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27 Cards in this Set
- Front
- Back
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Venous thrombosis
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- Intravascular clot (red) forms in deep veins, especially in the legs, when flow is sluggish
- Fragment may bud off (embolus) and block blood vessels, often a pulmonary artery Therapy: anticoagulant drugs |
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Arterial thrombosis
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Platelets aggregate (white), usually at the site of a ruptured atherosclerotic plaque, then encapsulated by clot (red)
- Coronary artery > myocardial infarction - Cerebral artery > thrombotic stroke |
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Therapy for arterial thrombosis
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Immediate: dissolve existing clots with thrombolytics
Long term: anti-platelet drugs |
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Anticoagulants in vitro
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Employed when blood is to be stored
1. Heparin 2. Calcium chelators e.g. citrate, EDTA |
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Anticoagulants in vivo
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1. Heparin
2. Oral anticoagulants e.g. vitamin K antagonists, newer thombrin inhibitors and factor Xa inhibitors |
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Mechanism of action of heparin
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- Heparin binds to and enhances the action of the endogenous anticoagulant, antithrombin III (protease inhibitor)
- Heparin-antithrombin III complex binds to and inhibits the action of clotting factors IIa, IXa, Xa, XIa and XIIa - Low MW heparins inhibits factor Xa only |
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Administration of heparin
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- Not orally active (prevented by high MW and charge)
- Given intravenously or sub-cutaneously - Does not cross the placenta or blood brain barrier |
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Uses of heparin
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- Deep vein thrombosis
- Can be used safely in pre-eclampsia of pregnancy - In vitro anticoagulant |
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Side effects and their reversal
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- Allergic reaction
- Haemorrhage Reversal: protamine - A polycationic protein that binds and inactivates heparin |
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Oral anticoagulants
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Vitamin K antagonists, e.g. warfarin
- Structural analogue of vitamin K - Blocks synthesis of coagulation factors in the liver |
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Mechanism of action of warfarin
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- Reduced vitamin K is essential for post-ribosomal gamma-carboxylation of glutamic acid residues at N-terminals of factors II, VII, IX and X.
- Warfarin blocks vitamin K reductase, so blocking carboxylation - No gamma-carboxyglutamate residues means no calcium binding and no coagulation |
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Uses of warfarin
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- Venous thrombosis
- To prevent pulmonary embolism - To prevent embolism in patients with atrial fibrillation - Prophylaxis of thrombosis after insertion of prosthetic heart valves etc |
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Activity of warfarin
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- Active in vivo but not in vitro
- Effect delayed 1-3 days (time for existing pool of functional clotting factors to be replaced by dysfunctional factors |
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Administration of warfarin
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- Orally active (more convenient than heparin)
- 99% bound to plasma albumin - Aspirin displaces warfarin from binding sites on albumin, increasing plasma [warfarin] - Aspirin also inhibits platelet function > major risk of haemorrhage |
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Side effects of warfarin and their reversal
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- Haemorrhage
- Crosses placenta and blood-brain barrier Reversal of side effects: - Transfuse wit plasma or coagulation factor concentrates - Oral vitamin K, but requires carboxylation to resume (1-3 days) |
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Why do we need to replace warfarin?
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- Difficulties in getting dose right due to complicated pharmacokinetics resulting from plasma protein binding and accumulation in adipose tissue
- high incidence of haemorrhage - INR monitoring is inconvenient and expensive |
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International normalisation ratio
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- Monitors patient's clotting time
- INR derived from the ratio of a patient's prothrombin time to a normal (control) sample - INR target range on warfarin 2.0-3.0 Higher INR increases risk of haemorrhage Lower INR increases risk of thrombosis. |
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Newly introduced oral anticoagulants
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- Potential to replace warfarin, but high cost currently restricts use
- No need to monitor patients - Dabigatran exilate: direct thrombin inhibitor - Rivaroxaban: direct factor Xa inhibitor - No involvement of AT III - Active immediately |
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Antiplatelet drugs
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Treatment of arterial thrombosis. Platelets are not normally active, activated by:
- collagen - thrombin - thromboxane A2, ADP and 5-HT synthesised by adjacent platelets |
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How is platelet activaion normally suppressed?
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Prostacyclin and nitric oxide:
PGI2: stimulates adenyl cyclase, increases cAMP - Inhibits Ca2+ mobilisation - Inhibits aggregation NO: stimulates soluble guanylate cyclase, increases cGMP - Inhibits Ca2+ mobilisation - Inhibits aggregation and adhesion |
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Low dose aspirin
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Anti thrombotic agent:
- Irreversibly inhibits cyclooxygenase (COX) acetylation of terminal serine-530 - Inhibits synthesis of platelet TXA2. This cannot recover as platelets have no nucleus - Also inhibits endothelial products of prostacyclin, recovered by synthesis of new COX |
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Dipyridamole
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Antithrombotic agent:
- Inhibits cyclic nucleotide phosphodiesterases, leading to increased cAMP and cGMP (potentiates prostacyclin and NO) - So inhibits platelet activation |
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Epoprostenol
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Antithrombotic agent:
- Stabilised prostacyclin - Must be given IV - Short duration of action (t1/2=~3min) - Used during haemodialysis |
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Clopidogrel
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- Blocks platelet ADP (P2Y12) receptors, preventing GPIIb/IIIa receptor exposure
- Used during surgical exploration, clearing of intravascular blockage eg coronary artery thrombosis - Antigenic. Can only be used once. |
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Tissue plasminogen activator
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Fibrinolytic/thrombolytic agent:
- enzyme activated by vascular endothelium - activated only plasminogen bound to fibrin (clot selective) - human recombinant t-PA now available (alteplase), non-antigenic |
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Streptokinase
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Fibrinolytic/trombolytic agent:
- Isolated from group C haemolytic streptococci - Activates plasminogen systemically; high incidence of haemorrhage - Not an enzyme. Binds to plasminogen and activates it by inducing a conformational change. - Antigenic, so ineffective after recent streptococcal infection |
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Use of fibrinolytics
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- Venous thrombosis
- Myocardial infarction or trombotic stroke - Never used in haemorrhagic stroke Side effects: allergy and haemorrhage Haemorrhage can be treated with tranexamic acid, an inhibitor of plasminogen activation. |
