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Overcoming thrombolytic resistance

Rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction

^a Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

View larger version (32K): [in a new window]   Figure 1 Thrombolytic resistance. FDP = fibrin/fibrinogen degradation product. (Adapted with permission from Moliterno DJ, Topol EJ. Thromb Haemost 1997;78:214–9.)

View larger version (25K): [in a new window]   Figure 2 The three components of coronary thrombus are targets for therapy. Mechanism of action: aspirin—acetylates cyclooxygenase, decreases platelet activation; heparin—reduces clotting formation/propagation; GPIIb/IIIa inhibitors inhibit platelet aggregation; thrombolytic therapy—converts plasminogen to plasmin, which dissolves fibrin in clot. LMWH = low molecular weight heparin; t-PA = tissue-type plasminogen activator; r-PA = reteplase; SK = streptokinase; TNK-tPA = TNK–tissue-type plasminogen activator.

View larger version (26K): [in a new window]   Figure 3 Platelet adhesion, activation and aggregation and inhibition by GPIIb/IIIa inhibitors. In this diagram of events associated with platelet adhesion (a), activation (b) and aggregation (c), activated platelets undergo a conformational change in the shape of the GPIIb/IIIa receptors, which makes them receptive to ligand binding. Fibrinogen binds to the platelet GPIIb/IIIa receptors on adjacent platelets, forming bridges between them. As shown in (d), GPIIb/IIIa receptor inhibitors block this fibrinogen-binding receptor and therefore directly prevent platelets from aggregating. AA = arachidonic acid; ADP = adenosine diphosphate; ASA = aspirin; GPIIb/IIIa = glycoprotein IIb/IIIa; TXA2 = thromboxane A2; vWF = von Willebrand factor.

View larger version (28K): [in a new window]   Figure 4 New paradigm for mechanism of benefit of GPIIb/IIIa inhibitors.

View larger version (33K): [in a new window]   Figure 5 Results from the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. Comparison of 90-min accelerated tissue-type plasminogen activator (t-PA) with combination therapy using abciximab (abcix) and reduced-dose t-PA (15-mg bolus and 35-mg infusion over 60 min) (t-PA = tissue-type plasminogen activator). (Data from Antman et al. [57].)