Pharm 16: Haemostasis + thrombosis Flashcards
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
a) Prothrombin
e) Factors V, VII-XIII
f) Fibrinogen
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
b) Plasminogen
c) TFPI (Tissue factor pathway inhibitor)
d) Proteins C & S, Antithrombi
how does a thrombus form?
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
describe the amplification process of platelet activation
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
Thrombus formation is dependent on Virchow’s triad.
what are the 3 components of Virchow’s triad?
- Reduced blood Flow (stasis): if slow blood flow –> no replenishment of anticoagulant factors
- Blood consistency (viscosity): natural imbalance between procoagulation + anticoagulation e.g. factor V leiden (can’t inactivate co-factor V)
- Endothelial damage –> blood exposed to procoagulation factors e.g. TF
(most specific to vein)
explain the 3 stages of coagulation
- Initial - tissue Factor presentation –> Prothrombinase-mediated formation of factor IIa (thrombin)
- Amplification - thrombin (fIIa)-mediated platelet activation –> ADP activates P2Y12 receptor –> causes platelet aggregation via GPIIb/IIa
- Propagation - thrombin-mediated conversion of fibrinogen –> fibrin strands
What are some anticoagulant drugs targeting initiation?
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)
a) what is used for interim treatment of a thrombus?
b) what is used to maintain anticoagulation ?
a) interim treatment = dalteparin (parenteral)
b) maintain = warfarin + rivaroxaban (enteral)
Describe the activation of platelets
- 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
activation of PAR liberates ________
COX generates _______ from arachidonic acid
activation of PAR liberates arachidonic acid
COX generates TXA2 from arachidonic acid
activation of TXA2 causes expression of what receptors on surface of platelets?
GPIIb/IIIa
What are some anti platelets used to prevent platelet activation?
and how do they work?
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
when might you use anti platelets?
- Arterial thrombosis
o Acute coronary syndromes – MI (STEMI + NSTEMI)
o Arterial Fibrillation - prophylaxis of stroke
do anticoagulants + anti platelets remove pre formed clots?
No
how do thrombolytics work?
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
when might thrombolytics be used?
Arterial + venous thrombosis
o Stroke – 1st line treatment
o ST-elevated MI (STEMI)
why does DVT (deep vein thrombosis) form ?
o decreased rate of blood flow
o Damage to endothelium
how would you deal with DVT?
give anticoagulants
whats the difference between NSTEMI + STEMI?
- -
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
how would you deal with NSTEMI?
what re the drugs administrated ?
–> antiplatelet therapy
(decrease platelet activation/aggregation)
Prevent further arterial occlusion
aspirin + clipidogrel
how would you deal with STEMI?
–> anti-platelets + thrombolytic
decreases Platelet activation/aggregation + dissolves clot
note: ultrasound scan = used to confirm DVT
-
how does treatment of DVT vs PE differ?
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
note:
thrombus in coronary artery/ arteries = aka white thrombus
thumbs in vein = aka red thrombus
-
antithrombin inhibits factors ___ + _____
inhibits factor 2a + 10a
how would you deal with ischemic stroke?
- thrombolytic therapy –> alteplase (tPA )
note: thrombus forming in atria of heart –> likely if atrial flutter / fibrillation/ supraventricular tacchyarrythmia –> can get lodges in cerebral artery –> ischemic necrosis
-
Describe the propagation stage
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
how would you treat atherosclerosis?
anti platelet drugs
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
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