Understanding the complexity of abciximab-related thrombocytopenia.

Patients with a rare bleeding disorder characterised by skin and mucosal bleeding – typical of thrombocytopenia – but with a normal platelet count, and later characterised by a defective aggregation to all agonists, described as Glanzmann thrombasthenia, have mutations in a platelet membrane glycoprotein (GP) called GP IIb/IIIa, also known as the integrin αIIbβ3 (1). Such discovery paved the road to a molecular understanding of how platelets aggregate, with GPIIb/IIIa acting as a main ligand for fibrinogen, which in turn provides the main molecular bridge between two adjacent platelets. This was the basis, now more than 15 years ago, for starting the development of a new class of antiplatelet agents directed against GP IIb/IIIa, blocking the final common pathway of platelet aggregation. The first such drug was derived from a murine monoclonal antibody (7E3) recognising activated, but not resting platelets, and binding to an epitope on the GPIIb/IIIa complex close to a critical binding site for fibrinogen (2). To decrease the immunogenicity of the antibody, the pharmaceutical abciximab (ReoPro, developed by Centocor and Eli Lilly), was produced. Abciximab is a chimeric (human/mouse) Fab fragment derived from 7E3, where the N-terminal sequences that control its specificity were incorporated into a human IgG1 framework. The intact chimeric IgG molecule was then cleaved by papain to produce the Fab fragment abciximab. Abciximab is therefore a Fab chimera that retains the mouse-derived variable portion of murine 7E3 joined to the constant region of human IgG Fab. Out of several other molecules developed for intravenous and oral use to target GP IIb/IIIa, two other compounds of this class have become available for intravenous use only. One is the Lys-Gly-Asp (KGD)containing cyclic heptapeptide eptifibatide (Integrilin, developed by ScheringPlough), derived from disintegrins, a class of proteins found in snake venoms and interfering with the binding of Arg-Gly-Asp (RGD)-containing adhesive proteins to cellular integrins. The other is tirofiban (Aggrastat, developed by Merck), developed by engineered synthesis to mimic the charge and spatial conformation of the RGD sequence. These compounds, which are small molecules not per se immunogenic, are collectively termed ligand-mimetic. Abciximab, eptifibatide and tirofiban are currently approved and recommended for therapeutic use in acute coronary syndromes (both ST-elevation myocardial infarction and non-ST elevation acute coronary syndromes), especially in the setting of percutaneous coronary interventions (PCI) (3, 4). Here, in patients with complex anatomy and receiving coronary stents, in the highly thrombogenic setting of acute coronary syndromes, abciximab is currently, within the category, the agent of choice when given at the time of PCI, having shown superiority in one face-to-face trial against tirofiban (5). In earlier clinical trials (6, 7) and in immediate post-marketing surveillance of abciximab, it was found that about 1% of patients develop thrombocytopenia. Thrombocytopenia (nadir platelet count <100x109 cells/l) developed actually in 2.4% of patients treated with abciximab and 0.5% of those treated with tirofiban (p<0.001) in a large series of patients undergoing coronary stenting in the setting of the TARGET study. Here abciximab use was independently associated with the risk of thrombocytopenia Correspondence to: Raffaele De Caterina, MD, PhD Institute of Cardiology and Center of Excellence on Aging “G. d’Annunzio” University – Chieti C/o Ospedale SS. Annunziata Via dei Vestini, 66013 Chieti, Italy Tel.: +39 0871 41512, Fax: +39 0871 402817 E-mail: [email protected]