Lecture 6 - Warfarin Flashcards
What are the two pathways of the coagulation cascade and what is the differences between them?
Extrinsic pathway: main pathway, faster, initiated when blood comes into contact with cells outside the vascular endothelium, due to trauma/tissue damage
Intrinsic pathway: slower, initiated by trauma inside the vascular system, where the surface of platelets have become damaged
Describe how the following work together in the coagulation cascade
- zymogen
- proteolysis
- serine protease
- glycoprotein co-factor
Zymogens are inactive precursors. They have regulatory domains attached that keeps them in the inactive form. The domains are cleaved off by proteolysis to form the active enzyme. The enzyme they form is a type of serine protease. The serine protease goes on to break down another zymogen. Sometimes it requires a glycoprotein co-factor to work
What are the steps of the final common pathway of the coagulation cascade?
Factor 10a (plus its cofactor, 5a) catalyses the conversion of prothrombin into thrombin Thrombin catalyses the conversion of fibrinogen into fibrin Insoluble fibrin strands hold together sticky platelets to form a clot
What are the 3 parts of the coagulation tried?
- Coagulation factors
- Platelets
- The endothelium
What is the role of platelets in the coagulation cascade?
They recognise when there is damage to the vasculature and form a sticky plug
They provide a surface on which coagulation factors can interact
They provide phospholipids and calcium ions for use in the coagulation cascade
Release factors that attract more platelets so they can aggregate
Define haemostasis and thrombosis
Haemostasis is the physiological response to vascular damage in order to prevent bleeding
Thrombosis is the result of excessive haemostasis when it is not necessary, leading to thrombus formation
How can atherosclerosis lead to thrombosis?
Atherosclerosis = deposits of fat and build up of plaques on artery walls, which causes hardening and reduces lumen size
Blood pressure increases
Damage to artery walls causes release of factors that activate platelets, initiating coagulation
What are the consequences of thrombus formation?
Occlusion of a cerebral artery - Stroke
Occlusion of a coronary artery - Myocardial infarction
What is Warfarin and what is its mechanism of action?
Oral anticoagulant
Inhibits vitamin K epoxide reductase, therefore preventing hepatic synthesis of vitamin K dependent coagulation factors such as prothrombin
What is the gene encoding vitamin K epoxide reductase?
How will expression levels of this gene affect Warfarin dosage
VKORC1
High activity = higher Warfarin dose required
Low activity = lower Warfarin dose required
What are the consequences of taking
- a too high dosage of Warfarin
- a too low dosage of Warfarin
Too high: Cannot form blood clots, excessive bleeding
Too low: Thrombus formation, stroke and myocardial infarction
Name 4 things that Warfarin is used in the treatment of
Venous thrombosis/Arterial thrombosis/Pulmonary embolism
Atrial fibrillation
Cardiac valve replacement
Recurrent myocardial infarction
What is the bioavailability of Warfarin, and how does it travel in the blood?
Almost 100%
99% bound to albumin
Describe the metabolism of Warfarin
Active drug
Warfarin has S and R enantiomers
S enantiomer metabolised by CYP2C9
R enantiomer metabolised by other CYP450 enzymes
How does your diet affect the efficacy of Warfarin?
Diets high in reduced vitamin K (found in green leafy vegetables) will required a higher dose of Warfarin to be effective
