Moore Chapter: Thrombolysis
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Moore Chapter: Thrombolysis

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  • Also blocks platelet-vWF binding by GP 1b cleavage
  • Early vein graft failure best treated with redo bypass

Moore Chapter: Thrombolysis Moore Chapter: Thrombolysis Presentation Transcript

  • Thrombolytic TherapyThrombolytic Therapy for Vascular Diseasefor Vascular Disease July 16, 2012July 16, 2012
  • HistoryHistory  Morgagni (1761) noted blood forms clotsMorgagni (1761) noted blood forms clots post-mortem, followed by reliqueficationpost-mortem, followed by reliquefication  Dastre (1893) coined term “fibrinolysis” toDastre (1893) coined term “fibrinolysis” to describe disappearance of fibrin from dogsdescribe disappearance of fibrin from dogs who repeatedly hemorrhagedwho repeatedly hemorrhaged  Morawitz (1906) noted post-mortem bloodMorawitz (1906) noted post-mortem blood destroys fibrinogen and fibrin in normaldestroys fibrinogen and fibrin in normal bloodblood
  • The Fibrinolytic SystemThe Fibrinolytic System  Astrup (1958) proposed the concept ofAstrup (1958) proposed the concept of “dynamic equilibrium”“dynamic equilibrium”  Delicate balance of fibrinolysis and fibrinDelicate balance of fibrinolysis and fibrin deposition throughout bodydeposition throughout body  Limited activation of coagulation systemLimited activation of coagulation system  Feedback loop to prevent systemicFeedback 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 pathwayFinal pathway  Plasminogen > PlasminPlasminogen > Plasmin  PlasminogenPlasminogen  Produced by liverProduced by liver  Has a N and C terminalHas a N and C terminal  4 types found in plasma4 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 thrombusHigh 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, lamininprekallikrein, fibronectin, collagen, laminin
  • The Fibrinolytic SystemThe Fibrinolytic System
  • Fibrinolytic AgentsFibrinolytic Agents  Indirect ActivatorsIndirect Activators  Fibrinolysis without direct activity on plasminogenFibrinolysis without direct activity on plasminogen  MOA variableMOA variable  Unproven clinical valueUnproven clinical value  Multiple agentsMultiple agents  EpinephrineEpinephrine  Nicotinic AcidNicotinic Acid  DDAVP – clinically insignificant compared to its procoagulantDDAVP – clinically insignificant compared to its procoagulant effectseffects  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,Plasminogen steal – activates circulating plasminogen, paradoxical decrease of clot lysisparadoxical 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 fromProduced 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 thrombosisOnly thrombolytic approved by FDA for arterial/venous thrombosis  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 streptokinaseResults similar to streptokinase  Bleeding in 5-10% of patientsBleeding in 5-10% of patients  Significantly more expensiveSignificantly more expensive  Taken off market from 1998-2002Taken 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,Plasminogen steal – activates circulating plasminogen, paradoxical decrease of clot lysisparadoxical 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 activatorDirect 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 inRCT 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 urokinaseRecombinant urokinase  MOAMOA  Direct plasminogen activatorDirect 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 with10% (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,Plasminogen steal – activates circulating plasminogen, paradoxical decrease of clot lysisparadoxical 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 efficacyAddition of GpIIB/IIIa inhibitors may increase efficacy  INJECT and GUSTO III TrialsINJECT 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 mutantTPA mutant  High fibrin selectivityHigh fibrin selectivity  Resistant to plasminogen activator inhibitorsResistant to plasminogen activator inhibitors  Very effective in arterial thrombosis andVery effective in arterial thrombosis and  Case series for peripheral arterial thrombolysisCase series for peripheral arterial thrombolysis (48 patients)(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 plasminogenActivates thrombus bound plasminogen  Minimal systemic effectsMinimal systemic effects  Activity confined to thrombus through rapidActivity confined to thrombus through rapid inactivation of circulating plasmininactivation of circulating plasmin  High antigenicityHigh antigenicity
  • ImmunofibrinolysisImmunofibrinolysis  Monoclonal anti-fibrin antibodies bondedMonoclonal anti-fibrin antibodies bonded to urokinase or streptokinaseto urokinase or streptokinase  Increased fibrin selectivityIncreased fibrin selectivity  No cross-reactivity with fibrinogenNo cross-reactivity with fibrinogen  Clinical application remains to beClinical 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 peripheralStreptokinase less desirable for peripheral thrombosis due to complex mechanismthrombosis due to complex mechanism and dosingand dosing  Similar rates of bleeding due to interactionSimilar rates of bleeding due to interaction with hemostatic plugs in addition towith hemostatic plugs in addition to pathological thrombuspathological thrombus  Induction of systemic fibrinolysisInduction of systemic fibrinolysis
  • Thrombolytic AgentsThrombolytic Agents
  • Application of ThrombolyticsApplication of Thrombolytics  SystemicSystemic  Bleeding complications outweighBleeding complications outweigh benefitsbenefits  Intra-arterialIntra-arterial  Prevention of systemic complicationsPrevention of systemic complications  Useful for peripheral arterial and graftUseful for peripheral arterial and graft occlusionocclusion  Intra-operativeIntra-operative
  • Contraindications of SystemicContraindications of Systemic ThrombolyticsThrombolytics
  • Indications for SystemicIndications 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 SystemicIndications 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 pulmonary7 yr F/U – Thrombolysis group had better preservation of normal pulmonary vasculature and higher pulmonary capillary blood volumesvasculature and higher pulmonary capillary blood volumes  Urokinase Pulmonary Embolism Trial – Phase IUrokinase Pulmonary Embolism Trial – Phase I  Compared treatment with 12h urokinase, 24h urokinase, and 24hCompared 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 SystemicIndications 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 ThrombolysisNo Absolute Contraindication to Thrombolysis  Anticoagulation Recommended forAnticoagulation Recommended for Hemodynamically Stable PatientsHemodynamically Stable Patients
  • Indications for SystemicIndications for Systemic ThrombolyticsThrombolytics  Deep Venous ThrombosisDeep Venous Thrombosis  GoalGoal  Prevention of PEPrevention of PE  Prevention of post-phlebitic syndromePrevention of post-phlebitic syndrome  Anticoagulation ineffective therapyAnticoagulation ineffective therapy Complete clotComplete clot lysislysis Normal valveNormal valve function @ 6function @ 6 monthsmonths PE/mortalityPE/mortality BleedingBleeding complicationcomplication HeparinHeparin 4%4% 7%7% SameSame 4%4% LyticsLytics 35%35% 50%50% SameSame 17%17%
  • Indications for SystemicIndications 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 lysis 33%Catheter directed: 83% success, complete lysis 33%  No evidence of improved lysis with systemicNo evidence of improved lysis with systemic administrationadministration
  • Indications for SystemicIndications 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 SystemicIndications 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 threateningMassive ilio-femoral thrombus causing limb threatening venous outflow obstructionvenous outflow obstruction  20-40% Mortality Rate20-40% Mortality Rate  High Amputation RiskHigh Amputation Risk  Venous thrombectomy burdened by re-thrombosisVenous thrombectomy burdened by re-thrombosis
  • Indications for SystemicIndications for Systemic ThrombolyticsThrombolytics  Axillary Vein ThrombosisAxillary Vein Thrombosis  AKA Effort ThrombosisAKA Effort Thrombosis  Younger PatientsYounger Patients  Poor Resolution with AnticoagulationPoor Resolution with Anticoagulation  Thrombolysis Indicated for Short SymptomThrombolysis Indicated for Short Symptom DurationDuration  Systemic and Local Infusion Equally EffectiveSystemic and Local Infusion Equally Effective  Post-Treatment Evaluation for TOSPost-Treatment Evaluation for TOS  Venography performed with Arm Abducted andVenography performed with Arm Abducted and Externally RotatedExternally Rotated
  • Indications for SystemicIndications for Systemic ThrombolyticsThrombolytics  Superior Vena Cava ThrombosisSuperior Vena Cava Thrombosis  Mediastinal Etiologies– Poor ResponseMediastinal Etiologies– Poor Response  CancerCancer  TraumaTrauma  InfectionInfection  Catheter-Induced ThrombosisCatheter-Induced Thrombosis  Response Dependent on Duration of SymptomsResponse Dependent on Duration of Symptoms  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-Blockade?Protective Effect of Concomitant Beta-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 TherapyIncreased Number of Invasive Procedures during Therapy  Increased Duration of TherapyIncreased Duration of Therapy  Patients with Lower Fibrinogen LevelsPatients with Lower Fibrinogen Levels  Bleeding Occurs During Lap Period btw Cessation ofBleeding Occurs During Lap Period btw Cessation of Lysis and Initiation of HeparinLysis and Initiation of Heparin  TreatmentTreatment  FFPFFP  CryoprecipitateCryoprecipitate
  • Application of Intra-arterialApplication 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-arterialPatient Selection of Intra-arterial ThrombolyticsThrombolytics  Low doses of thrombolytic administered close toLow doses of thrombolytic administered close to thrombusthrombus  Minimizes systemic effectsMinimizes systemic effects  Dissolution of thrombus requires 12-72 hrs of therapyDissolution of thrombus requires 12-72 hrs of therapy  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 outcomePoor surgical outcome  Multiple previous surgeriesMultiple previous surgeries  Adjunct to surgeryAdjunct to surgery
  • Patient Selection of Intra-arterialPatient 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%) andEqual response for prosthetic grafts (78%) and native arteries (72%)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-arterialContraindications to Intra-arterial ThrombolyticsThrombolytics
  • Indications for Intra-arterialIndications 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 pseudoaneurysmRisk of bleeding and pseudoaneurysm formationformation
  • Indications for Intra-arterialIndications for Intra-arterial ThrombolyticsThrombolytics  Native Vessel OcclusionNative Vessel Occlusion  Determine the Mechanism of OcclusionDetermine the Mechanism of Occlusion  More effective in peripheral embolization (80%) thanMore effective in peripheral embolization (80%) than thrombotic occlusions (50-60%)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 occlusionsLess likely with resolution of large vessel occlusions
  • Indications for Intra-arterialIndications for Intra-arterial ThrombolyticsThrombolytics  Native Vessel OcclusionNative Vessel Occlusion  Popliteal Artery Occlusion with Distal ClotPopliteal 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 LysisSurgical Exploration with Intraoperative Intra-arterial Lysis  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-arterialIndications 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 revisionAdjunct to convert urgent surgical therapy to elective revision  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 graftsLong grafts  Low flow graftsLow flow grafts  Early graft failure (<1 year old)Early graft failure (<1 year old)
  • Indications for Intra-arterialIndications 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 hourstPA 0.05 mg/kg/hr for 12 hours oror urokinase (250K bolus,urokinase (250K bolus, then 4000 u/min for 4 hour, then 2000 u/min for up to 36 hrs)then 4000 u/min for 4 hour, then 2000 u/min for up to 36 hrs)  Thrombolysis GroupThrombolysis Group  Failure to pass catheter in 28% of patients (Treatment Failure)Failure to pass catheter in 28% of patients (Treatment 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-arterialIndications for Intra-arterial ThrombolyticsThrombolytics  Lower Extremity IschemiaLower Extremity Ischemia  STILE ConclusionsSTILE Conclusions  Surgery was safer and more effective in patients withSurgery was safer and more effective in patients with symptoms < 6 months duration, >14 dayssymptoms < 6 months duration, >14 days  Lytics showed improved amputation free survival inLytics showed improved amputation free survival in patients with <14 days of ischemiapatients with <14 days of ischemia  No difference in outcome for tPA vs. urokinaseNo difference in outcome for tPA vs. urokinase
  • Indications for Intra-arterialIndications for Intra-arterial ThrombolyticsThrombolytics  Lower Extremity IschemiaLower Extremity Ischemia  RCT of 114 limb threatening ischemic patients of <7RCT of 114 limb threatening ischemic patients of <7 days durationdays 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. $12,253)Lytics slightly more expensive ($15,672 vs. $12,253)
  • Indications for Intra-arterialIndications 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-arterialIndications for Intra-arterial ThrombolyticsThrombolytics  Acute StrokeAcute Stroke  Must be administered within 3 hrs of onsetMust be administered within 3 hrs of onset  PROACT IIPROACT II  Superior response of intra-arterial urokinase (67%)Superior response of intra-arterial urokinase (67%) vs. heaprin (18%)vs. heaprin (18%)  10% risk of ICH10% risk of ICH
  • Technique of Intra-arterialTechnique 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 lesionIf unsuccessful, avoid branches between catheter and lesion  High doseHigh dose  Short Length of TimeShort 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-arterialTechnique of Intra-arterial ThrombolyticsThrombolytics  Begin TPA at 0.5-1 mg/hourBegin 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 PTTExpect 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 ofIf 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-arterialTechnique of Intra-arterial ThrombolyticsThrombolytics  Heparin administrationHeparin administration  Recommended to prevent peri-catheter thrombosisRecommended to prevent peri-catheter thrombosis  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 normalizeIf surgery required, give FFP to normalize fibrinogen levelfibrinogen level
  • Indications for IntraoperativeIndications for Intraoperative ThrombolyticsThrombolytics  30% of embolectomies are incomplete30% of embolectomies are incomplete  Residual intravascular defects seen onResidual intravascular defects seen on completion angiographycompletion angiography  Further mechanical manipulation increasesFurther mechanical manipulation increases thrombogenicitythrombogenicity  AdvantagesAdvantages  Bulk of thrombus removed, less lysis neededBulk of thrombus removed, less lysis needed  Employment of higher concentrations ofEmployment of higher concentrations of thrombolyticthrombolytic
  • Indications for IntraoperativeIndications for Intraoperative ThrombolyticsThrombolytics  Multiple trials with streptokinase andMultiple 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 giventPA not studied, but would be ideal given its selectivity for fibrin and short half lifeits selectivity for fibrin and short half life