The Oral, Direct Factor Xa Inhibitor BAY 59-7939 Does Not Cross-React with Anti-Heparin/PF4 (Heparin-Induced Thrombocytopenia) Antibodies.

BAY 59-7939 is an orally bioavailable, small-molecule, direct Factor Xa (FXa) inhibitor in advanced clinical trials for the prevention and treatment of thromboembolic disorders. Unfractionated heparin and the low molecular weight heparins (LMWHs) are the current standards of care for patients requiring anticoagulation. However, their use can be restricted by heparin-induced thrombocytopenia (HIT), which may be associated with severe thrombotic complications. It has been reported previously that fondaparinux, a heparin-derived pentasaccharide that indirectly inhibits FXa, does not cross-react with anti-heparin/PF4 (HIT) antibodies. However, we have shown that increased sulfation of fondaparinux does result in strong cross-reactivity with HIT antibodies, leading to platelet activation/aggregation. Previous studies have shown that direct thrombin inhibitors (DTIs), such as argatroban and lepirudin, do not cross-react with HIT antibodies. Current guidelines for patients who have HIT recommend use of a DTI to prevent or treat associated thrombosis. This study was performed to evaluate whether BAY 59-7939 cross-reacts with HIT antibodies, in order to examine its potential as an alternative anticoagulant for the management of patients with HIT. The effect of BAY 59-7939 on platelet activation mediated by HIT antibodies was examined in sera collected from 63 patients diagnosed with HIT (HIT sera), using platelet aggregation assays, the [¹⁴C]serotonin release assay, and flow cytometry for the detection of platelet P-selectin expression and platelet microparticle formation. Heparin, the LMWH enoxaparin, fondaparinux, and the DTI melagatran were included for comparison. BAY 59-7939 did not activate platelets or cause aggregation with any of the HIT sera tested, establishing that there is no interaction between BAY 59-7939 and HIT antibodies. As expected, heparin strongly activated platelets and caused their aggregation, and gave a positive response with 100% of the HIT sera tested. Enoxaparin showed positive responses with 73% of the sera. Of all the HIT sera tested, one exhibited a weak positive response with fondaparinux. As has been observed with other DTIs, melagatran did not cause any platelet activation or aggregation responses with the HIT sera. This study clearly demonstrates that BAY 59-7939, a novel, orally active, direct FXa inhibitor, does not interact with preformed HIT antibodies. Therefore, BAY 59-7939 has potential as a new option for the prevention and treatment of thrombosis in patients with HIT.