactive FIX/FX zymogens to activated FIXa/Fxa
TFPI (Tissue factor pathway inhibitor) binds to FXa, FVIIa, and TF to sequester in inactive form to dampen and stop pathway as soon as begins
If large enough stimulus, FXa converts FII to thrombin
Thrombin forms FV and FVIII- which are cofactors for FXa and FIXa respectively- Ca2+, PL, FIXa, FVIIIa] which converts FX to FXa, and [Ca2+, PL, FXa, FVa] which converts FII to thrombin

24
Q

What is thrombin

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A

Thrombin cleaves fibrinogen (soluble and bulk) to fibrin (insoluble and forms mesh)

25
Describe the amplification effect of these complexes
cofactor and enzyme have massive amplification effect - 105 x normal activity, working in cascade to make thrombin from FII (prothrombin)
26
Describe the thrombin burst
Tissue stimulated with tissue factor- lag phase whilst things get activated Massive spike in thrombin release- soon returns to normal as thrombin is mopped up Less pronounced thrombin release in patients with Haemophilia A.
27
What is the importance of the thrombin burst
``` Essential for normal haemostasis A thrombin burst generates a stronger, denser clot which is more resistant to fibrinolysis Factor XIII is activated by thrombin cross links fibrin and inhibits fibrinolysis Deficiency of coagulation factor(s) causes a bleeding disorder due a to failure of thrombin burst Thrombin activates TAFI – an inhibitor of fibrinolysis ```
28
Describe secure haemostasis
primary haemostatic plug forms, and then secondary haemostatic net forms on top (made of fibrin linked by FXIII)
29
Summarise haemostasis
1. Simply viewed, it is a cascade or amplification system 2. There are zymogens (inactive) which are converted to proteinases, cofactors which need to be activated and surfaces 3. The surface is made of activated platelets (Pl) which localise and accelerate the reactions 4. The trigger to initiate coagulation in vivo is tissue factor 5. Although FXII can be activated to FXIIa, this is mainly an in vitro reaction, useful for some diagnostic tests
30
Is FXII physiologically necessary
No- but used for diagnostic tests- part of the contact activation system No F12- you won't bleed No F8- you will bleed.
31
Why does blood not clot completely
Coagulation inhibitory mechanisms prevent this
32
Describe the anticoagulant function of the endothelium at rest
collagen/tissue factors kept separate from circulation; endothelial proteins are anti-thrombotic (heparin/heparans/PGI2, NO and ADPase)
33
Describe the regulation of completed coagulation
Direct Inhibition: Antithrombin (sometimes known as antithrombin III), which is an inhibitor of thrombin and other clotting proteinases TFPI – in the initiation phase Indirect inhibition: Inhibition of thrombin generation by the protein C anticoagulant pathway This deals with the cofactors.
34
Describe the role of heparin
Heparin accelerates the action of antithrombin Makes it more reactive x1000. Bridges thrombin and antithrombin activity
35
What is antithrombin
(i) Antithrombin is a direct inhibitor of thrombin and other proteinases antithrombin can then also clear activated enzymes (XIa, IXa, Xa)
36
Describe the role of protein C
ii) the protein C pathway down-regulates thrombin generation TM binds free thrombin TM redirects thrombin function from cleaving fibrinogen and producing FV and FVIII to protein C. Activated Protein C + cofactor protein S down-regulates thrombin generation by degrading Va and VIIIa- forming Vai and VIIIai EPCR presents protein C to TM
37
What will the thrombin trying to escape also meet
Binds to AT on heparans- or in free solution Coagulation system cannot propagate further. Response is limited to the site where it is needed.
38
What is fibrinolysis
process of degrading the clot.
39
Describe the process of fibrinolysis
Localised response tPA (tissue plasminogen activator) converts Pgn (plasminogen) to form Plasmin when meet on Fibrin Plasmin (enzyme) cleaves fibrin to fibrin degradation products (FDPs) Antiplasmin stops plasmin moving to rest of system and degrading all fibrin (to localise)
40
What happens if the coagulation inhibitory mechanisms fail
``` Inappropriate clot formation = thrombosis DUE TO Antithrombin deficiency Protein C deficiency 3. Protein S deficiency ```
41
Describe normal haemostasis
Equilibrium Anti-coagulant factors: Anticoagulant proteins AT, PC, PS Fibrinolytic factors tPA, Pgn Antiplatelet factors PGI2 Endothelium TM, EPCR, TFPI, Heparan Pro-coagulant factors: Coagulation factors I-XI Fibrinolysis inhibitors AP, PAI-1, FXIII, TAFI Platelets Inflammatory mediators IL-6, TNF
42
What is thrombosis
Inappropriate clot formation- in an intact vessel- pathological.

Cardiovascular system (19 decks)

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