thrombus susceptibility and the vulnerable plaque
DESCRIPTION
Thrombus Susceptibility and the Vulnerable Plaque. Relationship Between Inflammation and Thrombosis. Interaction between inflammation and hemostasis in vulnerable plaque. Wagner DD. Arterioscler Thromb Vasc Biol . 2005;25:1321-4. No shear Txnip Thioredoxin inactive. - PowerPoint PPT PresentationTRANSCRIPT
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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