Drugs Affecting Coaguation Flashcards
What is the difference between haemostasis and coagulation?
Haemostasis: Arrest of blood loss from damaged vessels
Coagulation: Formation of a fibrin clot in a blood vessel
What is the difference between an arterial and venous thrombus?
Thrombus: Forms in vivo
Arterial thrombus (white):
- Platelets plus white blood cells in a fibrin mesh - Usually associated with vessel wall damage (atherosclerosis) - Breaks off leading to blood vessel obstruction (eg myocardial infarction)
Venous thrombus (red):
- Fibrin, platelets and red blood cell - Usually associated with blood stasis (eg DVT with air travel) - Breaks off leading to embolus lodging in lungs or brain
Explain the terms:
Thrombosis
Thromboembolis
Clot
Thrombosis: Pathological formation of a haemostatic plug in a blood vessel in the absence of blood loss
Thromboembolus: A blockage in a blood vessel caused by a dislodged thrombus
Clot: Forms in static blood in vitro
Explain how damage to a blood vessel can cause vasoconstriction?
Mechanism:
- Collagen exposed on damaged vessel wall - Platelets stick to collagen and “activate” - ADP and 5-HT released from platelets - 5-HT is a powerful vasoconstrictor
Explain how damage to a blood vessel can cause platelet adhesion and activation (thrombus formation)?
Mechanism:
- ADP from activated platelets causes others to activate and change shape - Granule contents are secreted (eg ADP, 5-HT) - Mediators are synthesised (eg Thromboxane) - Platelets aggregate and adhere via fibrinogen bridging between GPIIb/IIIa receptors - Soft plug formed Stimuli for Platelet Activation: - Collagen - Thrombin - Thromboxane - ADP
Explain how damage to a blood vessel can cause fibrin formation (thrombus formation)?
Mechanism:
- Fibrin is formed from fibrinogen (a soluble plasma protein) - Thrombin cleaves fibrinogen--> fibrin (insoluble monomers) - Thrombin is not present in plasma: is produced by activation of prothrombin
How is prothrombin activated?
- A “cascade” reaction where inactive precursors are activated in series- each giving rise to more of the next
- Two pathways in the cascade:
– Extrinsic- in vivo: damaged tissues release thromboplastin
– Intrinsic- in vitro: exposed collagen or other material, negative charges (eg glass)
Explain the coagulation cascade?
- A small signal (eg FXII) leads to a large amount of product (fibrin)
- Each step leads to formation of more product ie amplification
- The ‘factors’ are proteases
- The extrinsic pathway is faster than intrinsic pathway (that has many more steps)
- Each step leads to more product - AMPLIFICATION
How is blood coagulation controlled?
- Control is inhibited by:
- Enzyme inhibitors (ie/ antithrombin III–> cascade inhibition)
- Fibrinolysis by plasmin
Why do coagulation drugs work?
Drugs that are used affect haemostasis and thrombosis because:
- Some situations of blood stasis leading to thrombus formation:
- Atrial fibrillation
-> cerebral embolism or -> renal embolism
- Deep vein thrombosis (DVT)
– Pulmonary embolism
- Some situations of blood vessel damage leading to thrombus formation:
- atherosclerosis
– In coronary vessels–> myocardial infarction
– In carotid arteries –> stroke
What processes can coagulation drugs affect?
- coagulation (fibrin formation)
- platelets
– adhesion and activation - fibrinolysis
Explain some drugs that affect Fibrin formation.
- Procoagulant drugs eg vitamin K
Vitamin K:- Essential for formation of clotting factors II, VII, IX, and X
- These molecules all require gamma carboxylation after synthesis
- Reduced vitamin K is a cofactor in carboxylation of glutamate
- Injectable anticoagulants eg heparin, low-molecular-weight heparins
– Used acutely for short term action
Heparin:
- Enhances activity of antithrombin III
- AT III is a natural inhibitor that inactivates Xa and thrombin
- Heparin binds AT III to expose active site
- LMW heparins:
– have same effect on factor Xa, less effect on thrombin
– Anticoagulant effects are similar
– Large negatively charged (MW 60-100kD)
– Not orally available
Low Molecular Weight Haparin (MW 2-9kD)
– Not orally available
– Longer elimination half life
– Used for patient self administration @ home
- Averse Effects:
- Haemorrhage
- Thrombocytopaenia (platelet deficiency)
- Osteoporosis (mechanism unknown)
- Oral anticoagulants eg warfarin
– Used for prolonged therapy
– Coumarin derivatives eg warfarin
– Inhibit reduction of vitamin K, thereby inhibiting gamma carboxylation of glutamate in factors II, VII, IX and X
Warfarin: - Only active in vivo - Delayed onset of action - Doesn’t affect already active factors - Adverse Effects: - haemorrhage – titrate dose – dosage determined by INR - reversal – vitamin K (oral) – phytomenadione natural vitamin K (i.v.) – fresh frozen plasma - the moody drug (Warfarin levels and anticoagulant level effects are very labile) - Pharmacokinetics: - orally active - rapidly absorbed - strongly bound to plasma protein (99%)
- Increased Warfarin activity:
- vitamin K deficiency
- hepatic disease – impaired synthesis of clotting factors
- hypermetabolic states – increased metabolism of clotting factors
- drug interactions
- impaired platelet aggregation eg aspirin
- competition for plasma protein binding eg NSAIDs
- Competition for Cytochrome p450 pathway so reduced warfarin clearance- increased availability
- cimetidine ( a H2 receptor blocker- gastric ulcer treatment)
- Acute alcohol consumption - Decreased Warfarin activity:
- pregnancy
- drug interactions
– induction of liver enzymes eg barbiturates, chronic alcohol consumption increases warfarin clearance
– vitamin K supplements
What is the monitoring effect?
Prothrombin Time (PT) – time for clot formation of plasma after addition of Ca2+ and tissue factor – extrinsic pathway
International Normalised Ratio (INR) – ratio of patient PT to normal PT
What are some new anticoagulant agents?
- Low molecular weight
- Orally available
- More predictable dose-response
- Reduced laboratory monitoring
- Indirect Factor Xa (FXa) inhibitors
- Direct Factor Xa inhibitors
- Direct Thrombin Inhibitors
What are some Drugs that Affect Platelet Activation and Adhesion?
- ADP receptor antagonists (eg clopidogrel)
- Thromboxane synthesis inhibitors (cyclo-oxygenase inhibitors eg aspirin)
- Glycoprotein IIb/IIIa receptor antagonists (eg tirofiban, abciximab)
