Thrombus Susceptibilityand 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