An Additional Mechanism of Action of Abciximab: Dispersal of Newly Formed Platelet Aggregates

Abstract

SummaryThe ability of abciximab to prevent fibrinogen binding to activated platelets indicates it may also promote dissolution of platelet-rich thrombi. The present study examined the capacity of abciximab to reverse platelet aggregation in vitro. Experiments were performed on blood from healthy non-medicated donors. Platelet aggregate formation and disaggregation were monitored turbidimetrically. Platelet-bound fibrinogen was measured by flow cytometry. For disaggregation studies, platelets were first stimulated with either ADP or the 11-mer thrombin receptor activating peptide (TRAP), then varying amounts of abciximab were added at periodic intervals after agonist addition. Platelet disaggregation was detected by comparing the extent of light transmittance at 4 min after addition of either abciximab or saline to PRP. ATP release was simultaneously monitored by chemi-luminescence. When added 1 min after low concentrations of ADP, abciximab rapidly (<1 min) dispersed platelet aggregates in a dose-dependent manner, with complete disaggregation observed with 6.25 µg/mL of the β3 antagonist. In contrast, equivalent concentrations of abciximab did not induce appreciable disaggregation to platelets stimulated with TRAP (10 µM). Platelet counts of samples that had undergone complete disaggregation, as assessed by aggregometry, were equivalent to baseline, indicating dispersal of aggregates to single cells. Concentrations of abciximab that produced complete disaggregation induced partial displacement of platelet-bound fibrinogen (52 ± 8% inhibition of fibrinogen binding at 12.5 µg/ml abciximab). The disaggregation effectiveness of abciximab decreased as the time between ADP and subsequent abciximab addition widened, and as the amount of both dense granule release and agonist stimulation increased. However, pre-treatment of platelets with acetylsalicylic acid (ASA) did not potentiate platelet disaggregation induced by abciximab.These data indicate that abciximab facilitates the dispersal of newly formed platelet aggregates in vitro, by partially displacing fibrinogen from activated GPIIb/IIIa receptors. In vivo, abciximab may destabilize coronary thrombi by preventing aggregate formation and dispersing mural thrombi.

Comparison between the Outcomes of Intracoronary and Intravenous Administration of Eptifibatide during Primary Percutaneous Coronary Intervention in Patients with Acute ST-Elevation Myocardial Infarction

“…Some studies have demonstrated that GPIs have dose-dependent antiplatelet, antithrombotic, and antiinflammatory features. Local delivery of GPIs directly into the coronary circulation during PPCI in patients with STEMI was a relatively simple way that with the rationale of reach higher local concentration of drug at the culprit lesion may enhance the benefits of this adjunctive therapy [6][7][8] . Thus, this method was investigated, and some studies showed these clinical benefits.…”

“…Thus, this method was investigated, and some studies showed these clinical benefits. Despite previous studies on abciximab, clinical experience in the efficacy of IC administration of eptifibatide as another GPI is limited 6,[9][10][11][12] . Hence, we thought to present this study that compares the clinical outcomes of IC eptifibatide administration that is used during PPCI with those of IV eptifibatide administration.…”

Intracoronary Compared With Intravenous Bolus Abciximab Application in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

“…Concentrations that produced complete platelet disaggregation also induced partial displacement of platelet-bound fibrinogen, which might play a role in the clinical setting. 29 Previous trials assessing the effect of intracoronary abciximab administration were limited to case reports, retrospective registries, and small randomized trials. [12][13][14][15][16] In one of these trials, angiographic reperfusion was improved in the intracoronary abciximab group as assessed by the corrected TIMI frame count.…”

Mortality Reduction with Administration of Abciximab during Primary PCI is Confined to STEMI Patients with Complex Lesions

“…Since the waiting period between diagnosis and treatment has shortened the time for abciximab to work is correspondingly short. Since the action of abciximab relies mainly on inhibition of thrombus formation and propagation [20][21][22], and possibly also exhibits some degree of thrombus disaggregation [23][24][25], only in the cases were thrombus is actually present, one can expect an effect of abciximab. If thrombus is not present the effect will be absent and the treatment might even be harmful, since the side effects of abciximab, that is bleeding, will outweigh the potential benefit.…”