CVS 6 - Haemostasis Flashcards

1
Q

Causes of thrombosis

A

• Endothelial Injury
– Major cause of thrombus occurring in heart/arteries
– Sheer stress (hypertension), hyperlipidemia, other vascular injury (eg smoking)
• Abnormal blood flow
– Replace laminar flow with
» Turbulent flow (plaques, arrhythmia ) damages endothelium
» Stasis major cause of thrombus in vein – active co-agulation factors “pool”
• Hypercoagulability
– Genetic (eg in Factor V)
– Acquired (eg herparin induced, eg estrogens increase synthesis of coagulation factors)

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2
Q

Virchow’s triad

A

3 factors affect one another to induce thrombosis

  • Endothelial injury
  • Abnormal blood flow
  • Hypercoagulability
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3
Q

Arterial and venous thrombosis are different

A

Arterial thrombosis

  • More platelet rich
  • Outcome: Stroke, heart attack
  • Risk factors –vascular disease: smoking, diabetes, b.p., weight, cholesterol
  • Treatment: Reduce risk factors, Anti-platelet drugs

Venous thrombosis

  • More fibrin rich
  • Outcome: DVT, Pulmonary embolism
  • Risk factors: genetic predisposition slow blood flow
  • Treatment: Prophylactic treatment with anti- coagulants
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4
Q

Haemostasis: clinical applications

A

• Anti-platelet drugs
– Inappropriate platelet aggregation
» Due to endothelial injury, abnormal blood flow, hypercoagulability
– Examples of application
» prevention of stroke
» Prevention of MI in stable angina, unstable angina or peripheral vascular disease
» after M.I.
» during bypass surgery, haemodialysis
– much less/not effective against venous thrombosis !
• Anti-coagulants
– deep vein thrombosis leading to pulmonary embolism
» high risk of DVT in persons over 40 admitted to hospital for major surgery
– thrombosis triggered by prosthetic heart valves
– atrial fibrillation increases risk of arterial thromboembolism
• Fibrinolytic agents – acute MI
– pulmonary embolism

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5
Q

Anti-platelet drugs (1): aspirin

A

• Mechanism
– inhibits COX1 by acetylation, inhibits prostaglandin synthesis in platelets
– platelets are anucleate (no nucleus to encode mRNA)-> irreversible
» low infrequent dose suffices (little analgesia) 75 mg to inhibit platelets, but
300mg for suspect MI
– minimal ADR at low dose and simple dosing often treatment of choice
• Indications
– primary and secondary prevention of thromboembolism in artherosclerotic disease: angina, MI, stroke, peripheral vascular disease
– analgesia; anti inflammatory for rheumatoid arthritis
• PK
Acetyl salicylic acid -> (liver) Salicylate -> glucoronide conjugate -> (kidney) urine

t1⁄215 min
600 mg: t1⁄2 3 hours
>600 mg: t1⁄2 9 hours “Non-linear pharmacokinetics”

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6
Q

t 1/2 of platelets

A

7 days

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7
Q

Anti-platelet drugs (1): aspirin - ADR, caution, contraindication and interaction

A

• ADR
– 6 serious haemorrhages per 1000 patients per year !
– hypersensitivity - rash
• Cautions & contraindications
– avoid in patients at high risk of serious bleeding (eg peptic ulcer, hypertension, hepatic & renal insufficiency, haemophilia, pregnancy (intrauterine bleeding risk)
– can cause and worsen asthma
– avoid in renal insufficiency
– hypertension increases risk of bleeding
• Drug interactions
– care when used with anticoagulants and other anti-platelet drugs
– can be antagonised by other NSAIDS!
– can antagonise effect of diuretics

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8
Q

Interaction between NSAID and aspirin

A

NSAIDS compete with aspirin, reducing its ability to acetylate COX1

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9
Q

Anti-platelet drugs (2): PDE inhibitor

A

Dipyridamole
• Mechanism
– cAMP Phosphodiesterase inhibitor - promotes activation of PKA which inhibits platelet activation
– also inhibits reuptake of adenosine into platelets
• Indications
– weak anti-platelet drug – not often used on own
– in prevention of embolism from prosthetic heart valve (combination with warfarin)
– prevents vessel block in patients with ischaemic stroke (combination with low dose aspirin)
• ADR
– bleeding – but less common than with other anti-platelet drugs
– headache, diarrhoea
– facial flushing (from vasodilation)
• Cautions
– avoid in patients at high risk of serious bleeding (eg peptic ulcer, hypertension, hepatic & renal insufficiency, haemophilia, pregnancy (intrauterine bleeding risk)
• Drug- interactions
– may cause haemorrhage in patients taking anticoagulants

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10
Q

Don’t get confused with role of cAMP in cardiac tissue

A
  • In cardiac myocytes, cAMP (protein kinase A) promotes contractility •In Vascular smooth muscle cAMP promotes relaxation and hence vasodilation
  • In platelets cAMP inhibits aggregation
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11
Q

Anti-platelet drugs (3): ADP receptor (P2Y) antagonists 2nd gen

A

Clopidogrel (2nd gen)

• Mechanism
– ADP receptor antagonist
(efficacy reduced by P450 inhibitor)
– pro-drug activated by p450 2C19 metabolism potential for drug-drug interaction
– active metabolite binds irreversibly to receptor
• PK
– 300 mg loading dose helpful to speed up platelet inhibition then 75 mg p.o.
– excreted in urine
• Indications
– acute coronary syndromes
– secondary prevention of artherosclerosis in angina, after MI, stroke, peripheral vascular disease
– useful in patients intolerant of aspirin
• ADR
– Haemorrhage – made problematic by irreversibility
– abdominal pain, nausea
• Cautions
– avoid in patients at high risk of serious bleeding (eg peptic ulcer, hypertension, hepatic & renal insufficiency, haemophilia, pregnancy (intrauterine bleeding risk)
• Contraindications
– active bleeding and breast feeding
• Drug interactions
– increases risk of bleeding if used with aspirin, other anti-platelet drugs, warfarin

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12
Q

Anti-platelet drugs (3): ADP receptor (P2Y) antagonists 1st + 3rd gen

A

Ticlopidine (1st generation)
• causes neutropenia, thrombocytopenia – need monitor blood cell counts so used less frequently

Pasugrel (3rd generation)
• Also pro-drug, rapidly activated by P450
• Also irreversible

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13
Q

Anti-platelet drugs (4): GPIIb/IIIa antagonists

• Mechanism

A
• Mechanism
– GPIIbIIIa antagonists – very effective because inhibit “end-point” of platelet aggregation”
• Drugs
– Eptifibatide
» peptide antagonist
– Abciximab
» chimaeric mouse human mAb (Fc is human, Fab is murine)
» i.v. bolus then continuous infusion
» dissociates very slowly from receptor (dissoc t1⁄2~ 24 h) long lasting blockade, need platelet infusion to reverse
– Tirofiban
» reversible inhibitor
• Indications
– only used under specialist supervision
– unstable angina
• ADR
– all can cause bleeding.
• Caution
– avoid in patients at high risk or if active bleeding - could be catastrophic
– long list! Check these!
• Contraindications
– recent abnormal bleeding or stroke
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14
Q

Anti-coagulants:Heparin (1)

A

• Mechanism
– sulphated polysaccharide extracted from bovine lung or porcine intestine
– inhibit Factors IX, Xa, XIa, XIIa and thrombin by catalysing irreversible binding of anti-thombin III
• Drugs
– Unfractionated heparin: 3-30 kD
» Poor Foral i.v. admin and short t1/2< 1 h
– low molecular weight heparin (LMWH) – fraction < 7 kD
» enoxaprin, dalteparin, tinzaparin - more commonly used than unfractionated heparin
» longer t1/2
» good absorption by s.c. injection
• Indications
– full dose – when rapid anticoagulation needed, eg acute coronary syndromes, thromboembolic disease
– lower dose –prophylactic treatment
• PK
– only given parenterally, so short term use only

• ADR
– low therapeutic index – monitoring usual with unfractionated heparin because effects less predictable. Monitoring not required for LMWH
– haemorrhage (esp. in elderly)
– thrombocytopenia (heparin induced anti-platelet antibodies causing platelet aggregation!). Risk lower with LMWH
• Cautions
– Risk/benefit should always be considered
– factors to consider include:
» age (elderly at greater risk of bleeding)
» recent trauma/surgery
» peptic ulcer
» severe hypertension
» pregnancy
» severe renal insufficiency (greater risk of bleeding)
• Contra-indications
» haemophilia, thrombocytopenia (see ADR!), severe hepatic disease
• Drug interactions
– care if used with drugs that increase likelihood of bleeding eg NSAIDS

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15
Q

Anti-coagulants : warfarin (1)

A

• Mechanism of action
– Inhibition of vitamin K synthesis & synthesis of clotting factors.
– “Delayed effect” – it takes a few days for pre-existing vitamin K and clotting factors to be turned over. Use other treatment for rapid effect
– few days to reverse drug effect on stopping.
• Indications
– when long-term anti-coagulation required eg prophylatic treatment of thromboembolic disease
• PK
– Foral high – p.o. admin
– long t1/2 ~ 1 day
• ADR
Haemorrhage, Low therapeutic window
• Caution
Need for monitoring – I.N.R.
– assess risk benefit
• Contraindications
– teratogenic – avoid during pregnancy
– peptic ulcer
• Drug interactions –need serious consideration!:
– 99% plasma protein bound - other drugs may displace (eg NSAIDS) →↑ [drug]free
– antibiotics (bacteria can produce vitamin K – bypass warfarin)
– cyt P450 metabolism esp 2C9
» drugs that inhibit p450 →↑ [drug] (eg amiodarone, cimetidine, clopidogrel, fluconazole, fluoexetine…..)
» drugs that induce P450 (eg barbiturates, carbamezapine, phenytoin, alcohol)→↑ elimination

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16
Q

Thrombin inhibitors

Dabigatran

A

• Mechanism
– Thrombin inhibitor (directly binds thrombin)
– Pro-drug = dabigatran etexilate, activated by plasma/liver esterase
• Indications
– Prophylactic treatment venous thromboembolism
• PK
– Renal elimination of unchanged drug
• ADR
– bleeding
• Cautions
– Assess renal function before use and annually
• Contraindications
– Active bleeding/risk of bleeding
• Interactions
– Other anti-coagulants
– Several other drugs increase plasma conc and/or risk of bleeding

17
Q

Thrombin inhibitors

Argatroban

A
  • Excreted by biliary secretion – may be preferred in renal insufficiency
  • t 1⁄2~ 1 hour – admin by continuous iv infusion
18
Q

Factor Xa inhibitors

A

• Rivaroxaban
– prophylaxis of venous thromboembolism
• PK
– renal elimination of unchanged drug & Cyp metabolite
• ADR
– bleeding
• Cautions
– INR monitoring not required – unreliable
– renal impairment – dose reduction may be required
– risk of bleeding
• Contraindications
– active bleeding
• Interactions
– With other anti-coagulants
– Several drugs alter plasma concentration (↑or↓)– may need avoid or monitor thrombosis

19
Q

Fibrinolytic agents

A

• Fibrinolysis- degradation of fibrin to remove a pre-existing thrombus
• Drugs
– tPA tissue plasminogen activator
» endogenous activator of plasminogen
» several genetically engineered variants of tPA (proteins!)
– Alteplase
» copy of endogenous tPA.
» short t1/2 ~ 30 min so iv infusion upto 24 hr
– Relteplase
» longer t1/2 – 2 x i.v. bolus
– Tenecteplase
» even longer t1/2 –single bolus i.v.
– Streptokinase
» forms complex with plasminogen and allows activation by another plasminogen molecule
» isolated from streptococci - repeated use contraindicated – anaphylaxis/reduced efficacy
» 1 hour i.v. infusion
• Indications
– when urgent need to break down a fibrin clot eg after MI, stroke, pulmonary embolism
• ADR
– Haemorrhage
– Hypotension with streptokinase – generates bradykinin from kininogen
– allergic reaction to streptokinase
• Cautions
– see heparin
• Contraindications
– patients who have previously received streptokinase should not receive it again (immune reaction possible )

20
Q

bradykinin causes

A

vasodilation