Week 5. Haemostasis Flashcards Preview

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Flashcards in Week 5. Haemostasis Deck (35):

What are the five main components of haemostasis?

1. Coagulation factors.
2. Platelets
3. Blood vessels- vasoconstriction
4. Coagulation inhibitors
5. Fibrinolysis


How are endothelial cells and the endothelium involved in haeostasis?

Allow vasodilation. Normal structure prevents adhesion of platelets, don't want them to stick usually. Endothelial lining is the source of some clotting factor and factors needed for haemostasis.
Von Willebrand factor. Tissue plasminogen activator (tpa)


How are platelets made?

Produced in bone marrow by fragmentation of megakaryocyte cytoplasm. 1 megakaryocyte= 4000 platelets.


How big are platelets?
How long do they live?
What is normal platelet count?
How are they destroyed?

1. 2-4um in diameter
2. 9-10 days
3. 150-400 x 10^9/L
4. Destroyed in spleen and in liver (kupffer cells)


Platelet production

Endomitotic synchronous nuclear replication. Cytplasmic volume increases as nuclear love number increases (In multiples of 2)

Cytoplasm becomes granular and platelets are released. Takes 10 days from stem cell to platelet. Similar time to make as its life span (relatively long)


How is platelet production controlled?

Negative feedback: number of circulating platelets.
Stimulated by TPO (thrombopoietin) which is produced in the liver and increases numbers of platelets.
IL-3 and GM-CSF stimulate precursor cells for platelet production.


Describe platelet structure.

Glycocalyx= outer layer. Has glycoproteins which help to adhere to either surface of damaged blood vessel or to each other.
Dense tubular system. Thromboxane promotes vasoconstriction. Prostoglandin made too.
Platel contraction proteins-make aggregation irreversible. Make it stable. (submembranous filaments)
Canalicular system allows granule release from delta and alpha granules. (cracks in sides of platelets)
Electron dense/delta granules- positive feedback release atp and adp for swelling.
Alpha granules have calcium, needed for every step of coagulation.
Glycogen= energy reserve


What is first thing to happen to limit blood loss?

Vasoconstriction. Immediate. Smooth muscle cells. This is very effective and then other mechanisms take over in an overlapping way.


3 main reactions of platelet plug formation?

1. Adhesion
2. Secretion (granule release rxn)
3. Aggregation


Describe adhesion in the platelet plug formation (first rxn)

Glycoprotein (GP) Ib binds to von Willebrand factor-> leads to adhesion to the subendothelium and exposes the GPIIb/IIa binding sites to fibrinogen and VWF, leading to platelet aggregation. The GPIIa site permits direct adhesion to collagen and explores the GPIIb/IIa


How are the platelet plugs formed?

The platelets develop pseudopodia, to contract more platelets.
Platelets release ADP and thromboxan A2-> increased aggregation.
Platelets swell due to ADP-> facilitates adhesion.
Positive feedback= release more ADP and TXA2. Produce platelet plug.


What is coagulation factor I?



What is coagulation factor II?



What is coagulation factor III?

Tissue Factor


What is coagulation factor XIII?

Fibrin stabilizing factor.


How is coagulation initiation started?

Tissue factor (TF) on surface of endothelial cells and leukocytes.
Not normally in direct contact with circulating blood but when the endothelium is damaged it's exposed to the circulation.
TF binds to coagulation factor VII-> factor VIIa. This starts initiation.


What are the stages of coagulation initiation?

1. Formation of extrinsic tenase complex. FVIIa, FX, Ca2+ and TF come together. Product-> FXa and a little bit of F9 is also activated.

2. Generation of trace thrombin. FXa being activated allows us to generate some trace thrombin, enought to keep process going. FII-> FIIa.

3. Down-regulation of initiation by TFPI. Down regulates production of activated factor X, which limits formation of thrombin.


Describe coagulation amplification

From initiation there's enough thrombin to go to the next step (but not enough to actually form a clot)
Thrombin goes back into system and activates more platelets (it's the most potent platelet activator.)
Also activates 2 cofactors- F8 and F5.
Now this means we can go forwards and produce way more thrombin and FX.
(feedback- f8 and f5 are needed to activate thrombin and more Fx)


Coagulation propogation

1.Formation of intrinsic tenase complex.
Now beginning to stabilise the platelet plug and enhancing it. Now the FIX comes in. Propogates the clot. F9 localises with her cofactor which is factor 8. These are now activated and activate FX. This it he intrinsic pathway. The intrinsic tenase complex needs to have F9 in there.
The aim of this again is to activate FX. This will activate about 90% mor FX than before. There's no inhibitor so can activate a lot more.

2. Formation of prothrombinase complex.
FX localises with its cofactor FV. Prothrombinase complex made.

3. Burst of thrombin generation.
End point. The thrombin will activate fibrinogen. Thrombin activates FVIII-> FVIIIa.
Feeds back to FV, F8,F& etc.
factor 13 (XIII) stabilizes fibrin clot. Irreversible!


What does each complex in coagulation comprise of?

An enzyme, a cofactor and a substrate
-Extrinsic tenase: FVIIa, TF, FX respectively
-Intrinsic tenase: FIXa, FVIIIa, FX
-Prothrombinase: FXa, FVa,FII


What do a lot of these factors in coagulation depend on?

Vitamin K (so can giev patients with too much of the factors vit K antagonists)


What are the inhibitors in coagulation?

-Tissue Factor Pathway Inhibitor (TFPI)- VIIa + Xa

-Antithrombin III- Xa and thrombin

-Protein C and protein SP inactivate TPA. Action of PS enhanced by PC. PC also enhances fibrinolysis.



1st inhibitor to act
Found in plasma and platelets
accumulation in plasma due to platelet activation
Inhibits factors VIIa and Xa


Antithrombin III

Made in liver and endothelium
Inactivates serine proteases, principally factor Xa and thrombin


Proteins C and S

Vitamin K dependent proteins
Made in liver
Protein c- activated via a complex which inactivates factors Va and VIIIa
Action of protein C enhanced by the action of S, binds protein C to the platelet surface.
Protein C enhances fibrinolysis by inactivating the tissue plasminogen activator inhibitor. Clot can break down.



tPA activates plasminogen to plasmin.
Plasmin degrades fibrin. Generates soluble fragments called fibrin degradation products. (FDPs).


Describe these lab platelt tests:
1. bleeding time
2. prothrombin time

1. 1cm incision on arn. tourneque on and leave to bleed. Normal 3-8 minutes. Longer =abnormal or low number of platelets. If abnormal could look at glycoprotein make up of platelet surface, could be mutated.

2. Prothrombin time(PT). (standardised as international normalised ratio, INR)
Tests factors in extrinsic pathway. 7,10,5, prothrombin and fibrinogen. Normal PT=10-14 seconds. Take sample and measure clotting factors. how we monitor people on oral coagulants like warfarin and prolonged liver disease


Activated partial thromboplastin time (APTT)

Measures factors 8,9,11,12 but also 10,5, prothrombin and fibrinogen.
Normal 3-40 seconds.
prolonged in Haemophilia and heparin therapy.
Looks at intrinsic pathway. In common pathway FV,10, prothrombin and fibrinogen. If botht ests are affected (PT and APTT) tells you there's a problem in the common pathway. Tells you where defct lies.
Haemophiliac lacks F8 so aptt affected.



Oral anticoagulant
Vitamin K antagonist - so decrease vit k dependent factors-> 2,5,7,9, and 10.
MOnitored with INR every 6 weeks. But almost every food and antibiotic affects warfarin absirption-> affects INR.
Takes 3-4 days to have an effects because have to wait for stored to be depleted first.
INR different ranges. 2-3 most conditions, 2.5-3.5 for mechanical heart valves.



Anticoagulant drug.
Increases action of antithrombin III on thrombin and FXa, acts immediately unlike warfarin. Low molecular weight heaprin- high bioavailability (95%), self administered by injection. Used in preganncy instead of warfarin because doesnt cross the placenta.
Used as prevention in various surgery procedures.


Fxa inhibitors

Fxa shown to activate clotting over wider concentration than thrombin in moedl systems.

Rivaroxana (xarelto)- NICE approval in UK for growing number of conditions.


Thrombin inhibitors

Thrombin is the final effector of blood coagulation and most potent platelet agonist.
Thrombin inhibitors:
Dabigatran etexilate (Pradaxa)- only ORAL direct thrombin inhibitor.
Others: Bivalirudin and Agatroban



Prevent platelet aggregation. Irreversible inactivation of COX enzyme (needed for prostaglandin and thromboxane synthesis)
INhibits production of htromboxane A2 -platelet aggregation.
Long term, low dose-prevent heart attacks, strokes etc. in high risk individuals. Low dose after heart attack to reduce risk of another one.



ADP receptor inhibitor.
Used in patients who cant tolerate aspirin and inhibits platelet aggregation.
Used in patients high risk of stroke.
Side effects- increases neutropenia (reduction in neutrophils)
Tolerance built up too easily, now clopidogrel usually chosen instead)



Action may be related to adp receptor on platelet membrane.
Prevents ischaemic events in patients with atherosclerosis.
Along with aspirin to prevent thrombosis after placement of intracoronary stent.
MI with (STEMI) or without ST-segment elevation (NSTEMI)