Haemostasis and Thrombosis Flashcards
What are the initial stages of thrombosis
Small-scale thrombin production
- Tissue factor bearing cells activate FX and FV forming a prothombinase complex
- Prothrombinase complex activates FII (prothrombin) to FIIa (thrombin)
- Antithrombin (AT-III) inactivates VIIa and FXa
What are the mechanisms by which drugs can be used to inhibit the initial stages of thrombosis and give examples of each
Inhibit factor IIa e.g. Dabigatran
Inhibit factor Xa e.g. Rivaroxaban
Increase AT-III activity e.g. heparin
Reduce levels of other factors e.g. warfarin
What are the risk factors of Virchow’s triad
Rate of blood flow
Consistency of blood
Blood vessel wall integrity
How does rate of blood flow contribute to DVT and pulmonary embolism risk
Blood flow is slow/stagnating -> no replenishment of anticoagulant factors + balance adjusted in favour of coagulation
How does consistency of blood contribute to DVT and pulmonary embolism risk
Natural imbalance between procoagulation + anticoagulation factors
How does blood vessel wall integrity contribute to DVT and pulmonary embolism risk
Damaged endothelia -> blood exposed to procoagulation factors
How does DVT and pulmonary embolism present
Swollen leg + pitting oedema
How is DVT investigated
2-level Wells score
D-dimer
Ultrasound to confirm
How is DVT treated
Positive D-dimer test - given interim treatment with parenteral anticoagulant (dalteparin)
Ultrasound scan confirms DVT - given maintenance treatment with oral anticoagulant (rivaroxaban/warfarin)
How do acute coronary syndromes present
History of hypertension + hyperlipidaemia
Shortness of breath, sweating, dizziness + chest pain
What are the investigations done for acute coronary syndromes present
ECG (no changes)
Troponin (elevated)
What is the treatment for acute coronary syndrome
Antiplatelet therapy -> ASPIRIN + CLOPIDOGREL
Used to stop the thrombus from growing larger
What is a NSTEMI
Non-ST elevated myocardial infarction (MI)
‘White’ thrombus -> partially occluded coronary artery
What is the treatment for NSTEMI
Antiplatelets
aspirin and clopidogrel as well as heparin to reduce DVT risk
What is a STEMI
ST elevated myocardial infarction
‘White’ thrombus -> fully occluded coronary artery
What is the treatment for STEMI
antiplatelets + thrombolytics
Aspirin and clopidogrel and thrombolysis (if within 12 hours of onset)
What are NSTEMIs and STEMIs caused by
Damage to endothelium
Atheroma formation
Platelet aggregation
Describe amplification stage of thrombosis
Platelet activation + aggregation
- Factor IIa (Thrombin) activates platelets
- Activated platelet changes shape and becomes ‘sticky’ and attaches other platelets
Explain how platelets become activated by thrombin during amplification
- thrombin binds to protease-activated receptor (PAR) on the platelet surface
- PAR activation causes a rise in intracellular calcium
- Calcium rises
- Exocytosis of ADP from dense granules
- ADP activates P2Y12 receptors
- platelet activation/ aggregation
- PAR activation liberates arachidonic acid (AA)
- Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2) from AA
- TXA2 activation leads to expression of GPIIb/IIIa integrin receptor on platelet surface (involved in platelet aggregation)
What are the ways in which the amplification stage of thrombosis can be inhibited by drugs
Prevent platelet activation/aggregation e.g. clopidogrel
Inhibit production of TXA2 e.g. aspirin
Prevent platelet aggregation e.g. abciximab
Describe what occurs in the propagation stage of thrombolysis
Generation of fibrin strands
- Activated platelets cause large-scale thrombin production
- Factor IIa (thrombin) binds to fibrinogen and converts to fibrin strands
What is the mechanism of action for thrombolytics and give an example
Convert plasminogen to plasmin (protease degrades fibrin) e.g. Alteplase (IV) -
What are the risk factors for a DVT
Surgery
Prolonged immobility
Obesity
How are PEs treated
Same way as DVTs
How are PEs treated when the patient is at a severe risk of a cardiac arrest
thromboylysis with a 50mg bolus of a tPA such as alteplase
Describe warfarin (class, pharmacokinetics, pharmacodynamics and side effects)
Vitamin K epoxide reductase inhibitor
Given orally
Reduces vitamin K epoxide (Needed for the conversion of glutamate to gamma-carboxyglutamate. This conversion normally activates factors 2, 7, 9 and 10)
No side effects
Describe Dalteparin (class, pharmacokinetics, pharmacodynamics and side effects)
Heparin
IV or subcutaneous
Potentiates activity of antithrombin III
No side effects
Describe Dabigatran (class, pharmacokinetics, pharmacodynamics and side effects)
Direct oral anticoagulant (DOAC)
Oral admin
Thrombin (IIa) inhibitor
Can cause excessive bleeding
Describe Rivaroxaban (class, pharmacokinetics, pharmacodynamics and side effects)
DOAC
Oral admin
Factor Xa inhibitor
No side effects
What are ischaemic strokes caused by
Thrombosis in one of the arteries supplying the brain or embolism from somewhere in the body (e.g. in AF)
What is the treatment for ischaemic strokes
Thrombolysis with alteplase may be considered if within 4.5 hours of onset
> 4.5 hours of onset ->aspirin and clopidogrel are given as well as heparin if the patient is at a high risk of more emboli
Describe aspirin (class, pharmacokinetics, pharmacodynamics and side effects)
Antiplatelet/NSAID/COX-1 inhibitor
Oral admin
Covalent binding to COX-1, preventing TXA2 production
Side effects: GI irritation and ulceration, bronchospasm, prolonged bleeding, nephrotoxicity
Describe Clopidogrel (class, pharmacokinetics, pharmacodynamics and side effects)
Antiplatelet
Oral admin
P2Y12 (ADP receptor) antagonist -> stops platelets activation
No side effects
Describe Abciximab (class, pharmacokinetics, pharmacodynamics and side effects)
Antiplatelet
IV or SC
Monoclonal antibody against GIpIIIa/IIb
No side effects
Describe Alteplase (class, pharmacokinetics, pharmacodynamics and side effects)
Recombinant tissue type plasminogen activator (rt-PA)
IV
Converts plasminogen into plasmin (Protease that degrades fibrin)
Excessive bleeding at higher doses
How do heparins work and how are they administered and why are they used as interim treatment
Activates AT-III (Reduces FIIa and FXa)
IV, SC (parenteral)
Rapid action to prevent immediate issues
