Haemostasis & Thrombosis Flashcards
Describe the initial stages of thrombosis and how different anticoagulant drugs can target these stages
Molecular level
Small-scale thrombin production
- Tissue factor (TF): TF bearing cells activate factors X and V forming –> prothrombinase complex
- Prothrombinase complex: This activates factor II (prothrombin) creating factor IIa (thrombin)
- Antithrombin (AT-III): AT-III –> inactivates fIIa (thrombin) and fXa
See diagram Drugs which do these are anticoagulants 1) Inhibit factor IIa 2) Inhibit factor Xa 3) Increase activity of AT-III 4) Reduce levels of other factors
What drug is a factor IIa inhibitor?
Dabigatran (oral) - Not really used cause can cause heavy intestinal bleeding.
What drug is a factor Xa inhibitor?
Rivaroxaban (oral) - routinely used. Maintenance treatment
What drug activates AT-III?
To categories:
Heparin (IV, SC) –> decreases fIIa and fXa.
Low molecular weight heparins (Dalteparin - IV) –> activate AT-III (decreases fXa) Usually given SC as a parenteral. Everything
What drug reduces levels of other factors?
Warfarin (oral) - vitamin K antagonist. Maintenance treatment
What is vitamin K required for?
Generation of factors II, VII, IX and X.
Vitamin K carboxylase enzyme.
What is Virchow’s Triad?
Risk factors that contribute to venous thrombosis
- Rate of blood flow - Blood flow is slow/stagnating –> no replenishment of anticoagulant factors and balance adjusted in favour of coagulation
- Consistency of blood (contents) - Natural imbalance between procoagulation and anticoagulation factors. In a normal physiological environment the anti-coagulants = pro-coagulants.
- Blood vessel wall integrity - Damaged endothelium –> blood exposed to procoagulation factors
Define NSTEMI?
Non-ST elevated myocardial infarction (MI)
‘White’ thrombus (atheroma forming in the artery associated to atherosclerosis) –> PARTIALLY occluded coronary artery due to atheroma formation.
Treatment: antiplatelets
Define STEMI?
ST elevated myocardial infarction
‘White’ thrombus –> fully occluded coronary artery. You start getting ischaemia and necrosis
Treatment: antiplatelets and thrombolytics
What are acute coronary syndromes caused by? (NSTEMI/STEMI)
Damage to endothelium
Atheroma formation
Platelet aggregation
Summarise the amplification stage of thrombosis?
Platelet activation and aggregation
- Thrombin: factor IIa –> activates platelets
- Activated platelet: changes shape and becomes sticky and attaches other platelets.
Describe what happens at the molecular level of the amplification stage?
1) Thrombin - binds to protease-activated receptor (PAR) on platelet surface.
2) PAR activation –> rise in intracellular Ca2+. PAR activation –> liberates arachidonic acid (AA) and COX
3) Ca2+ rise –> exocytosis of adenosine diphosphate (ADP) from dense granules
4) ADP activates P2Y12 receptors –> platelet activation/ aggregation
5) Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2) from AA
6) TXA2 activation –> expression of GPIIb/IIIa integrin receptor on platelet surface = Platelet aggregation
What is the difference between white and red thrombus?
White thrombus - arterial thrombus: typically composed of platelet aggregates
Red thrombus - venous thrombus: largely consists of fibrin and red blood cells
Describe the different antiplatelet pharmacokinetics during the amplification stages
- Prevent platelet activation/ aggregation
Clopidogrel (oral) - ADP (P2Y12) receptor antagonist - Inhibit production of TXA2
Aspirin (oral) - irreversible COX-1 Inhibitor
NB: High doses no more effective BUT more side-effects - Prevent platelet aggregation
Abciximab (IV, SC) (monoconal antibody GPIIb/IIIa antagonist)
Limited use AND only by specialists
Describe the propagation stage at the cellular level?
Generation of fibrin strands
1) Activated platelets
Large-scale thrombin production
2) Thrombin
Factor IIa –> binds to fibrinogen and converts to fibrin strands
