Pharm 16: Haemostasis + thrombosis

Question 1

which one of these are procoagulants:

a) Prothrombin
b) Plasminogen
c) TFPI (Tissue factor pathway inhibitor)
d) Proteins C & S, Antithrombin
e) Factors V, VII-XIII
f) Fibrinogen

Answer 1

a) Prothrombin
e) Factors V, VII-XIII
f) Fibrinogen

Question 2

which one of these are anti-coagulants:

a) Prothrombin
b) Plasminogen
c) TFPI (Tissue factor pathway inhibitor)
d) Proteins C & S, Antithrombin
e) Factors V, VII-XIII
f) Fibrinogen

Answer 2

b) Plasminogen
c) TFPI (Tissue factor pathway inhibitor)
d) Proteins C & S, Antithrombi

Question 3

how does a thrombus form?

Answer 3

initial stages - molecular level

1) tissue factor cells activate F10 + 5 –> to form prothrombinase complex (cell + TF + F10a + F5a)
2) which converts zymogen F2 –> F2a
* antithrombin (AT-III) –> inhibits f2a + F10a

amplification stage - cellular level
1) (thrombin) factor 2a –> activates platelets (platelet changes shape + becomes sticky + later aggregates)

• thrombin binds to PAR on platelet
• activation of PAR causes release of intracellular Ca2+
• which causes exocytosis of ADP
• ADP acts on P2Y12 receipts –> to cause platelet activation + platelet aggregation
• PAR frees AA –> COX makes TXA2 from AA
• TXA2 activation causes –> GPIIb / IIIa expression on platelet surface –> involved in platelet aggregation
• PAR = protease activated receptor

Question 4

describe the amplification process of platelet activation

Answer 4

amplification stage - cellular level
(thrombin) factor 2a –> activates platelets

1) thrombin binds to PAR on platelet
2) activation of PAR causes release of intracellular Ca2+
- -> which causes exocytosis of ADP
3) ADP acts on P2Y12 receptors –> to cause platelet activation + platelet aggregation

• PAR also frees AA –> COX converts AA –> TXA2
• TXA2 activation causes –> GPIIb / IIIa expression on platelet surface –> involved in platelet aggregation

Question 5

Thrombus formation is dependent on Virchow’s triad.

what are the 3 components of Virchow’s triad?

Answer 5

1. Reduced blood Flow (stasis): if slow blood flow –> no replenishment of anticoagulant factors
2. Blood consistency (viscosity): natural imbalance between procoagulation + anticoagulation e.g. factor V leiden (can’t inactivate co-factor V)
3. Endothelial damage –> blood exposed to procoagulation factors e.g. TF

(most specific to vein)

Question 6

explain the 3 stages of coagulation

Answer 6

1. Initial - tissue Factor presentation –> Prothrombinase-mediated formation of factor IIa (thrombin)
2. Amplification - thrombin (fIIa)-mediated platelet activation –> ADP activates P2Y12 receptor –> causes platelet aggregation via GPIIb/IIa
3. Propagation - thrombin-mediated conversion of fibrinogen –> fibrin strands

Question 7

What are some anticoagulant drugs targeting initiation?

Answer 7

a) Dabigatran (oral)= factor 2a inhibitor
b) Rivaroxaban (oral) = factor 10a inhibitor

c)
- Heparin (IV, SC) - activates AT-III (decreases F2a + F10a)
- Low-Molecular Weight heparins (e.g. Dalteparin ) - activate AT-III ( decrease factor 10a)
- -> Increase AT-III activity:

d) warfarin
- -> reduces risk of other factors
- -> vitamin K antagonist (facto 2,7,9,10)

Question 8

a) what is used for interim treatment of a thrombus?

b) what is used to maintain anticoagulation ?

Answer 8

a) interim treatment = dalteparin (parenteral)

b) maintain = warfarin + rivaroxaban (enteral)

Question 9

Describe the activation of platelets

Answer 9

• platelet = activated by thrombin
  o Changes shape
  o Becomes ‘sticky’ and attaches other platelets
• Thrombin binds to protease-activated receptor (PAR) on platelet
• PAR activation –> rise in intracellular Ca2+
• Ca2+ rise –> exocytosis of adenosine diphosphate (ADP) from dense granule
• ADP activates P2Y12 receptors –> cause platelet activation/aggregation

Question 10

activation of PAR liberates ________

COX generates _______ from arachidonic acid

Answer 10

activation of PAR liberates arachidonic acid

COX generates TXA2 from arachidonic acid

Question 11

activation of TXA2 causes expression of what receptors on surface of platelets?

Answer 11

GPIIb/IIIa

Question 12

What are some anti platelets used to prevent platelet activation?

and how do they work?

Answer 12

a) Clopidogrel (oral) – ADP/P2Y12 receptor antagonist
- -> Prevent activation/aggregation

b) Aspirin (oral) - irreversible COX-1 Inhibitor
- -> Inhibit production of TXA2

c) Abciximab (IV, SC) GPIIb/IIIa receptor antagonist
- -> Prevent platelet aggregation

Question 13

when might you use anti platelets?

Answer 13

• Arterial thrombosis

o Acute coronary syndromes – MI (STEMI + NSTEMI)
o Arterial Fibrillation - prophylaxis of stroke

Question 14

do anticoagulants + anti platelets remove pre formed clots?

Answer 14

No

Question 15

how do thrombolytics work?

Answer 15

Convert plasminogen –> plasmin (protease degrades fibrin)

o Alteplase (IV) - recombinant tissue type plasminogen activator (rt-PA)

• -> can lead to excess bleeding
• -> only used in emergency

Question 16

when might thrombolytics be used?

Answer 16

Arterial + venous thrombosis

o Stroke – 1st line treatment
o ST-elevated MI (STEMI)

Question 17

why does DVT (deep vein thrombosis) form ?

Answer 17

o decreased rate of blood flow

o Damage to endothelium

Question 18

how would you deal with DVT?

Answer 18

give anticoagulants

Question 19

whats the difference between NSTEMI + STEMI?

• -

Answer 19

NSTEMI + STEMI = both are acute coronary syndrome

• NSTEMI = ‘White’ thrombus PARTIALLY occluded coronary artery
• no ST elevation
• STEMI = White’ thrombus –> FULLY occluded coronary artery
• ST elevation

BOTH NSTEMI + STEMI Caused by:

• Damage to endothelium
• Atheroma formation
• Platelet aggregation

Question 20

how would you deal with NSTEMI?

what re the drugs administrated ?

Answer 20

–> antiplatelet therapy
(decrease platelet activation/aggregation)
Prevent further arterial occlusion

aspirin + clipidogrel

Question 21

how would you deal with STEMI?

Answer 21

–> anti-platelets + thrombolytic

decreases Platelet activation/aggregation + dissolves clot

Question 22

note: ultrasound scan = used to confirm DVT

Answer 22

-

Question 23

how does treatment of DVT vs PE differ?

Answer 23

DVT

a) interim treatment = dalteparin
b) maintain = warfarin + rivaroxaban

PE

a) interim treatment = dalteparin / Heparin
b) maintain = warfarin + rivaroxaban

they don’t differ that much in treatment

Question 24

note:
thrombus in coronary artery/ arteries = aka white thrombus
thumbs in vein = aka red thrombus

Answer 24

-

Question 25

antithrombin inhibits factors ___ + _____

Answer 25

inhibits factor 2a + 10a

Question 26

how would you deal with ischemic stroke?

Answer 26

- thrombolytic therapy --> alteplase (tPA )

Question 27

note: thrombus forming in atria of heart --> likely if atrial flutter / fibrillation/ supraventricular tacchyarrythmia --> can get lodges in cerebral artery --> ischemic necrosis

Answer 27

-

Question 28

Describe the propagation stage

Answer 28

propagation - cellular level (involves fibrin strand formation) - activation platelets form large scale thrombin produced - thrombin activate F2a --> which binds to fibrinogen --> and converts to fibrin strands

Question 29

how would you treat atherosclerosis?

Answer 29

anti platelet drugs

Question 30

not: thrombus in artery --> tends to form within a plaque (due to rapid blood flow) thrombus in vein --> tends to form on walls of the vein

Answer 30

-