Haemostasis and Thrombosis Flashcards
What happens in the the initiation stage of thrombosis?
small scale thrombin production
- Tissue factor
- TF bearing cells activate factors X and V -> formation of prothormbinase complex - prothrominase complex activates factor II (prothrombin) -> IIa (thrombin)
- antithrombin (AT-II) inactivates fIIa and fXa
What drugs can be used to inhibit the initiation phase?
anticoagulants
What are some anticoagulants and their targets?
How are they administered?
- Inhibit factor IIa: Dabigatran (oral) - factor IIa inhibitor
- Inhibit factor Xa: Rivaroxaban (oral) - factor Xa inhibitor
- Increase activity of AT-III:
- Heparin (IV, SC): activates AT-III ( decrease FIIa & FXa)
- Low-MW heparins (LMWHs, e.g. Dalteparin): activate AT-III (decrease FXa) - Reduce levels of other factors:
- Warfarin (oral): vitamin K antagonist (vitamin K needed for clotting)
- Vitamin K: required for generation of factors II, VII, IX & X
What are the risk factors for DVT and pulmonary embolism?
Virchow’s triad:
- rate of blood flow - slow or stagnating -> no replenishment of anticoagulant factors and balance adjusted in favour of coagulation
- consistency of blood - natural balance between procoagulation and anticoagulation factors
- blood vessel wall integrity - damaged endothelia -> blood exposed to procoagulation factors
What is an NSTEMI?
Non ST Elevated Myocardial Infarction - partially occluded coronary artery
forms a white thrombus (formed in artery)
What is a STEMI?
ST Elevated Myocardial Infarction - full occlusion of coronary artery
forms a white thrombus
What are the differences in the way we manage an NSTEMI and a STEMI?
NSTEMI :
- prevent further arterial occlusion ( decrease platelet activation/aggregation and use anti-platelets)
- aspirin, clopidogrel
STEMI:
- prevent death
- decreasePlatelet activation/ aggregation
- Dissolve clot
- Anti-platelets & thrombolytics
What causes NSTEMI and STEMI?
- damage to endothelium
- atheroma formation
- platelet aggregation
What happens in the amplification stage of a thrombus (cellular level)?
Subendothelial plaque
Platelet activation & aggregation
1. Thrombin: Factor IIa -> activates platelets
. Activated platelet: Changes shape and becomes ‘sticky’ -> attaches other platelets -> AGGREGATION
What happens in the amplification stage of a thrombus (molecular level)?
Thrombin binds to protease-activated receptor (PAR) on the platelet surface. PAR activation -> rise in intracellular Ca2+ -> exocytosis of ADP from dense granules
- ADP receptors: ADP can also act in an autocrine fashion on the platelet itself (activates P2Y12 receptors on platelet -> platelet activation/ aggregation)
- Cyclo-oxygenase: PAR activation -> liberates arachidonic acid (AA). PAR activates cyclo-oxygenase (COX), which generates thromboxane A2 from AA
- Glycoprotein IIb/IIIa receptor (GPIIb/IIIa): Thromboxane A2 activation -> expression of GPIIb/IIIa integrin receptor on platelet surface. GPIIb/IIIa is involved in platelet aggregation
What drugs are used to inhibit the amplification stage of thrombosis?
What are some examples?
antiplatelts
- Prevent platelet activation/aggregation: Clopidogrel (oral): ADP (P2Y12) receptor antagonist. Used as a preventative measure too
- Inhibit production of TXA2: Aspirin (oral): Irreversible COX-1 Inhibitor NB: High doses no more effective, BUT have more side effects
- Prevent platelet aggregation: Abciximab (IV, SC): Inhibit GpIIb/IIIa. Limited use AND only by specialists
What causes an ischaemic stroke?
thrombus in atria of heart (supraventricular tachycardia/atrial flutter/ atrial fibrillation) -> embolises -> lodges in lumen of cerebral artery -> stroke
rate of blood flow changed -> increases probability of thrombus forming
What happens in the propagation stage of thombosis?
Generation of fibrin strands
- Activated platelets: Large-scale thrombin production
- Thrombin: Factor IIa -> binds to fibrinogen and converts fibrinogen to fibrin strands
- Fibrin strands form a net, which traps many things to form a solid core.
What drugs are used to inhibit the propagation stage of thrombosis?
What is an example of one?
Anticoagulants & anti-platelets are involved in reducing the formation on a clot however, they DO NOT remove pre-formed clots – WE NEED THROMBOLYTIC/FIBRINOLYTIC DRUGS
Convert plasminogen -> plasmin (a protease that degrades fibrin) – this dissolves a pre-formed clot
- Thrombolytics are only used in emergency situations (can elad to excessive bleeding) - first line treatment in stroke and STEMI
Alteplase (IV) – recombinant tissue type plasminogen activator (rt-PA)
