Thrombolytic Therapy Thrombolytic Therapy for Vascular Diseasefor Vascular Disease

July 16, 2012July 16, 2012

HistoryHistory

Morgagni (1761) noted blood forms Morgagni (1761) noted blood forms clots post-mortem, followed by clots post-mortem, followed by reliqueficationreliquefication

Dastre (1893) coined term “fibrinolysis” Dastre (1893) coined term “fibrinolysis” to describe disappearance of fibrin from to describe disappearance of fibrin from dogs who repeatedly hemorrhaged dogs who repeatedly hemorrhaged

Morawitz (1906) noted post-mortem Morawitz (1906) noted post-mortem blood destroys fibrinogen and fibrin in blood destroys fibrinogen and fibrin in normal bloodnormal blood

The Fibrinolytic SystemThe Fibrinolytic System

Astrup (1958) proposed the concept Astrup (1958) proposed the concept of “dynamic equilibrium”of “dynamic equilibrium” Delicate balance of fibrinolysis and fibrin Delicate balance of fibrinolysis and fibrin

deposition throughout bodydeposition throughout body Limited activation of coagulation Limited activation of coagulation

systemsystem Feedback loop to prevent systemic Feedback loop to prevent systemic

fibrinolysisfibrinolysis Inhibitors at activator levelInhibitors at activator level Specific inhibitors of plasminSpecific inhibitors of plasmin

The Fibrinolytic SystemThe Fibrinolytic System

Final pathway Final pathway Plasminogen > PlasminPlasminogen > Plasmin

Plasminogen Plasminogen Produced by liverProduced by liver Has a N and C terminalHas a N and C terminal 4 types found in plasma 4 types found in plasma

Differences in N terminalDifferences in N terminal Degree of glycosylationDegree of glycosylation

2 Main forms: 2 Main forms: Glu-plasminogenGlu-plasminogen

High concentrations found in plasmaHigh concentrations found in plasma Lys-plasminogenLys-plasminogen

Converted through proteolysis of Glu-plasminogenConverted through proteolysis of Glu-plasminogen High affinity for fibrinHigh affinity for fibrin

High concentrations found in thrombus High concentrations found in thrombus

The Fibrinolytic SystemThe Fibrinolytic System

PlasminPlasmin Nonspecific proteaseNonspecific protease Targets factors V, VIII, vWF, kininogen, Targets factors V, VIII, vWF, kininogen,

prekallikrein, fibronectin, collagen, prekallikrein, fibronectin, collagen, lamininlaminin

The Fibrinolytic SystemThe Fibrinolytic System

Fibrinolytic AgentsFibrinolytic Agents

Indirect ActivatorsIndirect Activators Fibrinolysis without direct activity on Fibrinolysis without direct activity on

plasminogenplasminogen MOA variableMOA variable Unproven clinical valueUnproven clinical value Multiple agentsMultiple agents

EpinephrineEpinephrine Nicotinic AcidNicotinic Acid DDAVP – clinically insignificant compared to its DDAVP – clinically insignificant compared to its

procoagulant effectsprocoagulant effects Steroids (Stanozolol)** Steroids (Stanozolol)** Phenoformin**Phenoformin**

Direct Thrombolytic AgentsDirect Thrombolytic Agents First-Generation Thrombolytic DrugsFirst-Generation Thrombolytic Drugs

Not Fibrin SpecificNot Fibrin Specific Plasminogen steal – activates circulating Plasminogen steal – activates circulating

plasminogen, paradoxical decrease of clot lysisplasminogen, paradoxical decrease of clot lysis Efficacy improved with administration of plasminogenEfficacy improved with administration of plasminogen

Streptokinase, UrokinaseStreptokinase, Urokinase Second-Generation Thrombolytic DrugsSecond-Generation Thrombolytic Drugs

Fibrin SpecificFibrin Specific Avoids Systemic Thrombolytic StateAvoids Systemic Thrombolytic State

Tissue Plasminogen Activator, Pro-urokinaseTissue Plasminogen Activator, Pro-urokinase Third-Generation Thrombolytic DrugsThird-Generation Thrombolytic Drugs

Reteplase, Tenecteplase, StaphylokinaseReteplase, Tenecteplase, Staphylokinase

StreptokinaseStreptokinase Produced from Produced from ββ-hemolytic streptococci-hemolytic streptococci

Presence of circulating AbPresence of circulating Ab ComplicationsComplications

FeverFever Allergic ReactionsAllergic Reactions TachyphylaxisTachyphylaxis

MOAMOA Requires plasminogen as cofactorRequires plasminogen as cofactor Converts uncomplexed plasminogen to plasminConverts uncomplexed plasminogen to plasmin

Precise control of thrombolysis difficultPrecise control of thrombolysis difficult Varied dose response per patientVaried dose response per patient 2 separate half lifes: 16 and 83 minutes2 separate half lifes: 16 and 83 minutes

Standardized dosagesStandardized dosages Bleeding complications in 15-20% of patientsBleeding complications in 15-20% of patients Only thrombolytic approved by FDA for arterial/venous Only thrombolytic approved by FDA for arterial/venous

thrombosisthrombosis Infrequently usedInfrequently used

UrokinaseUrokinase Produced by renal tubular cellsProduced by renal tubular cells Dose-dependent responseDose-dependent response

Direct, specific plasminogen activatorDirect, specific plasminogen activator Lack of circulating antibodiesLack of circulating antibodies

Febrile responses from interleukinsFebrile responses from interleukins Results similar to streptokinase Results similar to streptokinase

Bleeding in 5-10% of patientsBleeding in 5-10% of patients Significantly more expensiveSignificantly more expensive

Taken off market from 1998-2002 Taken off market from 1998-2002 Deviated from FDA “good manufacturing guidelines”Deviated from FDA “good manufacturing guidelines”

Approved for use in PEApproved for use in PE Half life 14 minutesHalf life 14 minutes

Direct Thrombolytic AgentsDirect Thrombolytic Agents First-Generation Thrombolytic DrugsFirst-Generation Thrombolytic Drugs

Not Fibrin SpecificNot Fibrin Specific Plasminogen steal – activates circulating Plasminogen steal – activates circulating

plasminogen, paradoxical decrease of clot lysisplasminogen, paradoxical decrease of clot lysis Efficacy improved with administration of plasminogenEfficacy improved with administration of plasminogen

Streptokinase, UrokinaseStreptokinase, Urokinase Second-Generation Thrombolytic DrugsSecond-Generation Thrombolytic Drugs

Fibrin SpecificFibrin Specific Avoids Systemic Thrombolytic StateAvoids Systemic Thrombolytic State

Tissue Plasminogen Activator, Pro-urokinaseTissue Plasminogen Activator, Pro-urokinase Third-Generation Thrombolytic DrugsThird-Generation Thrombolytic Drugs

Reteplase, Tenecteplase, StaphylokinaseReteplase, Tenecteplase, Staphylokinase

Tissue Plasminogen Activator (t-PA)Tissue Plasminogen Activator (t-PA)

Originates from vascular endotheliumOriginates from vascular endothelium Tissue concentration correlates with vascularityTissue concentration correlates with vascularity

SourcesSources Bowes melanoma cell lineBowes melanoma cell line Recombinant DNA technology (rt-PA)Recombinant DNA technology (rt-PA)

MOAMOA Direct plasminogen activator Direct plasminogen activator

High affinity for thrombus-bound fibrinHigh affinity for thrombus-bound fibrin Inhibits platelet aggregation by inhibiting GpIb and vWFInhibits platelet aggregation by inhibiting GpIb and vWF

Half life 4-7 minutesHalf life 4-7 minutes Recommended dosage 0.05 mg/kg/hrRecommended dosage 0.05 mg/kg/hr RCT failed to demonstrate significant difference in RCT failed to demonstrate significant difference in

efficacy from other agentsefficacy from other agents Similar rates of bleeding complicationsSimilar rates of bleeding complications

Pro-urokinase (Saruplase)Pro-urokinase (Saruplase)

Recombinant urokinase Recombinant urokinase MOAMOA

Direct plasminogen activator Direct plasminogen activator High affinity for Lys-plasminogenHigh affinity for Lys-plasminogen

Most trials in acute MIMost trials in acute MI Higher incidence of intracranial hemorrhageHigher incidence of intracranial hemorrhage

Prolonged half-lifeProlonged half-life Increased risk of bleedingIncreased risk of bleeding

PROACT II StudyPROACT II Study 10% (vs. 2% of control) intracranial hemorrhage with 10% (vs. 2% of control) intracranial hemorrhage with

urokinase for acute ischemic strokeurokinase for acute ischemic stroke

Direct Thrombolytic AgentsDirect Thrombolytic Agents First-Generation Thrombolytic DrugsFirst-Generation Thrombolytic Drugs

Not Fibrin SpecificNot Fibrin Specific Plasminogen steal – activates circulating Plasminogen steal – activates circulating

plasminogen, paradoxical decrease of clot lysisplasminogen, paradoxical decrease of clot lysis Efficacy improved with administration of plasminogenEfficacy improved with administration of plasminogen

Streptokinase, UrokinaseStreptokinase, Urokinase Second-Generation Thrombolytic DrugsSecond-Generation Thrombolytic Drugs

Fibrin SpecificFibrin Specific Avoids Systemic Thrombolytic StateAvoids Systemic Thrombolytic State

Tissue Plasminogen Activator, Pro-urokinaseTissue Plasminogen Activator, Pro-urokinase Third-Generation Thrombolytic DrugsThird-Generation Thrombolytic Drugs

Reteplase, Tenecteplase, StaphylokinaseReteplase, Tenecteplase, Staphylokinase

ReteplaseReteplase Decreased endothelial bindingDecreased endothelial binding

Increased circulating levelsIncreased circulating levels Decreased fibrin bindingDecreased fibrin binding

Penetrates clot better with faster lysisPenetrates clot better with faster lysis Dependent on available plasminogenDependent on available plasminogen

Less effective for large clot burden or old thrombusLess effective for large clot burden or old thrombus Half life of 14-18 minutesHalf life of 14-18 minutes Addition of GpIIB/IIIa inhibitors may increase Addition of GpIIB/IIIa inhibitors may increase

efficacyefficacy INJECT and GUSTO III Trials INJECT and GUSTO III Trials

Compared reteplase to alteplase for MICompared reteplase to alteplase for MI Reteplase showed increased flow rates (thrombolysis)Reteplase showed increased flow rates (thrombolysis) No difference in mortalityNo difference in mortality

TenecteplaseTenecteplase

TPA mutant TPA mutant High fibrin selectivityHigh fibrin selectivity Resistant to plasminogen activator Resistant to plasminogen activator

inhibitorsinhibitors Very effective in arterial thrombosis and Very effective in arterial thrombosis and Case series for peripheral arterial Case series for peripheral arterial

thrombolysis (48 patients)thrombolysis (48 patients) 73% had complete lysis73% had complete lysis No deaths, bleeding, or embolic eventsNo deaths, bleeding, or embolic events

Half life of 15-19 minutesHalf life of 15-19 minutes

StaphylokinaseStaphylokinase

Plasminogen activator from S. aureusPlasminogen activator from S. aureus Activates thrombus bound Activates thrombus bound

plasminogenplasminogen Minimal systemic effectsMinimal systemic effects

Activity confined to thrombus through Activity confined to thrombus through rapid inactivation of circulating plasminrapid inactivation of circulating plasmin

High antigenicityHigh antigenicity

ImmunofibrinolysisImmunofibrinolysis

Monoclonal anti-fibrin antibodies Monoclonal anti-fibrin antibodies bonded to urokinase or streptokinasebonded to urokinase or streptokinase Increased fibrin selectivityIncreased fibrin selectivity

No cross-reactivity with fibrinogenNo cross-reactivity with fibrinogen Clinical application remains to be Clinical application remains to be

determineddetermined

Summary of ThrombolyticsSummary of Thrombolytics

Most experience with streptokinase, Most experience with streptokinase, urokinase, and TPAurokinase, and TPA

Streptokinase less desirable for Streptokinase less desirable for peripheral thrombosis due to peripheral thrombosis due to complex mechanism and dosingcomplex mechanism and dosing

Similar rates of bleeding due to Similar rates of bleeding due to interaction with hemostatic plugs in interaction with hemostatic plugs in addition to pathological thrombusaddition to pathological thrombus Induction of systemic fibrinolysisInduction of systemic fibrinolysis

Thrombolytic AgentsThrombolytic Agents

Application of ThrombolyticsApplication of Thrombolytics

SystemicSystemic Bleeding complications outweigh Bleeding complications outweigh

benefitsbenefits Intra-arterialIntra-arterial

Prevention of systemic Prevention of systemic complicationscomplications

Useful for peripheral arterial and Useful for peripheral arterial and graft occlusiongraft occlusion

Intra-operativeIntra-operative

Contraindications of Systemic Contraindications of Systemic ThrombolyticsThrombolytics

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Pulmonary EmbolismPulmonary Embolism Deep Venous ThrombosisDeep Venous Thrombosis Axillary Vein ThrombosisAxillary Vein Thrombosis Superior Vena Cava ThrombosisSuperior Vena Cava Thrombosis

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Pulmonary EmbolismPulmonary Embolism Urokinase Pulmonary Embolism Trial – Phase IUrokinase Pulmonary Embolism Trial – Phase I

Compared treatment with urokinase vs. heparinCompared treatment with urokinase vs. heparin Urokinase therapy resulted in accelerated resolution of PEUrokinase therapy resulted in accelerated resolution of PE No differences in mortality or recurrence ratesNo differences in mortality or recurrence rates Improved responseImproved response

<50 yo<50 yo PE <48 hoursPE <48 hours Large embolusLarge embolus Cardiogenic ShockCardiogenic Shock

7 yr F/U – Thrombolysis group had better preservation of normal 7 yr F/U – Thrombolysis group had better preservation of normal pulmonary vasculature and higher pulmonary capillary blood pulmonary vasculature and higher pulmonary capillary blood volumesvolumes

Urokinase Pulmonary Embolism Trial – Phase IUrokinase Pulmonary Embolism Trial – Phase I Compared treatment with 12h urokinase, 24h urokinase, and 24h Compared treatment with 12h urokinase, 24h urokinase, and 24h

streptokinasestreptokinase No difference in lytic resultsNo difference in lytic results No benefit to 24h urokinaseNo benefit to 24h urokinase

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Pulmonary EmbolismPulmonary Embolism FDA-Approved ThrombolyticsFDA-Approved Thrombolytics

t-PA (100mg over 2hrs)t-PA (100mg over 2hrs) UrokinaseUrokinase

IndicationsIndications Documented PEDocumented PE Evidence of Hemodynamic CompromiseEvidence of Hemodynamic Compromise No Absolute Contraindication to No Absolute Contraindication to

ThrombolysisThrombolysis Anticoagulation Recommended for Anticoagulation Recommended for

Hemodynamically Stable PatientsHemodynamically Stable Patients

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Deep Venous ThrombosisDeep Venous Thrombosis Goal Goal

Prevention of PE Prevention of PE Prevention of post-phlebitic syndromePrevention of post-phlebitic syndrome

Anticoagulation ineffective therapyAnticoagulation ineffective therapy

Complete Complete clot lysisclot lysis

Normal Normal valve valve

function @ function @ 6 months6 months

PE/mortalityPE/mortalityBleeding Bleeding

complicatiocomplicationn

HeparinHeparin 4%4% 7%7% SameSame 4%4%

LyticsLytics 35%35% 50%50% SameSame 17%17%

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Deep Venous ThrombosisDeep Venous Thrombosis Efficacy of Mode of AdministrationEfficacy of Mode of Administration

Pedal infusion: 20% successPedal infusion: 20% success Catheter directed: 83% success, complete Catheter directed: 83% success, complete

lysis 33%lysis 33% No evidence of improved lysis with systemic No evidence of improved lysis with systemic

administrationadministration

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Deep Venous ThrombosisDeep Venous Thrombosis Contraindications to ThrombolysisContraindications to Thrombolysis

> 5 days old> 5 days old Post-op/post-partumPost-op/post-partum Trauma patientsTrauma patients Spinal injury/recent CVASpinal injury/recent CVA Recurrent DVTsRecurrent DVTs

Already damaged valvesAlready damaged valves Distal ThrombusDistal Thrombus

Little benefitLittle benefit

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Deep Venous ThrombosisDeep Venous Thrombosis Indications for ThrombolysisIndications for Thrombolysis

No ContraindicationsNo Contraindications First IncidenceFirst Incidence Treatment Initiated < 5 Days of SymptomsTreatment Initiated < 5 Days of Symptoms Phlegmasia Cerulea DolensPhlegmasia Cerulea Dolens

Massive ilio-femoral thrombus causing limb Massive ilio-femoral thrombus causing limb threatening venous outflow obstructionthreatening venous outflow obstruction

20-40% Mortality Rate20-40% Mortality Rate High Amputation RiskHigh Amputation Risk

Venous thrombectomy burdened by re-Venous thrombectomy burdened by re-thrombosisthrombosis

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Axillary Vein ThrombosisAxillary Vein Thrombosis AKA Effort ThrombosisAKA Effort Thrombosis Younger PatientsYounger Patients Poor Resolution with Anticoagulation Poor Resolution with Anticoagulation Thrombolysis Indicated for Short Thrombolysis Indicated for Short

Symptom DurationSymptom Duration Systemic and Local Infusion Equally Systemic and Local Infusion Equally

EffectiveEffective Post-Treatment Evaluation for TOS Post-Treatment Evaluation for TOS

Venography performed with Arm Abducted Venography performed with Arm Abducted and Externally Rotatedand Externally Rotated

Indications for Systemic Indications for Systemic ThrombolyticsThrombolytics

Superior Vena Cava ThrombosisSuperior Vena Cava Thrombosis Mediastinal Etiologies– Poor ResponseMediastinal Etiologies– Poor Response

CancerCancer TraumaTrauma Infection Infection

Catheter-Induced ThrombosisCatheter-Induced Thrombosis Response Dependent on Duration of Response Dependent on Duration of

SymptomsSymptoms Idiopathic SVC Thrombosis (4%)Idiopathic SVC Thrombosis (4%)

Good ResponseGood Response

Complications of Systemic TherapyComplications of Systemic Therapy

Intracranial HemorrhageIntracranial Hemorrhage 1% Incidence1% Incidence Time to Onset 3-36 hrsTime to Onset 3-36 hrs 66% Mortality66% Mortality Risk FactorsRisk Factors

Oral Anticoagulation Prior to AdmissionOral Anticoagulation Prior to Admission <70kg<70kg >65yo>65yo Higher doses of tPAHigher doses of tPA

Protective Effect of Concomitant Beta-Protective Effect of Concomitant Beta-Blockade?Blockade?

Complications of Systemic TherapyComplications of Systemic Therapy

Life-Threatening HemorrhageLife-Threatening Hemorrhage 7-45% Incidence7-45% Incidence Risk FactorsRisk Factors

Increased Number of Invasive Procedures during Increased Number of Invasive Procedures during TherapyTherapy

Increased Duration of TherapyIncreased Duration of Therapy Patients with Lower Fibrinogen LevelsPatients with Lower Fibrinogen Levels

Bleeding Occurs During Lap Period btw Bleeding Occurs During Lap Period btw Cessation of Lysis and Initiation of HeparinCessation of Lysis and Initiation of Heparin

Treatment Treatment FFPFFP CryoprecipitateCryoprecipitate

Application of Intra-arterial Application of Intra-arterial ThrombolyticsThrombolytics

Thrombosis after PTAThrombosis after PTA Native Vessel OcclusionNative Vessel Occlusion Acute Graft OcclusionAcute Graft Occlusion Lower Extremity IschemiaLower Extremity Ischemia Hemodialysis AccessHemodialysis Access Acute StrokeAcute Stroke

Patient Selection of Intra-arterial Patient Selection of Intra-arterial ThrombolyticsThrombolytics

Low doses of thrombolytic administered Low doses of thrombolytic administered close to thrombusclose to thrombus Minimizes systemic effectsMinimizes systemic effects Dissolution of thrombus requires 12-72 hrs of Dissolution of thrombus requires 12-72 hrs of

therapytherapy Ensure viability of ischemic tissueEnsure viability of ischemic tissue

Shouldn’t do in patients with neurologic demiseShouldn’t do in patients with neurologic demise IndicationsIndications

High surgical risk of morbidity/mortalityHigh surgical risk of morbidity/mortality Poor surgical outcome Poor surgical outcome

Multiple previous surgeriesMultiple previous surgeries Adjunct to surgery Adjunct to surgery

Patient Selection of Intra-arterial Patient Selection of Intra-arterial ThrombolyticsThrombolytics

<14 d of acute ischemia<14 d of acute ischemia 71% successful lysis71% successful lysis Adjuntive procedures required in 72%Adjuntive procedures required in 72%

Less likely in UELess likely in UE Equal response for prosthetic grafts (78%) Equal response for prosthetic grafts (78%)

and native arteries (72%)and native arteries (72%) Vein grafts lower response rates (53%)Vein grafts lower response rates (53%)

Decreased response in diabeticsDecreased response in diabetics Predictors of successPredictors of success

Passage through occlusionPassage through occlusion Placement of catheter within thrombusPlacement of catheter within thrombus

Contraindications to Intra-arterial Contraindications to Intra-arterial ThrombolyticsThrombolytics

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Thrombosis after PTAThrombosis after PTA InfrequentInfrequent Onset typically <24 hrs following PTAOnset typically <24 hrs following PTA 80% Success rate80% Success rate Risk of bleeding and pseudoaneurysm Risk of bleeding and pseudoaneurysm

formationformation

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Native Vessel OcclusionNative Vessel Occlusion Determine the Mechanism of OcclusionDetermine the Mechanism of Occlusion

More effective in peripheral embolization (80%) More effective in peripheral embolization (80%) than thrombotic occlusions (50-60%)than thrombotic occlusions (50-60%)

Embolization from Atrial FibrillationEmbolization from Atrial Fibrillation WellWell-organized componenets-organized componenets Poor response to lytic therapyPoor response to lytic therapy Surgical embolectomy for proximal A-fib occlusionSurgical embolectomy for proximal A-fib occlusion

Thrombolysis for emboli from recent MIThrombolysis for emboli from recent MI Thrombotic Arterial OcclusionsThrombotic Arterial Occlusions

Success (>50%)Success (>50%) Adjunctive procedures to maintain patencyAdjunctive procedures to maintain patency

Less likely with resolution of large vessel occlusions Less likely with resolution of large vessel occlusions

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Native Vessel OcclusionNative Vessel Occlusion Popliteal Artery Occlusion with Distal Clot Popliteal Artery Occlusion with Distal Clot

Propagation or EmboliPropagation or Emboli Poor surgical resultPoor surgical result

Amputation risk – 40%Amputation risk – 40% Moderate IschemiaModerate Ischemia

Trial of Lytic TherapyTrial of Lytic Therapy Severe IschemiaSevere Ischemia

Surgical Exploration with Intraoperative Intra-arterial Surgical Exploration with Intraoperative Intra-arterial LysisLysis

Renal Artery OcclusionRenal Artery Occlusion Acute Mesenteric Artery OcclusionAcute Mesenteric Artery Occlusion

Acute Surgical Intervention w Change in Clinical StatusAcute Surgical Intervention w Change in Clinical Status

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Acute Graft OcclusionAcute Graft Occlusion Prosthetic GraftsProsthetic Grafts

Unsuccessful Non-Operative ManagementUnsuccessful Non-Operative Management Adjunct to convert urgent surgical therapy to elective Adjunct to convert urgent surgical therapy to elective

revisionrevision Thrombectomy treatment of choiceThrombectomy treatment of choice

Autogenous Vein GraftsAutogenous Vein Grafts 75% success if thrombosis <14 days old75% success if thrombosis <14 days old Poor ResponsePoor Response

Long grafts Long grafts Low flow grafts Low flow grafts Early graft failure (<1 year old) Early graft failure (<1 year old)

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Lower Extremity IschemiaLower Extremity Ischemia STILE (Surgery vs. Thrombolytics for Ischemia of LE)STILE (Surgery vs. Thrombolytics for Ischemia of LE)

393 pts with native arterial or graft occlusion393 pts with native arterial or graft occlusion tPA 0.05 mg/kg/hr for 12 hours tPA 0.05 mg/kg/hr for 12 hours oror urokinase (250K urokinase (250K

bolus, then 4000 u/min for 4 hour, then 2000 u/min for bolus, then 4000 u/min for 4 hour, then 2000 u/min for up to 36 hrs)up to 36 hrs)

Thrombolysis GroupThrombolysis Group Failure to pass catheter in 28% of patients (Treatment Failure to pass catheter in 28% of patients (Treatment

Failure)Failure) Acute Ischemia (<14 days)Acute Ischemia (<14 days)

Lower amputation and shorter hospital staysLower amputation and shorter hospital stays 55% had a reduction in surgical procedure55% had a reduction in surgical procedure

Surgery GroupSurgery Group Chronic Ischemia (>14 days)Chronic Ischemia (>14 days)

Less recurrent ischemia, lower amputation ratesLess recurrent ischemia, lower amputation rates

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Lower Extremity IschemiaLower Extremity Ischemia STILE ConclusionsSTILE Conclusions

Surgery was safer and more effective in patients Surgery was safer and more effective in patients with symptoms < 6 months duration, >14 dayswith symptoms < 6 months duration, >14 days

Lytics showed improved amputation free survival Lytics showed improved amputation free survival in patients with <14 days of ischemiain patients with <14 days of ischemia

No difference in outcome for tPA vs. urokinaseNo difference in outcome for tPA vs. urokinase

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Lower Extremity IschemiaLower Extremity Ischemia RCT of 114 limb threatening ischemic patients RCT of 114 limb threatening ischemic patients

of <7 days duration of <7 days duration Thrombolytics vs. SurgeryThrombolytics vs. Surgery

Similar limb salvage rates (12 months - 82%)Similar limb salvage rates (12 months - 82%) Survival improved in lytic group (84% vs. 58%)Survival improved in lytic group (84% vs. 58%)

Surgery Group – High Cardiopulmonary ComplicationsSurgery Group – High Cardiopulmonary Complications Lytics slightly more expensive ($15,672 vs. Lytics slightly more expensive ($15,672 vs.

$12,253) $12,253)

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Hemodialysis AccessHemodialysis Access Short onset of signsShort onset of signs Successful in 87%Successful in 87%

Most require revision of venous anastamosisMost require revision of venous anastamosis

Indications for Intra-arterial Indications for Intra-arterial ThrombolyticsThrombolytics

Acute StrokeAcute Stroke Must be administered within 3 hrs of Must be administered within 3 hrs of

onsetonset PROACT II PROACT II

Superior response of intra-arterial urokinase Superior response of intra-arterial urokinase (67%) vs. heaprin (18%)(67%) vs. heaprin (18%)

10% risk of ICH10% risk of ICH

Technique of Intra-arterial Technique of Intra-arterial ThrombolyticsThrombolytics

Arterial PunctureArterial Puncture Avoid sites distal to lesionAvoid sites distal to lesion Avoid sites where bleeding causes morbidityAvoid sites where bleeding causes morbidity

Axillary, translumbar, etc.Axillary, translumbar, etc. Below SFA – ipsilateral antegradeBelow SFA – ipsilateral antegrade Above SFA – contralateralAbove SFA – contralateral Upper Extremity - transfemoralUpper Extremity - transfemoral

Place catheter through clotPlace catheter through clot If unsuccessful, avoid branches between catheter and If unsuccessful, avoid branches between catheter and

lesionlesion High dose High dose Short Length of Time Short Length of Time

Bleeding related to duration of treatmentBleeding related to duration of treatment Should not infuse for > 96 hoursShould not infuse for > 96 hours

Technique of Intra-arterial Technique of Intra-arterial ThrombolyticsThrombolytics

Begin TPA at 0.5-1 mg/hour Begin TPA at 0.5-1 mg/hour 25-50 cc/hour of 10mg/500cc NS25-50 cc/hour of 10mg/500cc NS

Obtain baseline fibrinogen, PTT, and FSPObtain baseline fibrinogen, PTT, and FSP Repeat in 12 hours then dailyRepeat in 12 hours then daily Expect fibrinogen to drop, FSP to be +, and PTT Expect fibrinogen to drop, FSP to be +, and PTT

prolonged in 50% (suggests lytic state)prolonged in 50% (suggests lytic state) No specific parameters correlate with bleedingNo specific parameters correlate with bleeding

Fibrinogen <150 carries 4-fold increase in bleedingFibrinogen <150 carries 4-fold increase in bleeding FSP > 400 carries 2.5-fold increase in bleedingFSP > 400 carries 2.5-fold increase in bleeding

If no progress made and no evidence of If no progress made and no evidence of bleeding, can increase dosage to 1+ mg/hourbleeding, can increase dosage to 1+ mg/hour

Technique of Intra-arterial Technique of Intra-arterial ThrombolyticsThrombolytics

Heparin administrationHeparin administration Recommended to prevent peri-catheter Recommended to prevent peri-catheter

thrombosisthrombosis Aim for PTT 1.5-2x normalAim for PTT 1.5-2x normal Attempt to run through sheath in affected limbAttempt to run through sheath in affected limb

Usually run at 500-1000 unit/hourUsually run at 500-1000 unit/hour PTT should not exceed 60 secPTT should not exceed 60 sec

If surgery required, give FFP to normalize If surgery required, give FFP to normalize fibrinogen levelfibrinogen level

Indications for Intraoperative Indications for Intraoperative ThrombolyticsThrombolytics

30% of embolectomies are incomplete30% of embolectomies are incomplete Residual intravascular defects seen on Residual intravascular defects seen on

completion angiographycompletion angiography Further mechanical manipulation increases Further mechanical manipulation increases

thrombogenicitythrombogenicity AdvantagesAdvantages

Bulk of thrombus removed, less lysis Bulk of thrombus removed, less lysis neededneeded

Employment of higher concentrations of Employment of higher concentrations of thrombolyticthrombolytic

Indications for Intraoperative Indications for Intraoperative ThrombolyticsThrombolytics

Multiple trials with streptokinase and Multiple trials with streptokinase and urokinaseurokinase Few bleeding complicationsFew bleeding complications Improved outflow in 61-76% Improved outflow in 61-76%

tPA not studied, but would be ideal tPA not studied, but would be ideal given its selectivity for fibrin and given its selectivity for fibrin and short half lifeshort half life