Coagulation

Question 1

Overall balance between clot formation and clot dissolution

Answer 1

clot formation
* Primary haemostasis -> immediate reaction to injury/trauma - primary haemostatic plug
* coagulation cascade

imbalance will lead to bleeding tendancy or prothrombotic tendancy

Question 2

diagram to summarise haemostasis

Answer 2

injury ->
* vasoconstriction of blood wall (mechanical step - reduced flow -> minimise blood loss)
* plt activation -> aggregation -> primary plug
* plt aggregate provider for phospholipid component for coag cascade

Question 3

main function of leucocytes in blood clot formation

Answer 3

provide link with the tissue factor

Question 4

vasoconstriction in haemostasis

Answer 4

mechanical reflex
smooth muscle in subendothelail componenet of blood vessels

supported by collagen, elastin, glyosaminoglycans

Question 5

How is the endothelium involved in haemostasis

Answer 5

Acts as a barrier between coag proteins and subendothelial tissue
* if breached -> exposure of subendothelial connective tissue -> primary haemstatic plug and coag

produce
* PGI2 (prostaglandin) part of arachidonic acid metabolism for plt function
* VWF
* plasminogen activators - involved in breakdown of clot - fibrinolysis
* thrombomodulin - receptor essential for protein C pathway

Question 6

plt plug formation

Answer 6

subendo connective tissue exposed -> activate plts -> glued into area damaged

VWF involved -> stable plt plug

Question 7

origin of plts

Answer 7

start from plt precursers
megakaryocyte - stepwise proliferation in bone marrow - released in circ. each produce up to 4000 plts

plt lifespan 10days

governed by thrompoietic factors - thrombopoietin, interleukins 6 and 12
can use these if person has low plts

Question 8

when will you see the effect of stopping anti-plts

Answer 8

eg aspirin/clopidogrel

10 days - because paralyse plts for rest of lifespan (10days)

so have to stop 7-10days before surgery

Question 9

features of plts

Answer 9

glycoprotein as receptors - communication channel where interact with other plts, endothelium, VWF

dense granules - contain energy providing units
alpha granules - contain growth factors, fibrinogen and factor 5

open cannalicular system and microtubules and actomyosin - provide surface area when activated

Question 10

Mech of plt plug formation

Answer 10

1. subendo exposed
2. plt adhere to glycoprotein 1b with assistance from VWF or directly through glycoprotein 1a
3. release of ADP and thromboxane a2
4. plt aggregation - through glycoprotein IIbIIIa (ie fibrinogen receptor)

Question 11

presentation of VWF deficiency

Answer 11

present like dont have plts - because of lack of plt adhesion

Question 12

first thing given in suspected MI

Answer 12

aspirin - to give an antiplt effect

Question 13

production of PGI2 and thromboxane A2

Answer 13

metabolism of arachidonic acid
under cyclo-oxygenase enzymes (COX)

Question 14

Mechanism of aspirin

Answer 14

block COX irreversibly

Question 15

mech of NSAIDs

Answer 15

block COX
reversible - so effect on plts only last for transient period

Question 16

Main pathways of plt activation

Answer 16

arachidonic acid metabolism

ADP receptors - clopidogrel target this

Question 17

summarise clot formation

Answer 17

intrinsic pathway
extrinsic - activation of tissue factor and factor 7 - rate limiting factor for factor 10 so call them tenase

need phopsholipid

want prothrombin -> thrombin -> fibrinogen -> fibrinogen

amplication with each factor

thrombin formed following activation of plt plug -> activation of fibrinogen, plts. factor 5 and 8, zymogens (7 11, 13)

prothrombinanes -> activate activation of prothrombin -> thrombin -> catalyse fibrinogen (unstable monomer) into fibrin (stable polymer)

Question 18

initiation phase of clot formation

Answer 18

1. damage of epithelium
2. release of TF and factor 7
3. activate 9 and 10
4. factor 10 with actuvated 5 - go onto next step

Question 19

factor 5 leiden

Answer 19

commonest hereditory prothrombotic condition in caucasian
cant be involved with amplification stage

they are activated protein C resistant - factor 5 is resistant to break down by actuvted protein C because of nucleotide substitution

Question 20

amplification stage of clot formation

Answer 20

Question 21

propagation phase of clots

Answer 21

actuvated plts with 9 10 and 5 - result in more activation by recruitment of more activated 10 and 5 -> thrombin burst

Question 22

summarise amplification

Answer 22

formation of thrombin generation influenced by the number of components

Question 23

vit K dependent clotting factors

Answer 23

2 7 9 10
produced in liver
need vit K as co-enzyme for gamma carboxylase enzyme

if Vit K deficient - liver will still make the factors - they will just be inactive

Question 24

why would you be vit K deficient

Answer 24

diet
broad spectum Abx - kill flora needed to make vit K
obstruction of biliary tract - because vit K is fat soluble required bile form intestinal biliary system
warfarin

Question 25

summarise fibrinolysis

Answer 25

activated simultaniously to blood clot formation

plasminogen activator released from endothelium -> plasmin -> break down fibrin -> fibrin degradation products

plasminogen -> plasmin under tissue plasminogen activator (tPA) and urokinase - give tPA in thrombolytic therapy with MI, peripheral vascular disease, VTE, stroke - want to reperfuse

red arrows are inhibitors

Question 26

summarise antithrombins

Answer 26

antithrombin binds thrombin - then secreted through the kidney
most active is antithrombin 3

involved in neutralisation of thrombin

antithrombin deficiency is the strongest risk for thrombotic phenotype - present with VTE young

Question 27

How does heparin work

Answer 27

augment effect of antithrombin

Question 28

protein C/S pathway

Answer 28

activated 5 and 8 deactivated to stop thrombin generation
thrombin generate thrombomodulin (transmembrane receptor) -> bind protein C to endothelial protein c receptor -> activated protein C -> with protein S = activated protein C
-> inactivate 5 and 8

cause of activated protein C resistance - factor 5 mutations, or high levels of factor 8.

Question 29

tissue factor pathway inhibitor

Answer 29

intrinsic pathway - recruitment of TF and activation of actiavted factor 7
TFPI activated to neutralise TF and 7 once it ahs activated 9 and 10

dont have routien clincial test for this

Question 30

Mx of haemophilia

Answer 30

prophylactic increase in clotting factor