Validation of the Use of Apixaban As an Alternate Anticoagulant for the Management of Patients with Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT), an immune mediated disorder due to antibodies generated against platelet factor 4 (PF4) complexed with heparin, is associated with a pronounced hypercoagulable state, thrombin generation, endothelial cell damage, and upregulation of an inflammatory state. Alternative anticoagulants that do not interact with HIT antibodies are needed for the anticoagulant management of these heparin compromised patients. Intravenous use direct thrombin inhibitors (DTIs) such as argatroban and lepirudin became the first effective non-heparin anticoagulant drug treatments for patients with HIT. Although DTIs are effective, their use is associated with a bleeding risk and drug-specific limitations. For the long-term anticoagulation, patients are switched from the intravenous DTI to oral warfarin. Aside from the unpredictable pharmacokinetics and need for routine monitoring, the slow onset of action and potential to precipitate venous limb gangrene/skin necrosis due to inhibition of protein C are concerning aspects of warfarin treatment of patients with HIT. Apixaban is a new small molecule, direct acting oral FXa inhibitor that may be considered for the anticoagulant management of patients with HIT.

In order to determine if there is a lack of functional platelet activation and platelet aggregation for apixaban in the presence of HIT antibodies, the two traditional and widely used clinical laboratory tests for the diagnosis of HIT were utilized: the gold standard ¹⁴C-Serotonin Release Assay (¹⁴C-SRA; using washed platelets) and the heparin-induced platelet aggregation assay (PA-HIT; using platelet rich plasma). Based on different methodologies, these assays have different specificities and sensitivities to HIT antibodies and provide different yet complimentary information. This study employed HIT antibodies from multiple patients and platelets from different donors to assure the robustness of the data outcome. The response to apixaban concentrations covering the clinical dose range (0.05 to 50 mg/mL) was compared to the response obtained with clinically relevant concentrations of unfractionated heparin (UFH; 0.1 and 100 U/mL).

In the ¹⁴C-SRA (n=35) and in the PA-HIT (n=37), only baseline negative platelet activation and aggregation responses with all of the HIT specimens were observed at all apixaban concentrations (average across all concentrations: 11 ± 4 % serotonin release and 8 ± 3 % aggregation, respectively; mean ± SEM; positive responses are >20%). In comparison, UFH gave strong positive responses to each of the same HIT antibody specimen/platelet donor combinations (82 ± 3 % release and 78 ± 6 % aggregation at 0.1 U/mL; p<0.01 vs apixaban). Comparative studies demonstrated strong responses for enoxaparin (n=10; 73 ± 5 % release and 62 ± 7 % aggregation at 10 mg/mL) equal to UFH and no positive response for fondaparinux (n=20) in both test systems.

This study confirms a consistent absence of platelet activation and platelet aggregation with apixaban in the presence of HIT antibodies across a wide range of concentrations. Based on the inert response of apixaban in these in vitro studies and because it is structurally unrelated to heparin, apixaban is not expected to contribute to the propagation of the HIT syndrome and could potentially be used for the anticoagulant management of patients with HIT. Since apixaban is a potent inhibitor of thrombin generation it is expected to have an additional benefit in blunting the hypercoagulable state which is observed in the HIT syndrome. Apixaban may provide an option for oral anticoagulation in patients with HIT both for in-hospital and out-patient settings, for the extended management of heparin compromised patients, and for the prevention of HIT. Clinical trials to determine dosing regimens that provide safe and effective anticoagulation during the various clinical phases of HIT are warranted.

Walenga:Bristol-Myer Squibb: Research Funding. Prechel:Bristol-Myer Suibb: Research Funding. Hoppensteadt:Bristol-Myer Squibb: Research Funding. Escalante:Bristol-Myer Squibb: Research Funding. Chaudhry:Bristol-Myer Squibb: Research Funding. Jeske:Bristol-Myer Squibb: Research Funding. Bakhos:Bristol-Myer Squibb: Research Funding.