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064 vulnerable thrombogenic blood
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. 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
4. ACSACS and Stenotic Severityand Stenotic Severity
Falk E et al; Circulation 1995Falk E et al; Circulation 1995
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.
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
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. 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. 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. 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. BLOOD BORNE - TISSUE FACTORBLOOD BORNE - TISSUE FACTOR
Giesen P et al.Giesen P et al.
PNAS 1999; 96:2311PNAS 1999; 96:2311
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
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. 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. 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. 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. 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. 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. 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).
Notas do Editor
Several investigators have shown that
the risk of coronary occlusion is not proportional to the prior severity of coronary stenoses.
In fact, coronary occlusion and myocardial infarction most frequently evolve from plaques that are only mildly to moderately obstructive
