AntithrombosisAntithrombosis and and Intracranial HemorrhageIntracranial Hemorrhage

Peter CampbellPeter CampbellDecember 21, 2007December 21, 2007

Reversal of Reversal of AntithromboticAntithromboticAgents OutlineAgents Outline

•• I. OATI. OAT--ICHICH•• II. Reversal of LMWH in ICHII. Reversal of LMWH in ICH•• III. Reversal of III. Reversal of ThrombolyticsThrombolytics in ICHin ICH•• IV. IV. AntiplateletAntiplatelet reversalreversal

Antithrombotic Agents: Antithrombotic Agents: Mechanism of ActionMechanism of Action

•• Anticoagulants: prevent clot formation Anticoagulants: prevent clot formation and extensionand extension

•• ThrombolyticThrombolytic agents: dissolve existing agents: dissolve existing thrombithrombi

•• AntiplateletAntiplatelet drugs: interfere with drugs: interfere with platelet activityplatelet activity

Clotting Cascade, a quick Clotting Cascade, a quick reviewreview

WarfarinWarfarin

Synthesis of Synthesis of Non Non

Functional Functional Coagulation Coagulation

FactorsFactors

Antagonismof

Vitamin K

Warfarin Mechanism of Warfarin Mechanism of ActionAction

Vitamin KVitamin K

VIIVIIIXIXXXIIII

An INR of 3.7 to 4.3 results in an increase in the risk of bleedAn INR of 3.7 to 4.3 results in an increase in the risk of bleeding.ing.

Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120:897-902

Risk of Intracranial Hemorrhage Risk of Intracranial Hemorrhage in Outpatients on Oral in Outpatients on Oral

AnticoagulationAnticoagulation

Risk of Intracranial Hemorrhage Risk of Intracranial Hemorrhage in Outpatients on Oral in Outpatients on Oral

AnticoagulationAnticoagulation

Stroke. 2005;36:1588-1593

A Common Etiology of ICHA Common Etiology of ICH

Hart RG, et al. Stroke. 1995;26:1471-1477; Steiner T, et al. Stroke. 2006;37:256-262; Flibotte JJ, et al. Neurology. 2004;63:1059-1064; Rosand J, et al. Arch Intern Med.2004;164:880-884; Flaherty ML, et al. Stroke. 2006;37:623.

Warfarin indicated in DVT, PE, AFIncidence of anticoagulant-associated ICH rose from 5% to 18% of cases of spontaneous ICH in 1990sINR 2.5–4.5 increases risk of ICH 10XAssociated with longer duration of ICH expansionDoubles ICH mortality

Acquired Coagulopathy Acquired Coagulopathy –– AnticoagulationAnticoagulation

Warfarin and Hematoma Expansion

Prop

ortio

n of

H

emat

oma

Expa

nder

s 1.00

0.75

0.50

0.25

0.000 12 24 36 48 60

Time (h)

No Warfarin (n=9)

Warfarin (n=7)

P

Reversing AnticoagulationReversing Anticoagulation

GoalGoal Normalize INR to

Oral Anticoagulation Therapy Oral Anticoagulation Therapy (OAT)(OAT)--ICHICH

•• Anticoagulation to conventional intensities Anticoagulation to conventional intensities (international normalized ration [INR] 2.5(international normalized ration [INR] 2.5--4.5) 4.5) increases the risk of ICH 7increases the risk of ICH 7-- to 10to 10--fold, to an absolute fold, to an absolute rate of nearly 1.8% per year for many strokerate of nearly 1.8% per year for many stroke--prone prone patients.patients.

•• LifeLife--threatening intracranial hemorrhage, threatening intracranial hemorrhage, predominantly intracerebral hemorrhage (ICH), is predominantly intracerebral hemorrhage (ICH), is the most serious complication of oral anticoagulant the most serious complication of oral anticoagulant therapy (OAT), with mortality in excess of 50%. therapy (OAT), with mortality in excess of 50%.

•• Early intervention focuses on rapid correction of Early intervention focuses on rapid correction of coagulopathy in order to prevent continued bleeding.coagulopathy in order to prevent continued bleeding.

OATOAT--ICH and hematoma ICH and hematoma expansionexpansion

•• OATOAT--ICH may occur over a longer time ICH may occur over a longer time frame than in Spontaneous ICH, frame than in Spontaneous ICH, because of persistent coagulopathy.because of persistent coagulopathy.

•• A prolonged natural course of A prolonged natural course of hematoma expansion in OAThematoma expansion in OAT--ICH ICH would provide a longer time window would provide a longer time window for treatment with for treatment with hemostatichemostatic therapy.therapy.

Vitamin KVitamin K

•• Concomitant administration of Concomitant administration of coagulation factors is requiredcoagulation factors is required

•• At least 6 hours, and often more than 24 At least 6 hours, and often more than 24 hours, to achieve an effective response hours, to achieve an effective response to vitamin K administrationto vitamin K administration

•• The effect of vitamin K is more rapid The effect of vitamin K is more rapid when given intravenously.when given intravenously.

Vitamin KVitamin K——IV or SC?IV or SC?

Vitamin KVitamin K•• Grade 1C: IV vitamin K Grade 1C: IV vitamin K

supplemented with PCC or supplemented with PCC or rfVIIarfVIIa is recommended in cases is recommended in cases of of ““lifelife--threateningthreatening”” bleeding.bleeding.

•• Grade 1A: In patients with mild Grade 1A: In patients with mild to moderately elevated to moderately elevated INRsINRswithout major bleeding vitamin without major bleeding vitamin K is to be given it be K is to be given it be administered orally rather than administered orally rather than subcutaneously.subcutaneously.

•• About SC vitamin K: The About SC vitamin K: The response to vitamin K1 response to vitamin K1 administered SC is less administered SC is less predictable compared to oral predictable compared to oral vitamin K1 and is sometimes vitamin K1 and is sometimes delayed.delayed.

Vitamin K consVitamin K cons

•• The incidence of anaphylaxis was 3 per 10,000 dosesThe incidence of anaphylaxis was 3 per 10,000 doses•• The incidence of anaphylaxis after IV The incidence of anaphylaxis after IV phytonadionephytonadione is is

comparable or slightly less than other drugs known to comparable or slightly less than other drugs known to cause anaphylaxis (IV contrast and cause anaphylaxis (IV contrast and penicillinspenicillins).).

•• The factor responsible for the anaphylaxis is not The factor responsible for the anaphylaxis is not phytonadionephytonadione but the but the solubilizingsolubilizing vehicle, vehicle, polyethoxylatedpolyethoxylated castor oil, PEOcastor oil, PEO--CO.CO.

•• Literature review: 14 reported cases of anaphylaxis after Literature review: 14 reported cases of anaphylaxis after IV IV phytonadionephytonadione in 12 reports from 1966 to 2002.in 12 reports from 1966 to 2002.

Reversal with FFPReversal with FFP

•• FFP contains all coagulation factors in a FFP contains all coagulation factors in a nonnon--concentrated formconcentrated form

•• Standard of an FFP unit is based on its Standard of an FFP unit is based on its factor VIII content; the actual levels of factor VIII content; the actual levels of vitamin Kvitamin K––dependent coagulation dependent coagulation factors are not specified and vary factors are not specified and vary considerablyconsiderably

•• FFP volumes required to reduce the FFP volumes required to reduce the INR below 1.4 may vary considerably: INR below 1.4 may vary considerably: for example, between 800 and 3500 for example, between 800 and 3500 mLmL

FFP ConsFFP Cons

•• Increased time frame required for INR Increased time frame required for INR normalization.normalization.

•• The large volume required and a rapid The large volume required and a rapid transfusion rate can lead to circulatory transfusion rate can lead to circulatory overloadoverload

•• transfusiontransfusion--related acute lung injuryrelated acute lung injury•• bloodblood--borne infectionborne infection•• citrate toxicitycitrate toxicity•• allergic reactionsallergic reactions

ProthrombinProthrombin Complex Complex ConcentratesConcentrates

•• Contains VII, IX, X, and Contains VII, IX, X, and prothrombinprothrombin as as well as proteins C, S, and Z in a well as proteins C, S, and Z in a concentrated form.concentrated form.

•• Can be given without waiting for Can be given without waiting for compatibility testing and thawing.compatibility testing and thawing.

•• Given via 10min Given via 10min –– 1 hour infusion1 hour infusion•• Trials with small numbers of patients Trials with small numbers of patients

suggest that PCC corrects a prolonged suggest that PCC corrects a prolonged INR more rapidly than FFP.INR more rapidly than FFP.

PCC ConsPCC Cons•• The main concerns with PCCThe main concerns with PCC--use focus on the use focus on the

potential to induce thrombosis and potential to induce thrombosis and disseminated intravascular coagulation.disseminated intravascular coagulation.

•• Whether current Whether current PCCsPCCs are associated with are associated with thrombosis has never been substantiated.thrombosis has never been substantiated.

•• Most of the available data suggest that use of Most of the available data suggest that use of PCC in PCC in warfarinwarfarin--associated ICH is relatively associated ICH is relatively safe.safe.

•• One study reported 3 of 11 (2 with prosthetic One study reported 3 of 11 (2 with prosthetic heart valves) ischemic strokes in patients heart valves) ischemic strokes in patients treated with PCC for OATtreated with PCC for OAT--ICH, but did not ICH, but did not report dosages nor composition or PCC used. report dosages nor composition or PCC used.

rVIIarVIIa

•• rFVIIarFVIIa is FDA approved for the is FDA approved for the treatment of bleeding in patients with treatment of bleeding in patients with hemophilia.hemophilia.

•• 4 small trials with a total of 28 patients 4 small trials with a total of 28 patients on OAT reveals an INR

rVIIarVIIa MechanismMechanism

Activates Factors IX & X

rVIIarVIIa

•• SSøørensenrensen et al reported 6 patients who et al reported 6 patients who had been on OAT and were treated had been on OAT and were treated with with rFVIIarFVIIa for central nervous system for central nervous system bleeding. The doses used ranged from bleeding. The doses used ranged from 10 to 40 10 to 40 μμg/kg and the pretreatment g/kg and the pretreatment INRsINRs, which ranged from 1.7 to 6.6, , which ranged from 1.7 to 6.6, were normalized to 1.5 within 10 were normalized to 1.5 within 10 minutes after minutes after rFVIIarFVIIa administration.administration.

Recombinant factor Recombinant factor VIIaVIIaConsCons

•• Arterial thrombosis (ischemic stroke and Arterial thrombosis (ischemic stroke and myocardial infarction) occurred in 5% of myocardial infarction) occurred in 5% of those assigned to those assigned to rFVIIarFVIIa vsvs none assigned to none assigned to placebo.placebo.

By the wayBy the way……Recombinant Recombinant factor factor VIIaVIIa Phase III trial for Phase III trial for

SICHSICH……

•• Phase III blinded, randomized trial showed Phase III blinded, randomized trial showed rVIIarVIIadecreased hematoma volume, butdecreased hematoma volume, but•• Death and disability were unchanged at 90 daysDeath and disability were unchanged at 90 days

•• Novo Novo NordiskNordisk pulled application for FDA approval for pulled application for FDA approval for SICHSICH

PCC PCC vsvs rVIIarVIIa

•• No studies have compared No studies have compared rFVIIarFVIIainfusion with PCC in OATinfusion with PCC in OAT--ICH.ICH.

•• Those who advocate Those who advocate rFVIIarFVIIa for reversal for reversal of of warfarinwarfarin induced coagulation defects induced coagulation defects note that its short halfnote that its short half--life makes life makes induction of a induction of a thrombogenicthrombogenic state less state less likely compared with infusion of a PCClikely compared with infusion of a PCC

Timeline of coagulopathy Timeline of coagulopathy correction in OATcorrection in OAT--ICHICH

•• OATOAT--ICH, the natural course of hematoma ICH, the natural course of hematoma expansion is probably more prolonged, expansion is probably more prolonged, perhaps up to 24 or 48 hours, raising the perhaps up to 24 or 48 hours, raising the possibility that patients presenting as late as possibility that patients presenting as late as 24 hours (or even later) may benefit from 24 hours (or even later) may benefit from effective effective hemostatichemostatic treatment.treatment.

Timeline for various Timeline for various interventions to correct INRinterventions to correct INR

•• Vitamin K and Vitamin K and fresh frozen fresh frozen plasma (FFP) are plasma (FFP) are standard standard therapies to therapies to reverse reverse warfarinwarfarinanticoagulation, anticoagulation, but neither but neither agent is ideal for agent is ideal for emergency emergency anticoagulation anticoagulation reversal.reversal.

Guidelines for OATGuidelines for OAT--ICHICH

•• There are currently no standardized There are currently no standardized guidelines for reversal of the anticoagulant guidelines for reversal of the anticoagulant effect in patients with OATeffect in patients with OAT--ICH.ICH.

•• British Committee for Standards in British Committee for Standards in HaematologyHaematology recommend 5 mg of recommend 5 mg of intravenous or oral vitamin K, and 50 U/kg intravenous or oral vitamin K, and 50 U/kg of PCC or 15 of PCC or 15 mLmL/kg of FFP/kg of FFP

•• The American Thoracic Society recommends The American Thoracic Society recommends 10 mg of intravenous vitamin K and PCC, 10 mg of intravenous vitamin K and PCC, without specifying the dose of PCC.without specifying the dose of PCC.

Since no real guidelines exist; Since no real guidelines exist; some expert recommendationssome expert recommendations

Monitoring Monitoring HemostasisHemostasis in OATin OAT--ICHICH

•• PTPT--INR is routinely used for regulating OAT as well INR is routinely used for regulating OAT as well as monitoring the reversal of its anticoagulant effect.as monitoring the reversal of its anticoagulant effect.

•• test is sensitive to decreased levels of factor VII and test is sensitive to decreased levels of factor VII and factor X, and factor X, and prothrombinprothrombin, but not to decreased , but not to decreased levels of factor IX.levels of factor IX.

•• MakrisMakris et al found that administration of 800 et al found that administration of 800 mLmL FFP FFP decreased the mean INR from 6.73 to 2.38, whereas decreased the mean INR from 6.73 to 2.38, whereas the mean factor IX levels were essentially unchanged the mean factor IX levels were essentially unchanged (from 26.45 IU/(from 26.45 IU/dLdL to 27.36 IU/to 27.36 IU/dLdL).).

•• The use of the INR for monitoring patients treated The use of the INR for monitoring patients treated with with rFVIIarFVIIa is also problematic. is also problematic.

•• Pharmacological doses of Pharmacological doses of rFVIIarFVIIa will always lower will always lower the INR regardless of the levels of other coagulation the INR regardless of the levels of other coagulation factors.factors.

What is the risk of holding What is the risk of holding OAC???OAC???

Restarting Restarting Anticoagulation After ICH Anticoagulation After ICH ACC/AHA 2006 Guideline ACC/AHA 2006 Guideline

•• Discontinue anticoagulants and antiplatelets for at Discontinue anticoagulants and antiplatelets for at least least 11––2 weeks2 weeks

•• If required, resume oral anticoagulation after 3If required, resume oral anticoagulation after 3––4 4 weeks (rigorous monitoring, INR in lower range); if weeks (rigorous monitoring, INR in lower range); if anticoagulation is needed sooner after ICH, IV anticoagulation is needed sooner after ICH, IV heparin (with PTT 1.5 to 2.0 times normal) or heparin (with PTT 1.5 to 2.0 times normal) or LMWH may be better acute therapy than oral LMWH may be better acute therapy than oral warfarinwarfarin..

•• Higher risk of recurrent ICH if anticoagulation Higher risk of recurrent ICH if anticoagulation resumed in lobar resumed in lobar ICHsICHs, , microbleedsmicrobleeds, and suspected , and suspected CAA.CAA.

Adapted from Sacco RL, et al. Stroke. 2006;37:577-617.

Conclusions from OATConclusions from OAT--ICHICH

•• Current management of OATCurrent management of OAT--ICH is ICH is varied and not based on evidence from varied and not based on evidence from randomized controlled trials.randomized controlled trials.

•• Use IV Vitamin K, SC is the least Use IV Vitamin K, SC is the least effective route of administration.effective route of administration.

•• Consider PCC or Consider PCC or rFVIIarFVIIa with respect to with respect to risk of thrombosis.risk of thrombosis.

Reversal of patients treated with Reversal of patients treated with therapeutic doses of LMWHtherapeutic doses of LMWH

•• The reversal of LMWH has not been wellThe reversal of LMWH has not been well--defineddefined

•• The package insert for The package insert for tinzaparintinzaparin ((InnohepInnohep®®), ), enoxaparinenoxaparin ((LovenoxLovenox®®), and ), and dalteparindalteparin((FragminFragmin®®) all recommend reversal of ) all recommend reversal of LMWH antiLMWH anti--coagulant effects with coagulant effects with protamineprotaminesulfate. sulfate.

•• ProtamineProtamine reverses the prolonged reverses the prolonged aPTTaPTTcaused by caused by enoxaparinenoxaparin and and dalteparindalteparin in in animal studies, but fails to reverse the antianimal studies, but fails to reverse the anti--XaXaeffect.effect.

LMWH and reversal with LMWH and reversal with protamineprotamine

•• Reduced Reduced sulphatesulphatecharge density is the charge density is the primary reason that primary reason that LMWH are not LMWH are not completely completely neutralized by neutralized by protamineprotamine sulphatesulphate..

Reversal of patients treated with Reversal of patients treated with LMWHLMWH

•• Two commercially available varieties of LMWH, Two commercially available varieties of LMWH, tinzaparintinzaparin ((InnohepInnohep®®) and ) and dalteparindalteparin ((FragminFragmin®®) ) have higher degrees of have higher degrees of sulfonationsulfonation compared with compared with enoxaparinenoxaparin ((LovenoxLovenox®®). ).

•• These appear to be more susceptible to These appear to be more susceptible to protamineprotaminereversal.reversal.

Reversal of ICH in the setting of Reversal of ICH in the setting of thrombolyticsthrombolytics

•• ThrombolyticThrombolytic therapy with therapy with plasminogenplasminogen activators is activators is a highly effective modality for achieving both a highly effective modality for achieving both vascular reperfusion and clinical benefit in patients vascular reperfusion and clinical benefit in patients with arterial occlusions.with arterial occlusions.

•• Patients treated for ischemic stroke are especially Patients treated for ischemic stroke are especially prone to symptomatic or lethal ICH, with an prone to symptomatic or lethal ICH, with an occurrence of 6.4occurrence of 6.4--16% receiving IV 16% receiving IV tPAtPA or or streptokinase.streptokinase.

•• Very little clinical data exists regarding the reversal Very little clinical data exists regarding the reversal of these drugs, since the halfof these drugs, since the half--life ranges from 5life ranges from 5--20 20 minutes depending on the drug.minutes depending on the drug.

ICH S/P ICH S/P ThrombolyticThrombolytic

•• One study suggested treatment with One study suggested treatment with antifibrinolyticantifibrinolytic ((εε--aminocaproicaminocaproic acid) acid) and fibrinogen if and fibrinogen if throbolyticthrobolytic agent is agent is thought to be present at time of thought to be present at time of evaluation.evaluation.

•• Otherwise, symptomatic treatment Otherwise, symptomatic treatment focused around ICP and blood pressure focused around ICP and blood pressure management/surgical evacuation as management/surgical evacuation as indicated.indicated.

AntiplateletsAntiplatelets

Platelet/Fibrin Clot

Events Leading to Thrombus Events Leading to Thrombus FormationFormation

Adhesion

Activation

Aggregation

Platelet InhibitorsPlatelet Inhibitors

•• ASAASA•• Clopidogrel (Plavix), TiclidClopidogrel (Plavix), Ticlid•• Aspirin/Aspirin/DipyridamoleDipyridamole ((AggrenoxAggrenox))•• ReoProReoPro ((abciximababciximab) )

Platelet Activation Pathways

Arachidonicacid

TxA2

GP IIb/IIIa

Epinephrine

Collagen Thrombin

ADP

Effect of Effect of AntiplateletsAntiplatelets on ICH on ICH overall outcomesoverall outcomes

•• In the Stroke In the Stroke LiteratureLiterature……

•• Aspirin doubled Aspirin doubled the 3the 3--month month mortality of ICH mortality of ICH patients patients compared with compared with nonusersnonusers

Stroke. 2006;37:129-133

Effect of Effect of AntiplateletsAntiplatelets on ICH on ICH overall outcomesoverall outcomes

•• In the trauma In the trauma literatureliterature……

•• Patients on Patients on ASA or ASA or plavixplavixhave an overall have an overall mortality rate mortality rate of 23%, of 23%, approximately approximately a threefold a threefold increase over increase over the rate for a the rate for a matched matched control group.control group.

Reversal of Reversal of AntiplateletsAntiplatelets

•• The classic modality for treatment of The classic modality for treatment of platelet associated coagulopathy is platelet associated coagulopathy is platelet transfusion.platelet transfusion.

•• True reversal of this coagulopathy by True reversal of this coagulopathy by platelet transfusion has platelet transfusion has nevernever been been demonstrated.demonstrated.

Reversal of Reversal of AntiplateletsAntiplatelets--DDAVPDDAVP

•Desmopressinhas hemostatic effects by increasing the plasmalevels of coagulation factor VIII and von Willebrand factor.•Desmopressinsignificantly accelerated thrombus formation in aspirin-treated animals (rat model)•Overall platelet function was significantly increased by desmopressin.

Reversal of Reversal of AntiplateletsAntiplatelets--DDAVPDDAVP

•• Known elimination halfKnown elimination half--life is 4life is 4--5 5 hourshours

•• Desmopressin'sDesmopressin's effect on platelet effect on platelet function only lasts for about 3 hoursfunction only lasts for about 3 hours

•• Placebo bleeding time was 730 sPlacebo bleeding time was 730 s•• Aspirin bleeding time was Aspirin bleeding time was

significantly longer, 972 s (P . significantly longer, 972 s (P . 0.0166)0.0166)

•• Sixty minutes after Sixty minutes after desmopressindesmopressin,,•• the bleeding time had shortened the bleeding time had shortened

significantly; in the placebo period significantly; in the placebo period to 475 s (P . 0.0051)to 475 s (P . 0.0051)

•• In the aspirin period to 537 s (P . In the aspirin period to 537 s (P . 0.0093). 0.0093).

•• In the aspirin period the bleeding In the aspirin period the bleeding time was still shortened after 4 h as time was still shortened after 4 h as compared with baseline (P . 0.0249), compared with baseline (P . 0.0249), but after 6 h it was no longer but after 6 h it was no longer significantly different (P . 0.2845)significantly different (P . 0.2845)

Oral Oral antiplateletantiplatelet drugsdrugs•• AspirinAspirin

•• Irreversible inhibitor of Irreversible inhibitor of cyclooxygenasecyclooxygenase(COX) which prevents formation of the (COX) which prevents formation of the plateletplatelet--aggregating substance aggregating substance thromboxanethromboxaneAA22..

•• ClopidogrelClopidogrel•• Blocks platelet aggregation by inhibition of Blocks platelet aggregation by inhibition of

ADP receptor on the platelet membrane.ADP receptor on the platelet membrane.

Aspirin and other NSAIDSAspirin and other NSAIDS

•• Acetylsalicylic acid (ASA) irreversibly blocks Acetylsalicylic acid (ASA) irreversibly blocks the platelet COX the platelet COX system,preventingsystem,preventingformation of formation of thromboxanethromboxane A2 and inhibiting A2 and inhibiting platelet aggregation for the life of the affected platelet aggregation for the life of the affected platelet (approximately 10 d).platelet (approximately 10 d).

•• Transfusion of five random donor platelet Transfusion of five random donor platelet units or their equivalent is recommended to units or their equivalent is recommended to provide sufficient unaltered platelets to provide sufficient unaltered platelets to support clot formation.support clot formation.

•• DDAVP may have a beneficial shortDDAVP may have a beneficial short--term term effect.effect.

ADP InhibitorsADP Inhibitors

•• ClopidogrelClopidogrel ((PlavixPlavix) and ) and TiclopidineTiclopidine ((TiclidTiclid) ) alter platelet aggregation via irreversible alter platelet aggregation via irreversible noncompetitive inhibition of the ADP surface noncompetitive inhibition of the ADP surface binding site and reduction of ADP release binding site and reduction of ADP release from activated platelets.from activated platelets.

•• Because of this differing mechanism of action, Because of this differing mechanism of action, they are they are additiveadditive to the to the antiplateletantiplatelet effects of effects of ASA and are often concurrently prescribed.ASA and are often concurrently prescribed.

•• Platelet transfusion is recommended.Platelet transfusion is recommended.•• DDAVP may have a beneficial shortDDAVP may have a beneficial short--term term

effect.effect.

ClopidogrelClopidogrel ((PlavixPlavix) Reversal) Reversal•• A page from playbook of CT surgeryA page from playbook of CT surgery……

ApoprotininApoprotinin

•• Preserves of platelet adhesiveness via Preserves of platelet adhesiveness via kallikrein/kininkallikrein/kinin inhibition.inhibition.

•• Has been studied in numerous cardiac Has been studied in numerous cardiac and orthopedic populations.and orthopedic populations.

•• Risk of renal failure likely restricts its Risk of renal failure likely restricts its use to highuse to high--risk CABG patients only.risk CABG patients only.

ParenteralParenteral antiplateletantiplatelet drugsdrugs

•• Glycoprotein Glycoprotein IIb/IIIaIIb/IIIa InhibitorsInhibitors•• Abciximab (Abciximab (ReoproReopro®®), ), eptifibatideeptifibatide

((IntegrilinIntegrilin®®), ), tirofibantirofiban ((AggrastatAggrastat®®))•• Prevent fibrinogen binding to Prevent fibrinogen binding to GlyGly IIb/IIIaIIb/IIIa

receptor and block platelet aggregation receptor and block platelet aggregation producing profound platelet inhibition.producing profound platelet inhibition.

•• Most commonly used in conjunction with Most commonly used in conjunction with percutaneous coronary interventions (PCI). percutaneous coronary interventions (PCI).

•• Treatment usually combines a loading Treatment usually combines a loading bolus followed by an infusion.bolus followed by an infusion.

Glycoprotein (GP) Glycoprotein (GP) IIb/IIIaIIb/IIIaInhibitor ReversalInhibitor Reversal

•• Bleeding is the most frequent adverse event.Bleeding is the most frequent adverse event.•• Withholding the medication allows a return Withholding the medication allows a return

of normal platelet function, but requires of normal platelet function, but requires approximately 48 hours for approximately 48 hours for abciximababciximab and 4 and 4 to 8 hours for the others.to 8 hours for the others.

•• After infusion, platelet administration may be After infusion, platelet administration may be more effective little drug is freely circulating more effective little drug is freely circulating to attach to new platelets.to attach to new platelets.

•• There are currently no recommendations on There are currently no recommendations on how to treat such patients.how to treat such patients.

Glycoprotein (GP) Glycoprotein (GP) IIb/IIIaIIb/IIIaInhibitor ReversalInhibitor Reversal

•• Because these agents leave the GP Because these agents leave the GP receptor unharmed, platelet transfusion receptor unharmed, platelet transfusion increases the proportion of unaffected increases the proportion of unaffected platelets and is the primary platelets and is the primary intervention.intervention.

Glycoprotein (GP) Glycoprotein (GP) IIb/IIIaIIb/IIIaInhibitor ReversalInhibitor Reversal

•• Some evidence that Some evidence that DDAVP may serve as DDAVP may serve as the best means of the best means of reversal in an reversal in an emergency situation.emergency situation.

•• Combined use of Combined use of Platelet transfusion and Platelet transfusion and DDAVP additively DDAVP additively enhances recovery of enhances recovery of normal PLT function normal PLT function after after eptifibatideeptifibatideinfusion compared to infusion compared to DDAVP alone.DDAVP alone.

GeauxGeaux Tigers!Tigers!