Haemostasis and Thrombosis Flashcards
examples of pro-coagulants (plasma)
prothrombin
F5, F7-F13
fibrinogen
examples of anti-coagulants (plasma)
plasminogen
TFPI (Tissue Factor Pathway Inhibitor)
Protein C & S
anti-thrombin.
why does surgery make you susceptible to thrombosis?
immobility post-op
what is the difference between a red thrombus and a white thrombus?
red thrombus:
- veins
- high in fibrin content (fat clot)
- form in the vessel lumen
white thrombus:
- arteries
- high in platelets (hence use of antiplatelets)
- within atherosclerotic plaque i.e. within the endothelium
what are the 3 components of Virchow’s Triad?
1) rate of blow flow (stasis)
2) consistency of blood(coagulability)
3) blood vessel wall integrity (wall injury)
how does rate of blow flow affect thrombosis?
slow flow means that anti-coagulant factors are not replenished and promotes coagulation
how does consistency of blood affect thrombosis?
If there is an imbalance in the pro and anti-coagulation factors
how does blood vessel wall integrity affect thrombosis?
damage to the wall causes exposure of collagen to pro-coagulation factors.
what are the three steps in coagulation?
1) Initiation – small scale production of thrombin.
2) Amplification – large scale production of thrombin (on platelet surfaces).
3) Propagation – generation of fibrin strands by thrombin.
what targets the initiation step?
anti-coagulants
what targets the amplification step?
anti-platelets
what targets the propagation step?
thrombolytics
what does the Two-level Well score determine?
the higher the score, the more likely for thrombosis to occur
what does the D-dimer test detect and determine?
it detects fibrin breakdown products
a positive tests determine DVT
what occurs during the initiation step in coagulation?
1) Tissue Factor presenting cells activate F10 and F5 forming the prothrombinase complex.
2) the prothombinase complex activates F2 (pro-thrombin) into F2a (thrombin)
3) F2a (thrombin) and F10a is inactivated by anti-thrombin (AT-III)
what makes up the prothrombinase complex?
F5a and F10a
what are the anti-coagulant drugs that can target “initiation”?
o Dabigatran – inhibits thrombin.
o Rivaroxaban – inhibits F10a.
o Heparin – activates AT-III.
o Warfarin – vitamin k antagonist.
what is dabigatran?
direct oral anticoagulant
–>inhibits thrombin
oral
not used often due to GI bleeding side effect
what is rivaroxaban?
direct oral anti-coagulant
- ->inhibits F10a
oral
what is heparin?
give an example of a heparin
activates antithrombin-III
e.g. dalteparin
IV, SC
name a LMW heparin.
dalteparin (given SC)
what is warfarin?
vitamin K epoxide reductase inhibitor/antagonist
vitamin K creates F2, 7, 9, 10 and therefore is considered an indirect acting drug
what are the indications for the use of anti-coagulants?
- VTE
- DVT and PE
- thrombosis during surgery
- atrial fibrillation (prophylaxis to stroke)
what occurs in amplification stage?
1) thrombin (produced in large scale) activates platelets in a +ve FB effect
2) activated platelets change shape and become sticky causing aggregation
describe the platelet activation process
- Thrombin binds to the PAR (Protease Activated Receptor).
- thrombin is that protease - PAR activation causes a rise in intracellular [Ca2+].
- Raised [Ca2+] causes exocytosis of ADP from dense granules.
- ADP binds to another platelet’s P2Y12R, having auto- and paracrine effects, activating platelet.
what does activation of PAR lead to alongside the rise in intracellular calcium?
liberates arachidonic acid (AA) which is turned into TXA2 by COX enzymes.
what is the role of TXA2 in platelet aggregation?
induces the expression of GlpIIb/IIIa integrin receptor, which enables aggregation
what converts AA into TXA2?
COX enzymes
what are the anti-platelet drugs that can be used in “amplification”?
o Clopidogrel – ADP/P2Y12R antagonist.
o Aspirin – irreversible COX1 inhibitor.
o Abciximab – Glp2b/3a antagonist.
what is Clopidogrel?
what is its mechanism of action?
- anti-platelet
- ADP/P2Y12R antagonist
- competes with ADP, produced by platelet, for the P2Y12 receptor
- prevents platelet activation
oral
what is aspirin?
what is its mechanism?
irreversible COX1 inhibitor:
- covalent binding to COX-1
- reduces the production of TXA2
- no activation of platelet as a result
aspirin is also an NSAID
oral
lower doses have fewer side effects and can be just as effective as higher doses
what is abciximab?
- anti-platelet
- GlpIIIa/IIb antagonist
- monoclonal antibodies that target the integrin receptors
- prevents platelet aggregation
IV, SC
have limited, specialist uses
what are the indications for the use of anti-platelet drugs?
o Acute coronary syndromes – MI.
o Atrial fibrillation – prophylaxis of strokes.
what happens in the propagation step?
1) activated platelets cause the large scale production of thrombin
2) the thrombin binds to fibrinogen and converts it to fibrin strands
why are thrombolytics used in “propagation” and what are the drugs?
Anticoagulants and antiplatelet drugs do not remove pre-formed clots, thrombolytics will.
Alteplase – recombinant tissue-type plasminogen activator (rt-PA).
what is alteplase?
what is its mechanism of action
- thrombolytic
- recombinant tissue plasminogen activator analogue.
- Converts plasminogen to plasmin which then degrades fibrin and dissolves the clot.
IV
what are the indications for the use of thrombolytics?
- arterial thrombi
- VTE
- stroke (first line)
- ST elevated MI (more serious than NSTEMI)
what can a red thrombus cause and what a white thrombus cause?
red thrombus –> DVT
white thrombus–> NSTEMI and STEMI
what is DVT?
what is it caused by?
red thrombus of the deep veins of the leg (e.g. popliteal vein)
Caused by stasis of blood and damage to endothelium
how is a DVT managed?
Reduce levels of anticoagulant factors – anticoagulants.
E.G. Dabigatran, Rivaroxaban, Heparin, Warfarin.
what is the difference between NSTEMI and STEMI?
NSTEMI caused by a partially occluded coronary artery
STEMI is caused by a fully occluded coronary artery
drug: target
- clopi
- aspirin
- Abciximab
- P2Y12R
- COX-1
- GlpIIb/IIIa
what causes the white thrombus in STEMI and NSTEMI?
1) Atheroma formation.
2) Damage to endothelium.
3) Platelet aggregation–> thrombus
how is NSTEMI managed?
Reduce lipid formation and platelet aggregation/activation
use antiplatelets:
E.G. Clopidogrel, aspirin, Abciximab.
how is STEMI managed?
Reduce lipid formation, platelet aggregation/activation and dissolve thrombus
use antiplatelets and thrombolytics:
- APs – Clopidogrel, aspirin, Abciximab.
- TLs – Alteplase.
why is a CT scan important in stroke in an emergency?
to eliminate haemorrhagic stroke (bleeding) or determine ischaemic stroke
what treatment would ischaemic stroke receive?
alteplase therapy
what is the role of plasminogen?
converted to plasmin which degrades fibrin strands
too much plasmin can however cause excessive bleeding
what is the treatment for a suspected clot?
thrombolytics
what is the treatment for predicted clot in the venous system?
anti-coagulants
what is the treatment for predicted clot in the arterial system?
antiplatelets
summary of disease and drugs:
1) anti-coagulant
2) antiplatelets
3) thrombolytics
1) DVT, PE, AF
2) stroke, acute coronary syndromes, AF, AAneurysm, peripheral arterial disease
3) stroke, acute coronary syndromes, PE
what are the arterial and venous disease?
arterial:
- stroke
- acute coronary syndromes
- AF
- aortic aneurysm
- peripheral arterial disease
venous:
- DVT
- PE
what conversion that warfarin prevent?
2,7,9,10
reduced vitamin K epoxide is needed to convert glutamate to gamma-carboxyglutamate
what is NSTEMI?
Non-ST-elevated MI due to partially occluded coronary artery
how is NSTEMI treated?
aspirin
clopidogrel
heparin tp reduce DVT risk
what is STEMI?
ST elevated MI
fully occluded coronary artery
how is STEMI treated?
aspirin
clopidogrel
thrombolysis (if onset within 12 hours)
what is the logic behind using anti-platelets for acute coronary syndrome?
prevent further thrombus formation
thrombus formation makes use of platelets
what is aspirin, an anti-platelet, used for?
strokes
MI
aortic aneurysm
atrial fibrillation
what are the side effects of aspirin?
- gastric irritation and ulceration
- bronchospasm (PGE2 made by COX-1)
- prolonged bleeding
- nephrotoxicity
name a thrombolytic
alteplase (tPA)
name 3 anti-platelet drugs
aspirin
clopidogrel
abciximab
what are anti-platelets used for generally?
arterial disease
e.g. strokes and heart attacks
- blood here is usually faster so coagulation risk due to stasis is not an issue
- once a clot has formed, its growth further is the problem
what are anticoagulants used for generally?
venous disease
disease of static blood
e.g. atrial fibrillation, DVT, PE
what are the exceptions in the use of anti-platelets and anticoagulants?
Antiplatelets are still often given for stroke prevention in people with AF, despite anticoagulants being superior at preventing stroke compared to aspirin in AF
Anticoagulants are given in stroke and ACS if the patient has AF or is being kept in hospital and so is at risk of DVT
what does the suffix “-ban” mean?
inhibits factor 10a
