#23 Platelet Function Inhibitors

8/9/2019 #23 Platelet Function Inhibitors

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Platelet FunctionPlatelet Function

InhibitorsInhibitors

Michael J. Sanfelippo, M.S.Michael J. Sanfelippo, M.S.

Technical Director, Coagulation ServicesTechnical Director, Coagulation Services

Marshfield LabsMarshfield Labs


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Drugs that are Currently Used toDrugs that are Currently Used to

Inhibit Platelet FunctionInhibit Platelet FunctionAspirinAspirin

ClopidogrelClopidogrel

PrasugrelPrasugrelTiclopidineTiclopidine

IIb/IIIa receptor blocking antibodiesIIb/IIIa receptor blocking antibodies


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Mechanism of Platelet Inhibition byMechanism of Platelet Inhibition by

AspirinAspirinAspirin acetylates cyclooxygenase 1 enzymeAspirin acetylates cyclooxygenase 1 enzyme

(COX(COX--1)1)

COXCOX--1 needed to convert arachidonic acid to1 needed to convert arachidonic acid tothromboxanethromboxane

Thromboxane is platelet aggregation potentiatorThromboxane is platelet aggregation potentiator

and vasoconstrictorand vasoconstrictor

Aspirin also inhibits COXAspirin also inhibits COX--2 enzyme to lesser2 enzyme to lesser

degreedegree


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Need toMonitor Aspirin TherapyNeed toMonitor Aspirin Therapy

1515 45% patients are poor or non responders45% patients are poor or non responders

Patients have suffered cardiovascular orPatients have suffered cardiovascular or

neurovascular events while on aspirinneurovascular events while on aspirin


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Methods ofMonitoring AspirinMethods ofMonitoring Aspirin

Platelet aggregometry, light transmission absentPlatelet aggregometry, light transmission absent

aggregation response with arachidonic acidaggregation response with arachidonic acid

AspirinWorksAspirinWorks

-- measurement of thromboxanemeasurement of thromboxanemetabolite in urine 11 dehydrothromboxane B2metabolite in urine 11 dehydrothromboxane B2


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AspirinWorksAspirinWorks

ELISA assay measures 11dehydrothromboxane B2 inELISA assay measures 11dehydrothromboxane B2 in

urineurine

Metabolic breakdown product of thromboxaneMetabolic breakdown product of thromboxane

Reference levelsReference levels

Patients not taking aspirin = >1500 pgm/mg creatininePatients not taking aspirin = >1500 pgm/mg creatinine

Patients taking aspirin =


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Case History 60 Year OldMale onCase History 60 Year OldMale on

AspirinAspirin 6060--yearyear--old male taking 81 mg aspirin per dayold male taking 81 mg aspirin per day

because of history of neurovascular thrombosisbecause of history of neurovascular thrombosis

Platelet aggregation with arachidonic acidPlatelet aggregation with arachidonic acid nonoresponseresponse

AspirinWorksAspirinWorks -- 1900 pgm/mg creatinine1900 pgm/mg creatinine

Aspirin dose increased to 325 mg per dayAspirin dose increased to 325 mg per day

Repeat Aspirin WorksRepeat Aspirin Works -- 900 pgm/mg900 pgm/mg

creatininecreatinine


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Clopidogrel (Plavix)Clopidogrel (Plavix)

Prodrug metabolized in liver by cytochromeProdrug metabolized in liver by cytochrome

P450 in liver to active drugP450 in liver to active drug

Active drug irreversibly blocks platelet ADPActive drug irreversibly blocks platelet ADPP2Y12 receptorP2Y12 receptor this inhibits activation ofthis inhibits activation of

IIbIIIa receptorIIbIIIa receptor

Inhibitory effect on platelets is irreversible,Inhibitory effect on platelets is irreversible,

platelets inhibited for their life spanplatelets inhibited for their life span


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Clopidogrel Resistance or DrugClopidogrel Resistance or Drug

FailureFailure May be defined by thrombotic event while onMay be defined by thrombotic event while on

drugdrug

May be defined by laboratory test of plateletMay be defined by laboratory test of plateletinhibitioninhibition

Occurs in 4Occurs in 4 30% of patients taking drug30% of patients taking drug


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Causes ofDrug FailureCauses ofDrug Failure

Interference with P450 metabolism ofInterference with P450 metabolism of

clopidogrel, cytochrome P450 2C19 lossclopidogrel, cytochrome P450 2C19 loss--ofof--

function polymorphismfunction polymorphismAccelerated platelet turnoverAccelerated platelet turnover

Polymorphism of the P2Y12 receptor (platelet)Polymorphism of the P2Y12 receptor (platelet)


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Laboratory Test for Drug FailureLaboratory Test for Drug Failure

Platelet aggregation with ADP at 20 micromolesPlatelet aggregation with ADP at 20 micromoles

Expected result 40Expected result 40 60% inhibition of60% inhibition of

aggregation responseaggregation response


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Adverse Effects of ClopidogrelAdverse Effects of Clopidogrel

Increased bleeding and/or bruisingIncreased bleeding and/or bruising

Thrombotic thrombocytopenic purpura, TTPThrombotic thrombocytopenic purpura, TTP--

rarerare


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Prasugrel (Effient)Prasugrel (Effient)

Theinophyridine like clopidogrelTheinophyridine like clopidogrel

Prodrug metabolized to active metabolite in theProdrug metabolized to active metabolite in the

liver by cytochrome systemliver by cytochrome system Inhibits platelet function by irreversibly bindingInhibits platelet function by irreversibly binding

P2Y12 ADP platelet receptorsP2Y12 ADP platelet receptors

Appears to be unaffected by cytochromeAppears to be unaffected by cytochrome

polymorphisms that inhibit clopidogrelpolymorphisms that inhibit clopidogrel


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Adverse Effects of PrasugrelAdverse Effects of Prasugrel

Increased bleeding and/or bruisingIncreased bleeding and/or bruising

Thrombotic thrombocytopenic purpura, TTPThrombotic thrombocytopenic purpura, TTP--

rarerare


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Monitoring PrasugrelMonitoring Prasugrel

Light transmission platelet aggregometry, ADPLight transmission platelet aggregometry, ADP

20 mico moles20 mico moles

Target range 50Target range 50 70% inhibition of ADP70% inhibition of ADPinduced aggregationinduced aggregation


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TiclopidineTiclopidine

Drug inhibits platelet aggregation and release ofDrug inhibits platelet aggregation and release of

granule contents by inhibiting membranegranule contents by inhibiting membrane

functionfunction

Inhibitory effect is irreversible for life of plateletInhibitory effect is irreversible for life of platelet


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Adverse Affects of TiclopidineAdverse Affects of Ticlopidine

NeutropeniaNeutropenia

Thrombotic thrombocytopenic purpuraThrombotic thrombocytopenic purpura


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Use of TiclopidineUse of Ticlopidine

Rarely used due to adverse affectsRarely used due to adverse affects

Used in patients that did not respond toUsed in patients that did not respond to

clopidogrelclopidogrel Not monitored when usedNot monitored when used


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IIbIIIa Blocking AgentsIIbIIIa Blocking Agents

Abciximab (ReoPro)Abciximab (ReoPro) mouse antibodymouse antibody

Eptifibatide (Integrilin)Eptifibatide (Integrilin) cyclic heptapeptidecyclic heptapeptide


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Application of IIbIIIa BlockingApplication of IIbIIIa Blocking

AgentsAgents Used to treat patients with acute coronaryUsed to treat patients with acute coronary

syndromessyndromes

Rarely monitoredRarely monitoredWhen monitored, platelet aggregation is almostWhen monitored, platelet aggregation is almost

completely inhibited in response to ADP at 20completely inhibited in response to ADP at 20

microMolemicroMole

Inhibitory effect on platelets is reversibleInhibitory effect on platelets is reversible

#23 Platelet Function Inhibitors

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