haemostasis

Question 1

how does the blood maintain flow normally

Answer 1

red cells, white cells and platelets flowing through vessel

endothelium produces natural heparins, tissue factor pathway inhibitor, thrombomodulin which are all anti-coagulants

constant secretion of NO and prostacyclin from endothelium also prevent cells sticking to vessel wall

Question 2

what substances are involved in clot formation

Answer 2

platelets

vWF

coagulation factors

Question 3

how does a clot remain confined to the site of injury

Answer 3

natural anticoagulants

Question 4

how does the clot disappear over time after the injury has occurred

Answer 4

fibrinolytic system

Question 5

what signals result in platelets and coagulation factors being activated

Answer 5

abnormal surface

physiological activator

Question 6

how does platelet adhesion occur

Answer 6

platelets in the area become activated and sticky

platelet recognises exposed collagen as abnormal and binds to it to plug the hole

von willebrand factor in the circulation sticks the platelets to the abnormal surface

Question 7

what does physiological activator do

Answer 7

sets in place a variety of things including the coagulation cascade to form a definitive clot

Question 8

components of a clot

Answer 8

platelet

Question 9

surface of a platelet

Answer 9

ADP is released into circulation when there is cell/tissue damage

epinephrine is also released into the circulation and you generate thrombin

all these things are produced as a result of trauma and the platelet needs to be able to recognise them to be able to go on and make a clot

platelet glycoproteins bind lots of things:

• vWF
• fibrinogen
• collagen

Question 10

what happens inside a platelet

Answer 10

cell surface receptors

energy sources

tubule system - open canalicular system

Question 11

what is important about the open canalicular system inside platelets

Answer 11

allows the content of the platelets (which is held in granules - alpha, dense, lysosomes) to be secreted onto the surface of the platelets and make them sticky

Question 12

what do dense granules in platelets produce

Answer 12

ADP

calcium

serotonin

Question 13

what do alpha granules in platelets contain

Answer 13

thrombin

vWF

Question 14

process of clot formation

Answer 14

1. platelet travels to break in vessel wall
2. binds to collagen, vWF and to other platelets –> 1y platelet clot
3. platelet has also changed its confirmation to allow it to bind fibrinogen
4. once fibrinopeptides A and B are cleaved off it forms the fibrin clot –> definitive fibrin clot

Question 15

what is the role of platelets in haemostasis (3A +P)

Answer 15

adhere
activation
aggregation

provide phospholipid surface for coagulation

Question 16

process of platelet adherence

Answer 16

1. adheres to collagen (glycoprotein Ia)
2. adheres to vWF (glycoprotein Ib)
3. activation of platelets

Question 17

process of platelet activation and how can different pathways be targeted

Answer 17

1. ADP: P2Y12 pathway - targeted to prevent platelet becoming sticky (prasugrel, ticagrelor, clopidogrel)
2. cycloxygenase pathway - arachidonic acid –> thromboxane A2 (aspirin inhibits this pathway)

Question 18

process of platelet aggregation

Answer 18

thromboxane A2 causes platelets to aggregate

Question 19

process of platelet coagulation

Answer 19

scramblase acts on the internal membrane of the platelet and allows the phospholipid to be expressed on the external surface

Question 20

in what form is vWF produced

Answer 20

made as a molecule then dimerises and multimerises into a multimodal form

Question 21

what does vWF bind to

Answer 21

factor VIII - required for clot formation

glycoprotein Ib

glycoprotein IIb-IIIa

collagen surface

Question 22

von willebrand disease - variants

Answer 22

different variants depend on which site the mutation occurred in

e.g. D1 domain abnormality - prevents you forming high weight multimer (type IIA vWD)

D domain mutation - corresponds to factor VIII binding site (type IIA)

Question 23

fibrin formation

• just need to know that all the factors are there and working properly to be able make a solid fibrin clot

Answer 23

normal clotting sequence: factor XII, XI, IX, VIII, X, prothrombin, fibrinogen –> fibrin

1. tissue factor binds VII and activates it
2. activated VII activates X
3. X and V activates prothrombin –> thrombin
4. thrombin cleaves fibrinogen that’s sat on top of the platelets into fibrin - secures the clot

intrinsic pathway is then fed by thrombin:

1. cleave XI into XIa which then cleaves IX into IXa
2. IXa and VIIIa then cleaves X into Xa which produces a big burst of thrombin –> stable fibrin clot

Question 24

what factor is deficient in haemophilia A

Answer 24

facto VIII

Question 25

what factor is deficient in haemophilia B

Answer 25

IX

Question 26

what is the result of abnormalities in the clotting pathway

Answer 26

fibrinogen isn't cleaved into fibrin and bleeding continues

Question 27

how does the clot remain in place where it formed

Answer 27

1. tissue factor pathway inhibitor (TFPI) - binds to and inhibits activated factor VII and X, stop making thrombin - stop making clot 2. activated protein C system: binds to co-factor (protein S) and together they switch off activated factor VIII and V 3. antithrombin: protease inhibitor, binds to and inactivates activated factor X and binds to and inactivates thrombin

Question 28

how is the clot removed and remodelled

Answer 28

1. fibrinolysis

Question 29

fibrinolysis process

Answer 29

1. endothelial cells respond to formed clot by secreting activators of plasminogen tissue plasminogen activator (t-PA) and urokinase PA 2. t-PA and u-PA cleave plasminogen to make plasmin 3. plasmin is the serine protease and attacks the clot and breaks it down 4. fibrin degradation products are released (e.g. d-dimer)

Question 30

inhibitors of plasminogen

Answer 30

phi I - prevents plasminogen activator from degradation so no plasmin is produced phi II

Question 31

examples of P2Y12 pathway/ADP receptor inhibitors and when are they used

Answer 31

clopidogrel, prasugrel, ticagrelor STEMI, PCI pts

Question 32

mechanism of action of aspirin when is it used

Answer 32

inibits cycloxygenase (prevents production of thrombin and therefore prevents aggregation) used in combination w/ P2Y12 inhibitors

Question 33

GP IIb/IIIa inhibitors examples and how do they work when are they used

Answer 33

abciximab, tirofiban, eptifibatide prevent binding of fibrinogen to GP IIb/IIIa PCI patient - looks like they're continuing to thrombose their stent despite dual antiplatelet therapy

Question 34

how does warfarin work

Answer 34

vitamin K antagonist vit K is required for the pro-translational modification of factors II, VII, IX and X

Question 35

how can you reverse warfarin action

Answer 35

vit K administration (oral/IV) OR infusion of coagulation factor concentrate (II, VII, IX, X) - prothrombin complex concentrate

Question 36

how does low-molecular weight heparin differ from unfractionated heparins

Answer 36

LMWH is the same molecule but w/ cytokines cleaved off changes it's characteristics dosing, 1/2 life, bioavailability and metabolism relevant for individuals w/ abnormal renal function

Question 37

how do heparins work

Answer 37

bind to antithrombin - allows antithrombin to cleave thrombin and activating factor X more quickly

Question 38

new anticoagulants - examples and how do they work

Answer 38

rivaroxaban, edoxaban, apixaban inhibit serine proteases small molecules, sit on active site of activated factor X and prevent it cleaving prothrombin to thrombin no fibrin formation

Question 39

direct thrombin inhibitors how do they work examples

Answer 39

dabigatran, bivalirudin/argatroban directly stick to the thrombin and prevent it performing it's function