Thrombus Susceptibility and the Vulnerable Plaque Relationship Between Inflammation and Thrombosis.
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Transcript of Thrombus Susceptibility and the Vulnerable Plaque Relationship Between Inflammation and Thrombosis.
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Wagner DD. Arterioscler Thromb Vasc Biol. 2005;25:1321-4.
Interaction between inflammation and hemostasis in vulnerable plaque
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Harrison DG. Nat Med. 2005;11:375-6.
Txnip = thioredoxin interacting protein (vitamin D upregulating protein 1)ASK = apoptosis-signaling kinase; JNK = Jun-terminal kinase
Txnip links shear stress to inflammation
• No shear
• Txnip
• Thioredoxin inactive
• Normal shear
• Txnip
• Thioredoxin active
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Freedman JE. Circulation. 2005;112:2725-34.
ADP = adenosine diphosphate; NO = nitric oxide; R = platelet receptors; TXA2 = thromboxane A2; vWf = von Willebrand factor
Disrupted endotheliumGPIb-IX-V
ActiveGP IIb/IIIa
Fibrinogen
TXA2 ADP
InactiveGP IIb/IIIa
Unactivatedplatelet
NO
Subendothelial matrix
Platelet adhesion and aggregation
RR
vWf
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Chakrabarti S et al. Arterioscler Thromb Vasc Biol. 2005;25:2428-34.
0
5
10
sCD40L(ng/mL)
0 50 100 150 200 250 300 350
Time (minutes)
+ Thrombin
– Thrombin
Platelets release soluble CD40 ligand (sCD40L) after thrombin stimulation
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Chakrabarti S. et al. Arterioscler Thromb Vasc Biol. 2005;25:2428-34.
Recombinant sCD40L enhances platelet release of reactive oxygen species
Platelets + Dihydrorhodamine
Unstimulated TRAP TRAP + rsCD40L
TRAP = Thrombin receptor-activated platelets
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André P et al. Circulation. 2002;106:896-9.
Activated plateletUnstimulated platelet
GP IIb/IIIa antagonists block sCD40L release from platelets
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Curran MP, Keating GM. Drugs. 2005;65:2009-35.
Thrombolytics
AbciximabTirofiban
Eptifibatide
UFHLMWHsDirect thrombininhibitors
Aspirin
ThromboxaneA2
Collagen ADP Thrombin
Fibrinogen
Fibrin
GP IIb/IIIa activation
von Willebrand factor
Platelet aggregation
Thrombus formation
TiclopidineClopidogrel
Points of action for antithrombotics
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GP IIb/IIIa + PCI≥80% occupancy
GP IIb/IIIa + No PCI<80% occupancy>12 hours
Antman EM. Am Heart J. 2003;146(suppl):S18-22.
Proposed model for optimal use of GP IIb/IIIa inhibitors
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Furman MI et al. J Thromb Haemost. 2005;3:312-20.Giugliano RP, Braunwald E. J Am Coll Cardiol. 2005;46:906-19.
Potential mechanisms for reduction of thrombo-inflammation with GP IIb/IIIa inhibition
• Inhibit platelet activation
• Reduce sCD40L in ACS and PCI
• Blunt CRP increase in ACS and PCI
• Reverse endothelial dysfunction induced by PCI
• Reduce leukocyte-platelet aggregation in ACS