1. Section B: Science update
Thrombus formation: Most common cause of ACS
Content Points:
ACS is most commonly caused by reduced myocardial perfusion caused by a thrombus that has developed on a disrupted atherosclerotic plaque.
– A completely occlusive thrombus leads to ST-segment elevation on the ECG
– Less occlusive thrombi generally underlie UA and NSTEMI
As shown, there are two mechanisms of plaque disruption4:
– Fracture of the fibrous cap (which accounts for approximately 75% of cases), resulting in exposure to blood of the plaque’s internal contents
– Superficial erosion of the cap, exposing the subendothelial basement membrane

2. Overview of the coagulation cascade
Content Points:
Platelet adhesion and aggregation are accompanied by activation of the coagulation pathway.5
Thrombin (factor IIa), a downstream product of this pathway, converts fibrinogen to fibrin and activates coagulation factor XIII, which in turn, stabilizes the growing thrombus by cross-linking fibrin.
The coagulation pathway has two main branches6:
– Intrinsic system: This is triggered by activation of factor XII on negatively charged surfaces
– Extrinsic system: The predominant mechanism of coagulation in vivo; the initial trigger is injury-induced exposure or release of tissue factor (factor VII)
Following exposure of an atherosclerotic plaque’s thrombogenic components, adhesion and aggregation of platelets occurs.7,8 At the plaque site, platelets bind to von Willebrand factor (vWF) via the glycoprotein (GP) 1b receptor and to collagen via the GP 1a receptor. Adherent platelets release thromboxane A2 and adenosine diphosphate (ADP), which bind to their own platelet receptors and amplify the activation process.
Finally, there is exposure of the high-affinity fibrinogen-binding site on the GP IIb/IIIa receptor and subsequent cross-linking of platelets with fibrinogen.

3. Antithrombotic therapies: Main sites of action
Content Points:
Aspirin, thienopyridines (eg, clopidogrel), and GP IIb/IIIa inhibitors inhibit platelet aggregation.6
– Aspirin blocks formation of thromboxane A2
– The thienopyridines block the ADP receptor
– GP IIb/IIIa inhibition prevents the fibrinogen cross-linking mediated by this receptor
The heparins and the pentasaccharides bind to antithrombin.6,9 This complex inhibits factor IIa and factor Xa.
Warfarin inhibits production of factors II, VI, IX, and X.7
Low-molecular-weight heparins (LMWHs) are relatively more selective for factor Xa than for factor IIa; unfractionated heparin (UFH) is relatively nonselective.
Because of the cascading nature of coagulation, inhibition of a small quantity of factor Xa prevents formation of large amounts of thrombin. Thus, greater Xa activity is associated with greater antithrombotic effects.
Other effects of LMWHs may contribute to their antithrombotic action, since their antithrombotic effects are maintained even after disappearance of circulating anti-Xa activity. These effects are discussed on the next slide.

4. Antithrombotic effects of LMWH
Content Points:
Other effects of LMWHs that may contribute to their antithrombotic action include9:
– Release of tissue-factor–pathway inhibitor (TFPI)
- TFPI inactivates factor Xa and factor VIIa
- LMWHs (but not UFH) promote release of TFPI
– Reduction in vWF concentration
- Increased circulating levels of vWF occur frequently in patients with ACS and are predictive of an adverse outcome10
- LMWHs (dalteparin, enoxaparin) blunt this increase. Enoxaparin is more potent in this regard than dalteparin
– Interaction with heparin cofactor II
– Inhibition of the procoagulant effects of leukocytes
– Promotion of fibrinolysis

5. Antiplatelet therapies in ACS
Content Points:
The next three sections in this slide kit address, in turn, studies evaluating oral antiplatelet therapy, intravenous (IV) GP IIb/IIIa inhibition, and heparins.
As shown, oral antiplatelet therapy includes aspirin and the thienopyridines (ticlopidine, clopidogrel).
Available IV GP IIb/IIIa inhibitors include abciximab, eptifibatide, and tirofiban.1
A number of oral GP IIb/IIIa inhibitors have been investigated. However, large clinical outcomes trials of oral GP IIb/IIIa inhibition (orbofiban, sibrafiban, xemilofiban) have shown neutral or slightly negative results.11 The data do not support a role for these agents in management of ACS.

6. Antithrombotic therapies in ACS: Anticoagulants
Content Points:
Available heparins include UFH and LMWH.1
Direct thrombin inhibitors block thrombin effects without need for antithrombin or other cofactors.
– Hirudin is approved as an alternative to heparin in patients with heparin-induced thrombocytopenia1
– Bivalirudin and argatroban are synthetic analogs of hirudin and are under clinical investigation
Fondaparinux is a synthetic analog of the pentasaccharide sequence in heparin and is under clinical investigation.1
Warfarin is under clinical investigation for long-term anticoagulation in patients with ACS.1