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Thrombus Susceptibility and the Vulnerable Plaque

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.

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Thrombus Susceptibility and the Vulnerable Plaque

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  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. 2005;25:1321-4.

  3. No shear Txnip Thioredoxin inactive Txnip links shear stress to inflammation • 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. 2005;11:375-6.

  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. 2005;112:2725-34.

  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. 2005;25:2428-34.

  6. Recombinant sCD40L enhances platelet release of reactive oxygen species Platelets + Dihydrorhodamine Unstimulated TRAP TRAP + rsCD40L Chakrabarti S. et al. Arterioscler Thromb Vasc Biol. 2005;25:2428-34. TRAP = Thrombin receptor-activated platelets

  7. GP IIb/IIIa antagonists block sCD40L release from platelets Unstimulated platelet Activated platelet André P et al. Circulation. 2002;106:896-9.

  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. 2005;65:2009-35.

  9. Proposed model for optimal use of GP IIb/IIIa inhibitors 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.

  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 ThrombHaemost. 2005;3:312-20. Giugliano RP, Braunwald E. J Am Coll Cardiol. 2005;46:906-19.

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