Blood coagulation and Blood coagulation and

fibrinolysisfibrinolysis

March 2006March 2006

HaemostasisHaemostasis

adhesion adhesion shape changeshape change activation and activation and

secretion secretion aggregation aggregation interaction with interaction with

coagulation coagulation factors factors

Drug classesDrug classes

1. Anticoagulants 1. Anticoagulants

2. Antiplatelet drugs 2. Antiplatelet drugs

3. Thrombolytic Agents 3. Thrombolytic Agents

AnticoagulantsAnticoagulants

HeparinHeparin

Glycosaminoglycan containing a mixture of Glycosaminoglycan containing a mixture of

sulfated mucopolysaccharides of various sizes sulfated mucopolysaccharides of various sizes

- Unfractionated (5000-30000 Da)- Unfractionated (5000-30000 Da)

- Low molecular weight (LMWH) (1000-10000 - Low molecular weight (LMWH) (1000-10000

Da)Da)

Mechanism of ActionMechanism of Action

Heparin :Heparin :

- enhances the action of Antithrombin III- enhances the action of Antithrombin III (AT-III) (plasma (AT-III) (plasma

protease inhibitor) 1000 fold protease inhibitor) 1000 fold ↑ activity↑ activity

- antithrombin III inhibits clotting factor proteases,- antithrombin III inhibits clotting factor proteases,

Thrombin (IIa), IXa, Xa, XIa and XIIa, by forming stable complexesThrombin (IIa), IXa, Xa, XIa and XIIa, by forming stable complexes

- heparin binds to AT-III and causes a conformational change - heparin binds to AT-III and causes a conformational change

thereby activating AT-III thereby activating AT-III

LMWH:LMWH:

- predominantly inhibit factor Xa- predominantly inhibit factor Xa

Heparins do not affect thrombin bound to fibrin or Xa bound to plateletsHeparins do not affect thrombin bound to fibrin or Xa bound to platelets

Monitoring TherapyMonitoring Therapy

APTT (APTTR)APTT (APTTR)

(Activated Partial Thromboplastin (Activated Partial Thromboplastin Time) Time)

Intrinsic pathway (heparin)Intrinsic pathway (heparin) PT (INR)PT (INR)

(Prothrombin Time)(Prothrombin Time)

Extrinsic pathway (warfarin)Extrinsic pathway (warfarin)

Heparin - indicationsHeparin - indications

Rapid onset of action & short half lifeRapid onset of action & short half life When immediate anticoagulation requiredWhen immediate anticoagulation required When quick reversal may be requiredWhen quick reversal may be required Prevention and treatment of venous Prevention and treatment of venous

thrombosisthrombosis Pulmonary embolism Pulmonary embolism Acute Coronary syndromesAcute Coronary syndromes Given intravenously or subcutaneously Given intravenously or subcutaneously Can be used in pregnant women Can be used in pregnant women

Adverse effectsAdverse effects

Increased bleeding 3%Increased bleeding 3%

- antidote (protamine sulfate)- antidote (protamine sulfate)

Heparin induced thrombocytopaeniaHeparin induced thrombocytopaenia

- HITs 1% up to 3 days 5% >5 days- HITs 1% up to 3 days 5% >5 days

- Can precipitate thrombosis- Can precipitate thrombosis

Osteoporosis with long term high-dose administration Osteoporosis with long term high-dose administration

3-6mths3-6mths

Inhibit aldosterone synthesis – rarely causes Inhibit aldosterone synthesis – rarely causes ↑↑K+K+

Unfractionated heparinUnfractionated heparin

Unpredictable pharmacokineticsUnpredictable pharmacokinetics

Requires regular monitoringRequires regular monitoring

InfusionInfusion

Higher incidence of HITs Higher incidence of HITs

Rebound ischaemiaRebound ischaemia

Low Mol Weight Low Mol Weight HeparinsHeparins

Eg Enoxaparin; TinzaparinEg Enoxaparin; Tinzaparin

More predictable pharmacokineticsMore predictable pharmacokinetics

Lower incidence of heparin-associated thrombocytopenia Lower incidence of heparin-associated thrombocytopenia

Ease of administration s/c injectionEase of administration s/c injection

No need for monitoring No need for monitoring

Possible improvement in outcomes of acute coronary Possible improvement in outcomes of acute coronary

syndromessyndromes

(Such a benefit was suggested with enoxaparin in TIMI (Such a benefit was suggested with enoxaparin in TIMI

11B, ESSENCE, and EVET) 11B, ESSENCE, and EVET)

Oral AnticoagulantsOral Anticoagulants

Sweet Clover

CoumarinsCoumarins

Warfarin, DicumarolWarfarin, Dicumarol Mechanism of actionMechanism of action::

Block the Vitamin K-dependent glutamate Block the Vitamin K-dependent glutamate

carboxylation of precursor clotting carboxylation of precursor clotting

factors II, VII, IX and Xfactors II, VII, IX and X Also inhibits Proteins C & SAlso inhibits Proteins C & S 8-12 hour delay in action because of T1/2 8-12 hour delay in action because of T1/2

of clotting factors in plasma of clotting factors in plasma recovery needs synthesis of new clotting recovery needs synthesis of new clotting

factorsfactors action is reversed with vitamin K action is reversed with vitamin K

Monitoring TherapyMonitoring Therapy

PT (INR)PT (INR)

(Prothrombin Time)(Prothrombin Time)

Extrinsic pathway (warfarin)Extrinsic pathway (warfarin)

APTT (APTTR)APTT (APTTR)

(Activated Partial Thromboplastin Time) (Activated Partial Thromboplastin Time)

Intrinsic pathway (heparin)Intrinsic pathway (heparin)

WarfarinWarfarin

Highly plasma protein boundHighly plasma protein bound

Metabolised by liverMetabolised by liver

Substrate of CYP450 enzymesSubstrate of CYP450 enzymes

CYP1A2 (minor), CYP1A2 (minor), 2C8/9 (major)2C8/9 (major), 2C19 (minor), 3A4 , 2C19 (minor), 3A4

(minor); Inhibits CYP2C8/9 (moderate), 2C19 (minor); Inhibits CYP2C8/9 (moderate), 2C19

(weak) (weak)

Excreted in urine and stoolExcreted in urine and stool

IndicationsIndications

Prophylaxis and treatment ofProphylaxis and treatment of

1.1. venous thrombosisvenous thrombosis

2.2. pulmonary embolism pulmonary embolism

3.3. thromboembolic disordersthromboembolic disorders

4.4. atrial fibrillation with risk of embolismatrial fibrillation with risk of embolism

5.5. prophylaxis of systemic embolism post MI (LV prophylaxis of systemic embolism post MI (LV

thrombus)thrombus)

Adverse effectsAdverse effects

Bleeding Bleeding (risk depends on both the INR and patient factors)(risk depends on both the INR and patient factors)

Contraindicated in pregnancy Contraindicated in pregnancy - teratogenic effects, crosses placenta risk foetal - teratogenic effects, crosses placenta risk foetal

haemorrhagehaemorrhage

Warfarin induced skin necrosisWarfarin induced skin necrosis - paradoxical local thrombosis - paradoxical local thrombosis - increased in patients with protein C or S deficiency- increased in patients with protein C or S deficiency

"Purple toes syndrome," cholesterol microembolization "Purple toes syndrome," cholesterol microembolization

Hepatic dysfunctionHepatic dysfunction

PrecautionsPrecautions

Patient compliance Patient compliance

- eg dementia- eg dementia

Patient’s bleeding risk Patient’s bleeding risk

- eg falls, chronic liver disease, alcoholism, past history- eg falls, chronic liver disease, alcoholism, past history

Dietary factorsDietary factors

- eg malnutrition- eg malnutrition

Drug interactionsDrug interactions

InteractionsInteractions PharmacokineticPharmacokinetic

- changes in the absorption, protein binding, and/or metabolism - changes in the absorption, protein binding, and/or metabolism

- metabolism/elimination via cytochrome P450 system (common)- metabolism/elimination via cytochrome P450 system (common)

- - displacement of warfarin from plasma protein-binding sites eg

NSAIDs (less important)

PharmacodynamicPharmacodynamic

- alter the risk of bleeding or clotting by either effect on platelet - alter the risk of bleeding or clotting by either effect on platelet

aggregation or vitamin K catabolism aggregation or vitamin K catabolism

CYP450 and WarfarinCYP450 and Warfarin

CYP2C8/9 inducersCYP2C8/9 inducers ↓ ↓ warfarin effectwarfarin effect

eg eg Carbamazepine, phenobarbital, phenytoin, rifampinCarbamazepine, phenobarbital, phenytoin, rifampin

CYP2C8/9 inhibitors CYP2C8/9 inhibitors ↑ warfarin effect↑ warfarin effect

eg eg fluconazole, gemfibrozil, ibuprofen, ketoconazole, mefenamic fluconazole, gemfibrozil, ibuprofen, ketoconazole, mefenamic

acid, miconazole, nicardipine, pioglitazone, amiodarone, acid, miconazole, nicardipine, pioglitazone, amiodarone,

isoniazid, losartan, omeprazole, pantoprazole isoniazid, losartan, omeprazole, pantoprazole

CYP2C8/9 gene polymorphismCYP2C8/9 gene polymorphism

Alcohol and WarfarinAlcohol and Warfarin

Acute ethanol ingestion (binge drinking) Acute ethanol ingestion (binge drinking)

decreases the metabolism of warfarin decreases the metabolism of warfarin

and increases PT/INRand increases PT/INR

Chronic daily ethanol use increases the Chronic daily ethanol use increases the

metabolism of warfarin and decreases metabolism of warfarin and decreases

PT/INR PT/INR

Food and WarfarinFood and Warfarin

The anticoagulant effects of warfarin may be The anticoagulant effects of warfarin may be decreased if taken with foods rich in vitamin decreased if taken with foods rich in vitamin K eg liver, green tea and leafy green K eg liver, green tea and leafy green vegetables vegetables

Vitamin E may increase warfarin effectVitamin E may increase warfarin effect

Cranberry juice may increase warfarin effectCranberry juice may increase warfarin effect

Herbal/Nutraceuticals Herbal/Nutraceuticals

Cranberry, fenugreek, ginkgo biloba, glucosamine, Cranberry, fenugreek, ginkgo biloba, glucosamine,

may may enhance bleeding or increase warfarin's effectenhance bleeding or increase warfarin's effect

Ginseng (American), coenzyme Q10, and St John's Ginseng (American), coenzyme Q10, and St John's

wort may wort may decrease warfarin levels and effects decrease warfarin levels and effects

Antibiotics and Antibiotics and WarfarinWarfarin Cytochrome P450 High risk >75%Cytochrome P450 High risk >75%

- eg Erythromycin, Clarithromycin, Ciprofloxacin, - eg Erythromycin, Clarithromycin, Ciprofloxacin,

Co-trimoxazole, Metronidazole, Ketoconazole, Co-trimoxazole, Metronidazole, Ketoconazole,

FluconazoleFluconazole

Any broad-spectrum antibiotics can Any broad-spectrum antibiotics can suppress suppress

production of vitamin K by the gut flora production of vitamin K by the gut flora

Management of elevated Management of elevated

INRINR INR <6 No significant bleedingINR <6 No significant bleeding

- Reduce dose or hold the next dose until INR <5 - Reduce dose or hold the next dose until INR <5

INR >6 and <8 No significant bleedingINR >6 and <8 No significant bleeding

- Hold the next 1or 2 doses until INR <5 then resume lower dose- Hold the next 1or 2 doses until INR <5 then resume lower dose

INR >8: No significant bleedingINR >8: No significant bleeding

- Hold warfarin until INR <5- Hold warfarin until INR <5

- Vitamin K orally 5-10 mg or 0.5mg iv if high risk for bleeding- Vitamin K orally 5-10 mg or 0.5mg iv if high risk for bleeding

Any INR elevation + Serious bleedingAny INR elevation + Serious bleeding

- - Hold warfarin, give vitamin K (10 mg by slow I.V. infusion), and Hold warfarin, give vitamin K (10 mg by slow I.V. infusion), and supplement with fresh plasma transfusion or prothrombin complex supplement with fresh plasma transfusion or prothrombin complex concentrate (factor X complex) concentrate (factor X complex)

Vitamin K and Vitamin K and WarfarinWarfarin

Note: Use of high doses of vitamin K (10-15mg) Note: Use of high doses of vitamin K (10-15mg)

may cause resistance to warfarin for more than may cause resistance to warfarin for more than

a weeka week

Heparin or low molecular weight heparin can be Heparin or low molecular weight heparin can be

given until the patient becomes responsive to given until the patient becomes responsive to

warfarinwarfarin

Newer Newer AnticoagulantsAnticoagulants

Direct Thrombin InhibitorsDirect Thrombin Inhibitors

Eg Hirudin, a naturally occurring Eg Hirudin, a naturally occurring

anticoagulantanticoagulant

Bind directly to thrombin's catalytic site Bind directly to thrombin's catalytic site

rather than to antithrombin IIIrather than to antithrombin III

Inhibit clot-bound thrombinInhibit clot-bound thrombin

Increased risk of major hemorrhage with Increased risk of major hemorrhage with

hirudinhirudin

Possible role in HITsPossible role in HITs

XimelegatranXimelegatran

Oral direct thrombin inhibitorOral direct thrombin inhibitor Concerns re: hepatotoxicityConcerns re: hepatotoxicity No antidoteNo antidote

Antiplatelet agentsAntiplatelet agents

Antiplatelet agentsAntiplatelet agents

Predominantly prevent arterial Predominantly prevent arterial

thrombosisthrombosis

In acute setting of MI & ischaemic strokeIn acute setting of MI & ischaemic stroke

Secondary prevention of vascular eventsSecondary prevention of vascular events

Primary prevention when 10 yr risk >15% Primary prevention when 10 yr risk >15%

and BP controlledand BP controlled

Antiplatelet drug Antiplatelet drug targetstargets

Prostaglandin Prostaglandin

synthesissynthesis

ADP binding ADP binding

GPIIb/IIIa GPIIb/IIIa

receptor receptor

Cyclic AMPCyclic AMP

AspirinAspirin

inhibits cyclo-oxygenase inhibits cyclo-oxygenase

thromboxane A2 synthesisthromboxane A2 synthesis

inhibits both COX 1 and COX 2 inhibits both COX 1 and COX 2 irreversiblyirreversibly

Antiplatelet agentsAntiplatelet agents

COX-1 vs COX-2 COX-1 vs COX-2 inhibitorsinhibitors

AspirinAspirin

Pros -Pros -

InexpensiveInexpensive

Proven efficacyProven efficacy

Cons –Cons –

IntoleranceIntolerance

Limited potencyLimited potency

Adverse effectsAdverse effects

GI ulceration 6-31%GI ulceration 6-31%

HaemorrhageHaemorrhage

BronchospasmBronchospasm

Interstitial nephritis, papillary necrosis, Interstitial nephritis, papillary necrosis,

proteinuria, renal failure proteinuria, renal failure

Reye’s syndrome in children CI <16yrsReye’s syndrome in children CI <16yrs

Dangerous in overdoseDangerous in overdose

TheinopyridinesTheinopyridines

eg Clopidogrel, TiclopidineClopidogrel, Ticlopidine

Block activation of platelets by Block activation of platelets by

reducing ADP activation of Gp IIb / IIIa reducing ADP activation of Gp IIb / IIIa

receptor complexreceptor complex

Antiplatelet agentsAntiplatelet agents

ClopidogrelClopidogrel

Alternative to aspirinAlternative to aspirin

First choice for aspirin intolerance First choice for aspirin intolerance In addition to aspirin in context ofIn addition to aspirin in context of

Primary PCIPrimary PCI

Acute coronary syndromesAcute coronary syndromes

Secondary prevention of MI but Secondary prevention of MI but NOTNOT strokestroke

Adverse effectsAdverse effects

GI upsetGI upset BleedingBleeding Blood dyscrasiasBlood dyscrasias

Aspirin + ClopidogrelAspirin + Clopidogrel

significant increase in major (3.7 versus significant increase in major (3.7 versus

2.7 percent for aspirin alone) and minor 2.7 percent for aspirin alone) and minor

bleeding (5.1 versus 2.4 percent)bleeding (5.1 versus 2.4 percent)

bleeding risk with clopidogrel plus bleeding risk with clopidogrel plus

aspirin in patients who require coronary aspirin in patients who require coronary

artery bypass graft surgery (CABG)artery bypass graft surgery (CABG)

Glycoprotein IIb/IIIa inhibitorsGlycoprotein IIb/IIIa inhibitors

(eg abciximab, eptifibatide) (eg abciximab, eptifibatide)

– – inhibit cross-bridging of inhibit cross-bridging of

platelets by fibrinogenplatelets by fibrinogen

–– Fab fragment of monoclonal Fab fragment of monoclonal antibodyantibody

Antiplatelet agents Antiplatelet agents

GP IIb/IIIa inhibitorsGP IIb/IIIa inhibitors for ACSfor ACS

Among patients undergoing PCI with stentingAmong patients undergoing PCI with stenting

Periprocedural administration of GP IIb/IIIa Periprocedural administration of GP IIb/IIIa

inhibitors improves outcomes in patients with a inhibitors improves outcomes in patients with a

non-ST elevation ACSnon-ST elevation ACS

No evidence for benefit in context of No evidence for benefit in context of

thrombolysisthrombolysis

Glycoprotein IIb/IIIa Glycoprotein IIb/IIIa inhibitorsinhibitors

Adverse effectsAdverse effects

Drug-induced thrombocytopaeniaDrug-induced thrombocytopaenia

BleedingBleeding

Emergency CABG (abciximab-Emergency CABG (abciximab-treated patients were more likely treated patients were more likely to require surgical reexploration to require surgical reexploration for bleeding (12 versus 3 percent))for bleeding (12 versus 3 percent))

DipyridamoleDipyridamole

Inhibits platelet activation : by Inhibits platelet activation : by inhibiting platelet phospho-inhibiting platelet phospho-diesterase activity, stimulating diesterase activity, stimulating prostacyclin synthesis, and prostacyclin synthesis, and blocking adensoine uptakeblocking adensoine uptake

Antiplatelet agents Antiplatelet agents

DipyridamoleDipyridamole

pyrimido-pyrimidine derivative pyrimido-pyrimidine derivative vasodilatory effects on coronary resistance vasodilatory effects on coronary resistance

vessels vessels increases intracellular platelet cAMP increases intracellular platelet cAMP

activating the enzyme adenylate cyclase, activating the enzyme adenylate cyclase, and inhibiting uptake of adenosine from and inhibiting uptake of adenosine from vascular endothelium and erythrocytes vascular endothelium and erythrocytes

*even the usual oral doses of dipyridamole *even the usual oral doses of dipyridamole may enhance exercise-induced myocardial may enhance exercise-induced myocardial ischemia in patients with stable anginaischemia in patients with stable angina

ASAASA

DPDP

DP - ASADP - ASA

0.00.0 0.250.25 0.50.5 0.750.75 1.01.0 1.251.25 1.51.5 1.751.75 2.02.0

ASAASA

DPDP

DP - ASADP - ASA

StrokeStroke

Stroke and / or DeathStroke and / or Death

Dipyridamole + Aspirin ESPS 2Dipyridamole + Aspirin ESPS 2Odds ratios for active treatment versus placeboOdds ratios for active treatment versus placebo

ASAASA 19.319.3

DPDP 21.521.5

DP - ASADP - ASA 40.240.2

Risk Reduction %Risk Reduction %

ASAASA 15.415.4

DPDP 18.518.5

DP - ASADP - ASA 28.628.6

SummarySummary

Aspirin + Clopidogrel proven inAspirin + Clopidogrel proven in

- acute MI- acute MI

- ACS- ACS

- prior to PCA + stenting- prior to PCA + stenting

- but not indicated in stroke - but not indicated in stroke preventionprevention

SummarySummary

GP IIb/IIIa inhibitors proven benefitGP IIb/IIIa inhibitors proven benefit

- prior to PCI - prior to PCI

- provided CABG not required- provided CABG not required Dipyridamole possible role in strokeDipyridamole possible role in stroke UFH/LMWH proven benefit inUFH/LMWH proven benefit in

- acute coronary syndromes- acute coronary syndromes

- short term therapy only- short term therapy only

FibrinolyticsFibrinolytics

FibrinolyticsFibrinolytics

Streptokinase, Urokinase, Alteplase (rt-PA), Streptokinase, Urokinase, Alteplase (rt-PA),

Reteplase, TenecteplaseReteplase, Tenecteplase

MOA: Plasminogen activatorsMOA: Plasminogen activators

Plasmin degrades fibrin and breaks up thrombiPlasmin degrades fibrin and breaks up thrombi

StreptokinaseStreptokinase

Derived from bacterial proteinDerived from bacterial protein Antigenic (abys after 4 days)Antigenic (abys after 4 days) Cleaves PlasminogenCleaves Plasminogen Low fibrin specificityLow fibrin specificity CheapCheap

UrokinaseUrokinase

Intrinsic compoundIntrinsic compound Isolated from urine or renal cell Isolated from urine or renal cell

culturescultures Non-antigenicNon-antigenic Cleaves plasminogenCleaves plasminogen Not licensed for MINot licensed for MI

Tissue plasminogen Tissue plasminogen activatoractivator

Intrinsic compoundIntrinsic compound Recombinant DNA manufactureRecombinant DNA manufacture Non-antigenicNon-antigenic Short half-life – give heparin Short half-life – give heparin

afterwardsafterwards Higher fibrin specificityHigher fibrin specificity ExpensiveExpensive ? More effective? More effective

Reteplase/TenecteplaseReteplase/Tenecteplase

Variants of TPAVariants of TPA Longer half-lifeLonger half-life Easy to useEasy to use More fibrin specificMore fibrin specific

IndicationsIndications

Acute trans-mural MI within 12 hrsAcute trans-mural MI within 12 hrs Ischaemic stroke within 3 hrsIschaemic stroke within 3 hrs Massive PEMassive PE Peripheral arterial thrombusPeripheral arterial thrombus Blocked linesBlocked lines Massive DVTMassive DVT Thrombosed prosthetic valvesThrombosed prosthetic valves

Indications in MIIndications in MI

Clinical history of MI and either ST Clinical history of MI and either ST elevation or new LBBBelevation or new LBBB

True posterior MITrue posterior MI As early as possibleAs early as possible Little benefit after 12 hrs and no Little benefit after 12 hrs and no

benefit after 24benefit after 24

Contra-indicationsContra-indications

Aortic dissectionAortic dissection Recent or active bleedingRecent or active bleeding Recent major surgeryRecent major surgery Bleeding diathesis or coagulation Bleeding diathesis or coagulation

disorderdisorder PregnancyPregnancy Previous intracranial bleedPrevious intracranial bleed Recent embolic CVARecent embolic CVA

ComplicationsComplications

BleedingBleeding Allergic reactionsAllergic reactions HypotensionHypotension ArrhythmiasArrhythmias Re-perfusion injuryRe-perfusion injury