Thrombus Susceptibility and the Vulnerable Plaque

1
Thrombus Susceptibilityand the Vulnerable Plaque

• Relationship Between Inflammation and Thrombosis

2
Interaction between inflammation and hemostasis
in vulnerable plaque
Wagner DD. Arterioscler Thromb Vasc Biol.
2005251321-4.
3
Txnip links shear stress to inflammation

• No shear
• Txnip
• Thioredoxin inactive

• Normal shear
• Txnip
• Thioredoxin active

Txnip thioredoxin interacting protein (vitamin
D upregulating protein 1)ASK
apoptosis-signaling kinase JNK Jun-terminal
kinase
Harrison DG. Nat Med. 200511375-6.
4
Platelet adhesion and aggregation
InactiveGP IIb/IIIa
Unactivatedplatelet
R
TXA2 ADP
R
NO
Fibrinogen
ActiveGP IIb/IIIa
GPIb-IX-V
Disrupted endothelium
vWf
Subendothelial matrix
ADP adenosine diphosphate NO nitric oxide
R platelet receptors TXA2 thromboxane A2
vWf von Willebrand factor
Freedman JE. Circulation. 20051122725-34.
5
Platelets release soluble CD40 ligand (sCD40L)
after thrombin stimulation
10
Thrombin
sCD40L(ng/mL)
5
Thrombin
0
0
50
100
150
200
250
300
350
Time (minutes)
Chakrabarti S et al. Arterioscler Thromb Vasc
Biol. 2005252428-34.
6
Recombinant sCD40L enhances platelet release of
reactive oxygen species
Platelets Dihydrorhodamine
Unstimulated
TRAP
TRAP rsCD40L
Chakrabarti S. et al. Arterioscler Thromb Vasc
Biol. 2005252428-34.
TRAP Thrombin receptor-activated platelets
7
GP IIb/IIIa antagonists block sCD40L release
from platelets
Activated platelet
Unstimulated platelet
André P et al. Circulation. 2002106896-9.
8
Points of action for antithrombotics
Aspirin
ThromboxaneA2
Collagen
Thrombin
ADP
UFHLMWHsDirect thrombininhibitors
TiclopidineClopidogrel
Fibrinogen
GP IIb/IIIa activation
AbciximabTirofibanEptifibatide
von Willebrand factor
Platelet aggregation
Fibrin
Thrombus formation
Thrombolytics
Curran MP, Keating GM. Drugs. 2005652009-35.
9
Proposed model for optimal use of GP IIb/IIIa
inhibitors
GP IIb/IIIa PCI80 occupancy
GP IIb/IIIa No PCIlt80 occupancygt12 hours
Antman EM. Am Heart J. 2003146(suppl)S18-22.
10
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

Furman MI et al. J Thromb Haemost.
20053312-20. Giugliano RP, Braunwald E. J Am
Coll Cardiol. 200546906-19.