blood: haemostasis

Question 1

how does damage to blood vessel lead to platelet aggregation

Answer 1

damage to bv-> platelets exposed to collagen + von willebrand factor(vwf) in extracellular matrix + thrombin(later on)-> platelets adhere by adhesion molecules and activate-> mediators released-> vasoconstriction and platelet aggregation-> soft platelet plug forms

Question 2

clotting pathway (initiation– thrombin [2a] produced)

Answer 2

TF + 7-> TF:7A
which causes
9-> 9a
10-> 10a (Ca/PLD) ;
10a:5a causes 
2->2a

Question 3

clotting pathway (amplification– actions of thrombin on platelets); what does thrombin do

Answer 3

platelet activation/change shape
5-> 5a (on platelet surface, by alpha granules)
2a causes cleavage of 8xvwf-> 8a (on platelet surface) + vwf

Question 4

clotting pathway (propagation– production of more 2a)

Answer 4

11-> 11a (by 2a) 
9-> 9a (by 11a) 
8a:9a (TENASE) causes 
10-> 10a (ca/pld) 
10a:5a (PROTHROMBINASE) causes 
2-> 2a (ca/pld)

Question 5

fibrin deposition mechanism

Answer 5

gp2b/3a receptors on ACTIVATED PLATELETS bind to fibrinogen + vwf
thrombin causes fibrinogen-> fibrin monomers
fibrin monomers-> polymers (in presence of ca)
polymers-> blood clot (in presence of 13a)

Question 6

risks of vulnerable plaques

Answer 6

vulnerable plaque: lipid rich core + fibrous cap
unstable coronary artery disease: cap disrupts-> blood clot forms
thrombosis: full occlusion
thrombolysis: some of the clot breaks off-> downstream embolism

Question 7

characteristics of arterial thrombosis (white clots)

Answer 7

associated with atherosclerosis / vascular injury
large platelet component
treat with antiplatelet drugs
cause of most cases of MI + stroke

Question 8

characteristics of venous thrombosis (red clots)

Answer 8

associated with stasis/turbulent flow/vascular injury
hypercoagulability of blood
fibrin/rbc/platelet component
treat with anticoagulants

Question 9

3 antiplatelet drugs; how they work/are used; risk involved

Answer 9

aspirin/p2y12/g2b-3a antagonists (gpi)
reduce risk of arterial thrombosis by inhibiting platelet aggregation
often used for secondary prevention; dual anti-platelet therapy often used
risk of hemorrhage

Question 10

mechanism of aspirin; what about levels of prostacyclin2

Answer 10

aspirin inhibits COX 1 IRREVERSIBLY
COX1 produces TXA2 from acting on arachidonic acid to produce prostaglandin h2
TXA2 is a potent platelet agonist/mitogen/vasoconstrictor
levels of prostacyclin2 not affected, as COX2 still poduces it

Question 11

p2y12 antagonist mechanism and examples

Answer 11

normally p2y12 would cause activation by platelet agonists eg ADP + amplify aggregation by p2y1;
antagonists eg clopidogrel prevent this

Question 12

mechanism of g2b/3a antagonists; 2 drug classes and examples; uses; risk

Answer 12

competes with fibrinogen + vwf for binding with g2b/3a receptors of platelets -> platelet aggregation inhibited;
fab fragments eg abciximab
small molecules eg eptifibatide
both to be used IV;
prevents restenosis after coronary angioplasty;
might cause thrombocytopaenia (low platelet levels), not for LT use

Question 13

anticoagulant and fibrinolytic therapy mechanism/uses/examples

Answer 13

inhibit coagulation cascade, preventing propagation of blood clot but not solution of it.
for treating venous thrombus;
heparin and warfarin

Question 14

heparin mechanism; pros/cons of types of heparin; uses

Answer 14

inhibits serine-protease factors (2a/9a/10a/11a/12a) directly OR potentiates plasma serine-protease inhibitor anti-thrombin3;
UNFRACTIONATED pros: effective/cheap/short halflife; cons: variable bioavailability/continuous infusion/thrombocytopaenia(HIT)/haemorrhage
LMWH pros: high bioavailability/ long halflife/ lower risk of HIT; cons: expensive/haemorrhage

Question 15

wafarin mechanism; characteristics and use

Answer 15

vitamin K antagonist, inhibits vit K dependent epoxide reductase activity-> modifies 2a/7a/9a/10a during synthesis in liver;
orally active/LT therapy/ requires frequent monitoring/affected by diet and genetic variation/antidote with vit K

Question 16

10a inhibitors route/mechanism/examples

Answer 16

IV/SC:
acts indirectly via antithrombin/HIT rare/ eg fondaparinux
ORAL:
inhibits 10a directly; eg apixaban

Question 17

2a inhibitors route/mechanism/ examples

Answer 17

block active site of free and bound thrombin
IV: eg lepirudin
oral: eg dabigatran

Question 18

other naturally anti-clot substances in the blood; origin/activation/mechanism

Answer 18

NO/PGi2 from endothelial cells, inhibit platelet activation and aggregation;
Tissue factor pathway inhibitor(TPFI) from endothelial cells, inactivates and forms complex with 10a + inactivates TF:7a;
Active protein C (APC) activated by thrombin-thrombomodulin, inactivates 5a + 8a via co factor protein S;
antithrombin 3 activated by heparans on endothelial cells + heparin, inactivates 2a/9a/10a/11a/12a

Question 19

how fibrinolytics work; examples

Answer 19

tpa:fibrin AND also fibrinolytics cause plasminogen-> plasmin
plasmin causes clot to break up;
eg sterptokinase / alteplase