Disaggregation of in vitro preformed platelet-rich clots by abciximab increases fibrin exposure and promotes fibrinolysis

The glycoprotein IIb/IIIa receptor inhibitor abciximab has been shown to fa cilitate the rate and the extent of pharmacological thrombolysis with recom binant tissue plasminogen activator (rtPA) in patients with acute myocardia l infarction, However, the underlying mechanisms remain not fully determine d. We sought to demonstrate that this facilitating effect of abciximab coul d be related to its potential to modify the clot architecture and the clot physical properties. Compared with fibrin-rich clots, platelets dramaticall y modified the in vitro properties of the fibrin network, leading to a sign ificant increase of the permeability (K-s) and the viscoelasticity (G') ind exes but also leading to the appearance of platelet aggregates (surface are a [S,ag]). These modifications resulted in a 2.6-fold decrease of the fibri nolysis rate when rtPA (1 nmol/L) was added before the initiation of clotti ng. Adding aspirin (100 mug/mL) or abciximab (0.068 mu mol/L) before the cl otting of platelet-rich clots (PRCs) lowered K-s by 50% and 70%, respective ly (P<0.01), G' by 41% and 66%, respectively (P<0.01), and S.ag by 32% and 61%, respectively (P<0.01), As a consequence, the lysis speed was increased by 21% with aspirin (P<0.01) and 45% with abciximab (P<0.01), However, unl ike aspirin, permeation of preformed PRCs with abciximab (0.068 <mu>mol/L) decreased G' (37%, P<0.01), K-s (35%, P<0.001) and S.ag (25%, P=NS) and res ulted in a 27% (P<0.01) increase of the lysis speed when abciximab and rtPA (0.2 <mu>mol/L) were simultaneously permeated. This effect was found to be time dependent and was observed only with early permeation, starting withi n the first 10 minutes of clotting. These changes in the physical propertie s of the PRC architecture suggest that fibrin is removed from the platelet- fibrin aggregates and reexposed into the surrounding fibrin network, increa sing rtPA access to fibrin and therefore the fibrinolysis rate. The superio rity of abciximab over aspirin in accelerating fibrinolysis of forming and preformed PRCs is related to its ability to modulate the interactions of fi brinogen and fibrin with platelets. These findings provide new mechanistic information on reperfusion therapy.