Haemostasis Flashcards
What is the definition of haemostasis?
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
What is the haemostatic plug formation mainly used for?
Mainly important in small blood vessels
Local contractile response to injury
What are the steps in the formation of the platelet plug?
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
What are properties of platelets?
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.
Describe the production of platelets:
Bone marrow –> haemopoietic stem cells –> promegakaryocyte –> megakaryocyte
What are the other roles of platelets?
Haemostasis and thrombosis
cancer
Athersclerosis
Infection
Inflammation
Describe the normal blood vessel response to haemostasis:
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
Describe the difference in platelet shape once it is activated:
Flowing disc-shapes –> rolling- ball shaped platelet –>hemisphere shaped (reversible adhesion) —>spreading platelet once it has bound (reversible adhesion)
What is purpura?
This is blood dots all of the legs which is can be an indication of leukaemia
What is the main enzyme in the coagulation pathway?
Thrombin - cleaves the fibrinogen to allow them to associate and make the fibrin meshwork -acts as the glue to bring the fibres together.
Where are the clotting factors formed?
The liver - most plasma haemostatic proteins
Endothelial cells - VWF, TM, TFPI
Megakaryocyte - VWF , FV
How else is prothrombin indicated in the pathway?
Factor 2
What are the zymogens and serine protease differences?
Zymogens are inacivated where the serine proteases are activated- this is denoted with an a after the factor
How does the coagulation pathway begin?
There is damage of the blood vessel which exposes the sub-endothelial matrix.
What are the two pathways in the coagulation pathway?
Extrinsic and intrinsic
–> see more details in MCD last year
What is tissue factor?
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.
Which substances contain the same GIa domains and why is this significant?
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
Describe the GIa domain:
Defines vitamin K-dependent proteins - Warafrin affects this
Gla domains contain 9 - 11 y–carboxyglutamic acid residues
What does the removal of the activation peptide lead to?
How do you make a large amount of thrombin?
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.
What is the factor affected in haemophilia?
A = factor 8 deficiency B= factor 9 deficiency
X- linked disorder
What are the inhibitory pathways?
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
How do you confine the thrombin activity to just the area of damage?
Anti-thrombin - will mop up the active serine proteases.
Describe fibrinolysis:
plasminogen —> plasmin
TPA binds to the fibrin clot and this converts the plasminogen into plasmin which degrades the clot.
