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
Give an example of a thrombolytic/fribinolytics drug?
Anticoagulants and anti-platelets - DO NOT remove pre-formed clots
Thrombolytics
Convert plasminogen –> plasmin
Plasmin - protease degrades fibrin
Alteplase (IV) - recombinant tissue type plasminogen activator (rt-PA)
What are the class of drugs used to treat DVT and PE?
Anticoagulants
What are the class of drug used to treat atherosclerosis and subsequent rupture of the atherosclerotic plaque?
Atherosclerosis - Antiplatelet (prophylaxis not specifically used for the treatment of atherosclerosis)
Rupture of atherosclerotic plaque - thrombolytics (mainly used for ischaemic stroke)
