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064 vulnerable thrombogenic blood

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064 vulnerable thrombogenic blood

  1. 1. 5th Symposium Vulnerable Plaque Org5th Symposium Vulnerable Plaque Org March 29th, 2003March 29th, 2003 ChicagoChicago Vulnerable (Thrombogenic) BloodVulnerable (Thrombogenic) Blood Juan Jose BadimonJuan Jose Badimon Cardiovascular Biology Research LaboratoryCardiovascular Biology Research Laboratory Cardiovascular InstituteCardiovascular Institute Mount Sinai School of MedicineMount Sinai School of Medicine New York, NYNew York, NY
  2. 2. 3rd Symposium Vulnerable Plaque Org3rd Symposium Vulnerable Plaque Org March 16th, 2002March 16th, 2002 AtlantaAtlanta VulnerableVulnerable VulnerableVulnerable VulnerableVulnerable PlaquePlaque BloodBlood PatientPatient ++ == Juan Jose BadimonJuan Jose Badimon Cardiovascular Biology Research LaboratoryCardiovascular Biology Research Laboratory Cardiovascular InstituteCardiovascular Institute Mount Sinai School of MedicineMount Sinai School of Medicine New York, NYNew York, NY
  3. 3. ATHEROTHROMBOTICATHEROTHROMBOTIC DISEASEDISEASE
  4. 4. ACSACS and Stenotic Severityand Stenotic Severity Falk E et al; Circulation 1995Falk E et al; Circulation 1995
  5. 5. CULPRIT LESION VS. DIFUSE DISEASECULPRIT LESION VS. DIFUSE DISEASE One single culprit lesion but multiple plaqueOne single culprit lesion but multiple plaque ruptures in the same patientruptures in the same patient 11 .. The difuse disease may be responsible forThe difuse disease may be responsible for the widespread coronary inflammationthe widespread coronary inflammation observed in UAobserved in UA22 11 Rioufol G. Circ.2002;106:804-808Rioufol G. Circ.2002;106:804-808 22 Buffon A, NEJMBuffon A, NEJM 2002;347:5-122002;347:5-12 Multiple complex coronaryMultiple complex coronary plaques in AMI patients.plaques in AMI patients. Goldstein JA NEJM 2000;343:915Goldstein JA NEJM 2000;343:915 Systemic therapies more effective than local interventions in theSystemic therapies more effective than local interventions in the long-rangelong-range Is there a role for PCI’s in plaque stabilization?. Probably no.Is there a role for PCI’s in plaque stabilization?. Probably no.
  6. 6. AtherothrombosisAtherothrombosis Complicated MechanismsComplicated Mechanisms Plaque DisruptionPlaque Disruption BloodBlood ThrombogenicityThrombogenicity LocationLocation VulnerableVulnerable Non-VulnerableNon-Vulnerable CoronariesCoronaries ++++++ +/-+/- ++++ CarotidsCarotids +/-+/- ++++ +/-+/- Thoracic AortaThoracic Aorta ++ -- ++ PeripheralPeripheral -- -- ++++++ Suggested Predominant MechanismSuggested Predominant Mechanism
  7. 7. Vulnerable (High-risk) PlaqueVulnerable (High-risk) Plaque ++Vulnerable (High-Risk) BloodVulnerable (High-Risk) Blood == High-RiskHigh-Risk (Vulnerable)(Vulnerable) PatientPatient Plaque - Blood - PatientPlaque - Blood - Patient
  8. 8. W Kannel Am J Cardiol 1996; 77:6BW Kannel Am J Cardiol 1996; 77:6B Association of Cardiovascular Risk FactorsAssociation of Cardiovascular Risk Factors
  9. 9. Family/GenesFamily/Genes GenderGender Age (menopause)Age (menopause) DietDiet InflammationInflammation HypertensionHypertension ObesityObesity SedentarismSedentarism othersothers SmokingSmoking CathecholaminesCathecholamines FibrinogenFibrinogen Lp(a)/HomocysteinLp(a)/Homocystein Factor V LeidenFactor V Leiden Platelet polymorph.Platelet polymorph. HypercoagulabilityHypercoagulability HypofibrinolysisHypofibrinolysis Genetic ProteinGenetic Protein deficienciesdeficiencies Diabetes Hyperlipidemia Apoptosis? Shear rate Stress Depression ? cRP? ATHEROGENESISATHEROGENESIS THROMBOSISTHROMBOSIS Risk Factor and AtherothrombosisRisk Factor and Atherothrombosis
  10. 10. 00 40004000 80008000 1200012000 1600016000 SIMVASTATINSIMVASTATIN PRAVASTATINPRAVASTATIN p<0.05p<0.05 p<0.05p<0.05 ThrombusFormationThrombusFormation ((µµmm22 /mm/mm)) Pre treatmentPre treatment Post treatmentPost treatment LIPID LOWERING and BLOOD THROMBOGENICITYLIPID LOWERING and BLOOD THROMBOGENICITY 251±51251±51 176±44176±44 Total CHOTotal CHO 246+39246+39 202+41202+41 165±99165±99 151±83151±83 LDL-CHOLDL-CHO 141+56141+56 123±65123±65 Rauch U et al. Atherosclerosis 2000; 153: 181-89Rauch U et al. Atherosclerosis 2000; 153: 181-89
  11. 11. Effect of 2-year statin on Vessel WallEffect of 2-year statin on Vessel Wall Corti R, Badimon JJ et al. Circulation 2002 106:2884-87Corti R, Badimon JJ et al. Circulation 2002 106:2884-87
  12. 12. BLOODBLOOD ARTERIAL WALLARTERIAL WALL ACUTE CORONARY EVENTS PLASMA LIPIDSPLASMA LIPIDS plaque vulnerability plaque progression endothelial dysfunction platelet reactivity macrophages hyper- coagulability thrombus formation STATINSSTATINS plaque disruption
  13. 13. ““ Vulnerable /Hyper-reactive” BloodVulnerable /Hyper-reactive” Blood Several risk factors correlate with hyperreactive blood. TheseSeveral risk factors correlate with hyperreactive blood. These factors modulate the severity of the event after plaque disruptionfactors modulate the severity of the event after plaque disruption ““Classic”Classic” Diabetes Smoking Hyperlipidemia Inflammation/ Apoptosis/ Infection? Cathecholamines Fibrinogen Lp(a) Homocysteinemia Factor V Leiden Platelet polymorph Shear rate Genetic Protein deficiencies (AT III, Prot C or S) Hypercoagulable state (↑FVII, ↑ F1.2, ↑ FPA) Hypofibrinolytic state (↑PAI-1, ↓t-PA, ↓ u-PA) ““Not so-classic”Not so-classic” DepressionDepression Circulating TF activityCirculating TF activity StressStress
  14. 14. Inflammation Thrombosis Atherosclerosis Apoptosis Tissue factor micro-particles Aggregated Platelets PDGF Thrombin IL-6 TF MMP ICAM-1 IL-1 CRP CVRisk Factors ACS The Inflammation-ThrombosisThe Inflammation-Thrombosis LinkLink Clinical evidence: Septic shockClinical evidence: Septic shock Inflammation subsequent to bacterial endotoxin induces endothelialInflammation subsequent to bacterial endotoxin induces endothelial TF and PAI-1 expression leading to thrombotic complications (DIC)TF and PAI-1 expression leading to thrombotic complications (DIC)
  15. 15. CONTROLCONTROL TFPI-TreatedTFPI-Treated TF INHIBITION and THROMBOSISTF INHIBITION and THROMBOSIS Badimon Perfusion chamberBadimon Perfusion chamber Human lipid rich atherosclerotic lesionsHuman lipid rich atherosclerotic lesions Badimon JJ et al. Circulation 1999; 99:1780-1787Badimon JJ et al. Circulation 1999; 99:1780-1787
  16. 16. TF Plasma Levels and CADTF Plasma Levels and CAD Soejima H et al. Circulation 1999;99:2908 The existence of circulating particles with procoagulantThe existence of circulating particles with procoagulant activity have been reported by several groupsactivity have been reported by several groups (Mallat,Tedgui)(Mallat,Tedgui)
  17. 17. BLOOD BORNE - TISSUE FACTORBLOOD BORNE - TISSUE FACTOR Giesen P et al.Giesen P et al. PNAS 1999; 96:2311PNAS 1999; 96:2311
  18. 18. Risk factors and circulating TF activityRisk factors and circulating TF activity Control Smokers Hyperlipidemic Diabetics 0 100 200 300 400 500 TissueFactoractivity (pmolFXa/L) Sambola A. Circulation 2003; 107: 973-979
  19. 19. BloodThrombogenicityBloodThrombogenicity CirculatingTFactivityCirculatingTFactivity Glycemic ImprovementGlycemic Improvement No Glycemic ImprovementNo Glycemic ImprovementSambola Circulation 2003Sambola Circulation 2003 Glycemic Control, Circulating TF activityGlycemic Control, Circulating TF activity and Blood Thrombogenicityand Blood Thrombogenicity
  20. 20. Apoptosis and Tissue Factor Protein ExpressionApoptosis and Tissue Factor Protein Expression in Macrophages of Human Coronary Atheromain Macrophages of Human Coronary Atheroma Apoptosis and Tissue Factor Protein ExpressionApoptosis and Tissue Factor Protein Expression in Macrophages of Human Coronary Atheromain Macrophages of Human Coronary Atheroma R. HutterR. Hutter et al., 2002et al., 2002
  21. 21. Blood MonocytesBlood Monocytes in vitro oxLDLin vitro oxLDL Human CarotidHuman Carotid Lipid-rich lesionLipid-rich lesion aCAS-3aCAS-3 TFTF aCas-3/TFaCas-3/TF Hutter R et al, 2003Hutter R et al, 2003
  22. 22. monocyte TF PMN BLOOD VESSEL WALL AT plaque SMC lipid core macrophage fibroblast myocyte HEART myocardial ischemia TF Circulates in Blood: Possible Cellular Sources EndothelialEndothelial cellcell
  23. 23. Inhibitors of the intrinsic pathwayInhibitors of the intrinsic pathway HEPARINHEPARIN WARFARINWARFARIN LOW MOLECULAR WEIGHT HEPARINSLOW MOLECULAR WEIGHT HEPARINS DIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS Antiplatelet agentsAntiplatelet agents ASPIRINASPIRIN TICLOPIDIN, CLOPIDOGRELTICLOPIDIN, CLOPIDOGREL (±ASA)(±ASA) GP IIb/IIIa RECEPTOR ANTAGONISTSGP IIb/IIIa RECEPTOR ANTAGONISTS DIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS Other ApproachesOther Approaches:: THROMBOLYTICS,THROMBOLYTICS, ANTI IX,ANTI IX, P2T ANTAGONISTS,P2T ANTAGONISTS, TX-ANTAGONISTSTX-ANTAGONISTS Antithrombotic TherapyAntithrombotic Therapy
  24. 24. Inhibitors of the intrinsic pathwayInhibitors of the intrinsic pathway HEPARINHEPARIN WARFARINWARFARIN LOW MOLECULAR WEIGHT HEPARINSLOW MOLECULAR WEIGHT HEPARINS DIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS Antiplatelet agentsAntiplatelet agents ASPIRINASPIRIN TICLOPIDIN, CLOPIDOGREL (±ASA)TICLOPIDIN, CLOPIDOGREL (±ASA) GP IIb/IIIa RECEPTOR ANTAGONISTSGP IIb/IIIa RECEPTOR ANTAGONISTS DIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS Inhibitors of Tissue Factor PathwayInhibitors of Tissue Factor Pathway TFPITFPI TAPTAP INHIBITORS OF FACTORS VIIa and/or XaINHIBITORS OF FACTORS VIIa and/or Xa Other ApproachesOther Approaches:: THROMBOLYTICS, ANTI IX, P2T ANTAGONISTS, TX-ANTAGONISTSTHROMBOLYTICS, ANTI IX, P2T ANTAGONISTS, TX-ANTAGONISTS Antithrombotic TherapyAntithrombotic Therapy
  25. 25. XX XaXa IXIX IXaIXa ++ ++ VaVa VIIIaVIIIa Xa:VaXa:Va VIIIa:IXaVIIIa:IXa + Va+ Va ProthrombinProthrombin ThrombinThrombin TFTF ++ VIIaVIIa TF:VIIaTF:VIIa TF Pathway and its potential inhibitionTF Pathway and its potential inhibition TFPITFPI
  26. 26. Clinical Implications - BloodClinical Implications - Blood Inhibitors of TF pathwayInhibitors of TF pathway are the most promisingare the most promising antithrombotic agents being investigated.antithrombotic agents being investigated. TargetTarget AgentAgent TF:TF: Several humanized antibodiesSeveral humanized antibodies TF: FVIIaTF: FVIIa TFPITFPI ,, FFR-FVIIa,FFR-FVIIa, Corsevin MCorsevin M FXaFXa Dx-6905a, C-1031, DPC-906,Dx-6905a, C-1031, DPC-906, FondaparinuxFondaparinux Thrombin:Thrombin: Hirudin, Hirulog, BivalirudinHirudin, Hirulog, Bivalirudin ( parent.)( parent.) Ximelagatran and MCC-977Ximelagatran and MCC-977 (oral)(oral) Antithrombotic agents have reduced approx. 20%Antithrombotic agents have reduced approx. 20% of ACS in CAD patientsof ACS in CAD patients (BMJ 2002;324:71-86).BMJ 2002;324:71-86).

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