Critical Analysis of Thrombocytopenia Associated With Glycoprotein IIb/IIIa Inhibitors and Potential Role of Zalunfiban, a Novel Small Molecule Glycoprotein Inhibitor, in Understanding the Mechanism(s)

Thrombocytopenia is a rare but serious complication of the intravenous glycoprotein IIb/IIIa (GPIIb/IIIa; integrin aIIb beta 3) receptor inhibitors (GPIs), abciximab, eptifibatide, and tirofiban. The thrombocytopenia ranges from mild (50 000100 000 platelets/mu L), to severe (20 000 to <50 000/mu L), to profound (<20 000/mu L). Profound thrombocytopenia appears to occur in <1% of patients receiving their first course of therapy. Thrombocytopenia can be either acute (<24 hours) or delayed (up to similar to 14 days). Both hemorrhagic and thrombotic complications have been reported in association with thrombocytopenia. Diagnosis requires exclusion of pseudothrombocytopenia and heparin- induced thrombocytopenia. Therapy based on the severity of thrombocytopenia and symptoms may include drug withdrawals and treatment with steroids, intravenous IgG, and platelet transfusions. Abciximab-associated thrombocytopenia is most common and due to either preformed antibodies or antibodies induced in response to abciximab (delayed). Readministration of abciximab is associated with increased risk of thrombocytopenia. Evidence also supports an immune basis for thrombocytopenia associated with the 2 small molecule GPIs. The latter bind alpha IIb beta 3 like the natural ligands and thus induce the receptor to undergo major conformational changes that potentially create neoepitopes. Thrombocytopenia associated with these drugs is also immune-mediated, with antibodies recognizing the aIIb beta 3 receptor only in the presence of the drug. It is unclear whether the antibody binding depends on the conformational change and whether the drug contributes directly to the epitope. Zalunfiban, a second-generation subcutaneous small molecule GPI, does not induce the conformational changes; therefore, data from studies of zalunfiban will provide information on the contribution of the conformational changes to the development of GPI-associated thrombocytopenia.