Download Coagulation

Blood coagulation and
fibrinolysis
March 2006
Haemostasis
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adhesion
shape change
activation and
secretion
aggregation
interaction with
coagulation factors
Drug classes
1. Anticoagulants
2. Antiplatelet drugs
3. Thrombolytic Agents
Anticoagulants
Heparin
Glycosaminoglycan containing a mixture of sulfated
mucopolysaccharides of various sizes
- Unfractionated (5000-30000 Da)
- Low molecular weight (LMWH) (1000-10000 Da)
Mechanism of Action
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Heparin :
- enhances the action of Antithrombin III (AT-III) (plasma
protease inhibitor) 1000 fold ↑ activity
- antithrombin III inhibits clotting factor proteases,
Thrombin (IIa), IXa, Xa, XIa and XIIa, by forming stable complexes
- heparin binds to AT-III and causes a conformational change
thereby activating AT-III
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LMWH:
- predominantly inhibit factor Xa
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Heparins do not affect thrombin bound to fibrin or Xa bound to platelets
Monitoring Therapy
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APTT (APTTR)
(Activated Partial Thromboplastin Time)
Intrinsic pathway (heparin)
PT (INR)
(Prothrombin Time)
Extrinsic pathway (warfarin)
Heparin - indications
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Rapid onset of action & short half life
When immediate anticoagulation required
When quick reversal may be required
Prevention and treatment of venous thrombosis
Pulmonary embolism
Acute Coronary syndromes
Given intravenously or subcutaneously
Can be used in pregnant women
Adverse effects
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Increased bleeding 3%
- antidote (protamine sulfate)
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Heparin induced thrombocytopaenia
- HITs 1% up to 3 days 5% >5 days
- Can precipitate thrombosis
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Osteoporosis with long term high-dose administration 3-6mths
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Inhibit aldosterone synthesis – rarely causes ↑K+
Unfractionated heparin
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Unpredictable pharmacokinetics
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Requires regular monitoring
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Infusion
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Higher incidence of HITs
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Rebound ischaemia
Low Mol Weight Heparins
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Eg Enoxaparin; Tinzaparin
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More predictable pharmacokinetics
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Lower incidence of heparin-associated thrombocytopenia
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Ease of administration s/c injection
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No need for monitoring
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Possible improvement in outcomes of acute coronary syndromes
(Such a benefit was suggested with enoxaparin in TIMI 11B,
ESSENCE, and EVET)
Oral Anticoagulants
Sweet Clover
Coumarins
Warfarin, Dicumarol
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Mechanism of action:
Block the Vitamin K-dependent glutamate
carboxylation of precursor clotting
factors II, VII, IX and X
Also inhibits Proteins C & S
8-12 hour delay in action because of T1/2 of
clotting factors in plasma
recovery needs synthesis of new clotting factors
action is reversed with vitamin K
Monitoring Therapy
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PT (INR)
(Prothrombin Time)
Extrinsic pathway (warfarin)
APTT (APTTR)
(Activated Partial Thromboplastin Time)
Intrinsic pathway (heparin)
Warfarin
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Highly plasma protein bound
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Metabolised by liver
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Substrate of CYP450 enzymes
CYP1A2 (minor), 2C8/9 (major), 2C19 (minor), 3A4
(minor); Inhibits CYP2C8/9 (moderate), 2C19 (weak)
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Excreted in urine and stool
Indications
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Prophylaxis and treatment of
1.
venous thrombosis
2.
pulmonary embolism
3.
thromboembolic disorders
4.
atrial fibrillation with risk of embolism
5.
prophylaxis of systemic embolism post MI (LV thrombus)
Adverse effects
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Bleeding
(risk depends on both the INR and patient factors)
Contraindicated in pregnancy
- teratogenic effects, crosses placenta risk foetal haemorrhage
Warfarin induced skin necrosis
- paradoxical local thrombosis
- increased in patients with protein C or S deficiency
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"Purple toes syndrome," cholesterol microembolization
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Hepatic dysfunction
Precautions
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Patient compliance
- eg dementia
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Patient’s bleeding risk
- eg falls, chronic liver disease, alcoholism, past history
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Dietary factors
- eg malnutrition
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Drug interactions
Interactions
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Pharmacokinetic
- changes in the absorption, protein binding, and/or metabolism
- metabolism/elimination via cytochrome P450 system (common)
- displacement of warfarin from plasma protein-binding sites eg
NSAIDs (less important)
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Pharmacodynamic
- alter the risk of bleeding or clotting by either effect on platelet
aggregation or vitamin K catabolism
CYP450 and Warfarin
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CYP2C8/9 inducers
↓
warfarin effect
eg Carbamazepine, phenobarbital, phenytoin, rifampin
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CYP2C8/9 inhibitors ↑ warfarin effect
eg fluconazole, gemfibrozil, ibuprofen, ketoconazole, mefenamic acid,
miconazole, nicardipine, pioglitazone, amiodarone, isoniazid, losartan,
omeprazole, pantoprazole
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CYP2C8/9 gene polymorphism
Alcohol and Warfarin
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Acute ethanol ingestion (binge drinking)
decreases the metabolism of warfarin and
increases PT/INR
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Chronic daily ethanol use increases the
metabolism of warfarin and decreases PT/INR
Food and Warfarin
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The anticoagulant effects of warfarin may be
decreased if taken with foods rich in vitamin K
eg liver, green tea and leafy green vegetables
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Vitamin E may increase warfarin effect
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Cranberry juice may increase warfarin effect
Herbal/Nutraceuticals
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Cranberry, fenugreek, ginkgo biloba, glucosamine,
may enhance bleeding or increase warfarin's effect
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Ginseng (American), coenzyme Q10, and St John's
wort may decrease warfarin levels and effects
Antibiotics and Warfarin
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Cytochrome P450 High risk >75%
- eg Erythromycin, Clarithromycin, Ciprofloxacin, Cotrimoxazole, Metronidazole, Ketoconazole, Fluconazole
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Any broad-spectrum antibiotics can suppress production
of vitamin K by the gut flora
Management of elevated INR
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INR <6 No significant bleeding
- Reduce dose or hold the next dose until INR <5
INR >6 and <8 No significant bleeding
- Hold the next 1or 2 doses until INR <5 then resume lower dose
INR >8: No significant bleeding
- Hold warfarin until INR <5
- Vitamin K orally 5-10 mg or 0.5mg iv if high risk for bleeding
Any INR elevation + Serious bleeding
- Hold warfarin, give vitamin K (10 mg by slow I.V. infusion), and supplement with
fresh plasma transfusion or prothrombin complex concentrate (factor X complex)
Vitamin K and Warfarin
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Note: Use of high doses of vitamin K (10-15mg) may
cause resistance to warfarin for more than a week
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Heparin or low molecular weight heparin can be given
until the patient becomes responsive to warfarin
Newer Anticoagulants
Direct Thrombin Inhibitors
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Eg Hirudin, a naturally occurring anticoagulant
Bind directly to thrombin's catalytic site rather than
to antithrombin III
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Inhibit clot-bound thrombin
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Increased risk of major hemorrhage with hirudin
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Possible role in HITs
Ximelegatran
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Oral direct thrombin inhibitor
Concerns re: hepatotoxicity
No antidote
Antiplatelet agents
Antiplatelet agents
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Predominantly prevent arterial thrombosis
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In acute setting of MI & ischaemic stroke
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Secondary prevention of vascular events
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Primary prevention when 10 yr risk >15% and
BP controlled
Antiplatelet drug targets
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Prostaglandin
synthesis
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ADP binding
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GPIIb/IIIa
receptor
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Cyclic AMP
Antiplatelet agents
Aspirin
inhibits cyclo-oxygenase
 thromboxane A2 synthesis
inhibits both COX 1 and COX 2 irreversibly
COX-1 vs COX-2 inhibitors
Aspirin
Pros Inexpensive
Proven efficacy
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Cons –
Intolerance
Limited potency
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Adverse effects
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GI ulceration 6-31%
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Haemorrhage
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Bronchospasm
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Interstitial nephritis, papillary necrosis, proteinuria,
renal failure
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Reye’s syndrome in children CI <16yrs
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Dangerous in overdose
Antiplatelet agents
Theinopyridines
eg Clopidogrel, Ticlopidine
Block activation of platelets by reducing
ADP activation of Gp IIb / IIIa receptor
complex
Clopidogrel
Alternative to aspirin
First choice for aspirin intolerance
 In addition to aspirin in context of
Primary PCI
Acute coronary syndromes
Secondary prevention of MI but NOT stroke
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Adverse effects
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GI upset
Bleeding
Blood dyscrasias
Aspirin + Clopidogrel
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significant increase in major (3.7 versus 2.7
percent for aspirin alone) and minor
bleeding (5.1 versus 2.4 percent)
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 bleeding risk with clopidogrel plus aspirin
in patients who require coronary artery
bypass graft surgery (CABG)
Antiplatelet agents
Glycoprotein IIb/IIIa inhibitors
(eg abciximab, eptifibatide)
– inhibit cross-bridging of
platelets by fibrinogen
– Fab fragment of monoclonal antibody
GP IIb/IIIa inhibitors for ACS
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Among patients undergoing PCI with stenting
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Periprocedural administration of GP IIb/IIIa inhibitors
improves outcomes in patients with a non-ST
elevation ACS
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No evidence for benefit in context of thrombolysis
Glycoprotein IIb/IIIa inhibitors
Adverse effects
Drug-induced thrombocytopaenia
Bleeding
Emergency CABG (abciximab-treated
patients were more likely to require
surgical reexploration for bleeding (12
versus 3 percent))
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Antiplatelet agents
Dipyridamole
Inhibits platelet activation : by inhibiting
platelet phospho-diesterase activity,
stimulating prostacyclin synthesis, and
blocking adensoine uptake
Dipyridamole
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pyrimido-pyrimidine derivative
vasodilatory effects on coronary resistance vessels
increases intracellular platelet cAMP activating the
enzyme adenylate cyclase, and inhibiting uptake of
adenosine from vascular endothelium and
erythrocytes
*even the usual oral doses of dipyridamole may
enhance exercise-induced myocardial ischemia in
patients with stable angina
Dipyridamole + Aspirin ESPS 2
Odds ratios for active treatment versus placebo
Stroke
ASA
DP
DP - ASA
Stroke and / or Death
ASA
DP
DP - ASA
Risk Reduction %
ASA
19.3
DP
21.5
DP - ASA 40.2
ASA
15.4
DP
18.5
DP - ASA 28.6
0.0 0.25 0.5 0.75 1.0 1.25 1.5 1.75 2.0
Summary
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Aspirin + Clopidogrel proven in
- acute MI
- ACS
- prior to PCA + stenting
- but not indicated in stroke prevention
Summary
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GP IIb/IIIa inhibitors proven benefit
- prior to PCI
- provided CABG not required
Dipyridamole possible role in stroke
UFH/LMWH proven benefit in
- acute coronary syndromes
- short term therapy only
Fibrinolytics
Fibrinolytics
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Streptokinase, Urokinase, Alteplase (rt-PA), Reteplase,
Tenecteplase
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MOA: Plasminogen activators
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Plasmin degrades fibrin and breaks up thrombi
Streptokinase
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Derived from bacterial protein
Antigenic (abys after 4 days)
Cleaves Plasminogen
Low fibrin specificity
Cheap
Urokinase
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Intrinsic compound
Isolated from urine or renal cell
cultures
Non-antigenic
Cleaves plasminogen
Not licensed for MI
Tissue plasminogen activator
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Intrinsic compound
Recombinant DNA manufacture
Non-antigenic
Short half-life – give heparin afterwards
Higher fibrin specificity
Expensive
? More effective
Reteplase/Tenecteplase
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Variants of TPA
Longer half-life
Easy to use
More fibrin specific
Indications
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Acute trans-mural MI within 12 hrs
Ischaemic stroke within 3 hrs
Massive PE
Peripheral arterial thrombus
Blocked lines
Massive DVT
Thrombosed prosthetic valves
Indications in MI
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Clinical history of MI and either ST
elevation or new LBBB
True posterior MI
As early as possible
Little benefit after 12 hrs and no
benefit after 24
Contra-indications
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Aortic dissection
Recent or active bleeding
Recent major surgery
Bleeding diathesis or coagulation disorder
Pregnancy
Previous intracranial bleed
Recent embolic CVA
Complications
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Bleeding
Allergic reactions
Hypotension
Arrhythmias
Re-perfusion injury