Haemostasis

Question 1

What is the definition of haemostasis?

Answer 1

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

USED FOR: TO PREVENT BLOOD LOSS

Question 2

What is the haemostatic plug formation mainly used for?

Answer 2

Mainly important in small blood vessels

Local contractile response to injury

Question 3

What are the steps in the formation of the platelet plug?

Answer 3

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

Question 4

What are properties of platelets?

Answer 4

Small (2-4 um)
Anuclear
Life span = 10 days
Count = 150-350 x 10^9 /l

Have lots of receptors which help to change igt from resting to an activated form

Lots of granules - alpha granules (growth) , dense granules (ADP +ATP)

Phospholipid membrane - when the platelet is activated this gets turned inside out making the cell negatively charged which allows adherence.

Question 5

Describe the production of platelets:

Answer 5

Bone marrow –> haemopoietic stem cells –> promegakaryocyte –> megakaryocyte

Question 6

What are the other roles of platelets?

Answer 6

Haemostasis and thrombosis

cancer

Athersclerosis

Infection

Inflammation

Question 7

Describe the normal blood vessel response to haemostasis:

Answer 7

VWF is in the circulating in the blood and it hides the receptor binding sites until there is damage.

It responds to the collagen and then this leads it to change from a folded globular form to a long stringy form which exposes its binding sites- due to the shear pressure from the blood flow.

Platelets then bind to VWF by GpIb , platelets can also bind to collagen itself but this is only at low shear force by GP6 and a2B1.

Collagen and thrombin activate the platelets and this is what leads to a change in shape, phospholipid surface and release the granules.

Activated platelets (a2bB3) recruit additional platelets leading to aggregation —> also binds to fibrinogen,

–> primary haemostatic plug develops

Question 8

Describe the difference in platelet shape once it is activated:

Answer 8

Flowing disc-shapes –> rolling- ball shaped platelet –>hemisphere shaped (reversible adhesion) —>spreading platelet once it has bound (reversible adhesion)

Question 9

What is purpura?

Answer 9

This is blood dots all of the legs which is can be an indication of leukaemia

Question 10

What is the main enzyme in the coagulation pathway?

Answer 10

Thrombin - cleaves the fibrinogen to allow them to associate and make the fibrin meshwork -acts as the glue to bring the fibres together.

Question 11

Where are the clotting factors formed?

Answer 11

The liver - most plasma haemostatic proteins
Endothelial cells - VWF, TM, TFPI
Megakaryocyte - VWF , FV

Question 12

How else is prothrombin indicated in the pathway?

Answer 12

Factor 2

Question 13

What are the zymogens and serine protease differences?

Answer 13

Zymogens are inacivated where the serine proteases are activated- this is denoted with an a after the factor

Question 14

How does the coagulation pathway begin?

Answer 14

There is damage of the blood vessel which exposes the sub-endothelial matrix.

Question 15

What are the two pathways in the coagulation pathway?

Answer 15

Extrinsic and intrinsic

–> see more details in MCD last year

Question 16

What is tissue factor?

Answer 16

Primary initiator of coagulation.

47kDa integral membrane

normally located at extravascular sites
i.e not usually exposed to the blood (VSMC, fibroblasts etc…)

TF expressed higher in certain organs
(i.e. lungs, brain, heart, testis, uterus, and placenta)

TF in these locations provide further haemostatic protection in these organs.

Question 17

Which substances contain the same GIa domains and why is this significant?

Answer 17

Allow two negatively charged platelets to bind - bind to the phospholipid surface.

FVII, FIX, FX and PC share

EGF domain is involved in protein-protein interactions

all circulate in plasma in zymogen form

activated by proteolysis

Question 18

Describe the GIa domain:

Answer 18

Defines vitamin K-dependent proteins - Warafrin affects this

Gla domains contain 9 - 11 y–carboxyglutamic acid residues

Question 19

What does the removal of the activation peptide lead to?

Question 20

How do you make a large amount of thrombin?

Answer 20

Factor ten will only form a small amount of thrombin.

Thrombin cleaves factor 8 to factor 8a which is a co-factor to activate factor 9 to 9a.

This can actiavte more factor 10a and this leads to a larger amount of thrombin.

Thrombin also activates factor 5.

Feedback activation loop to catalyse fibrinogen into fibrin.

Question 21

What is the factor affected in haemophilia?

Answer 21

A = factor 8 deficiency 
B= factor 9 deficiency 

X- linked disorder

Question 22

What are the inhibitory pathways?

Answer 22

Anti-thrombin

Tissue factor pathway inhibitor - targets the initiation phase of coagulation –> exposure, factor 7 to factor 7a and factor 10 to factor 10a

APC (activated protein c - chops up factor 5a and 8a (co-factors))and protein S

Question 23

How do you confine the thrombin activity to just the area of damage?

Answer 23

Anti-thrombin - will mop up the active serine proteases.

Question 24

Describe fibrinolysis:

Answer 24

plasminogen —> plasmin

TPA binds to the fibrin clot and this converts the plasminogen into plasmin which degrades the clot.