Development of non-antithrombin-mediated heparin resistance models using platelet factor 4 and the effect of antithrombin in these models

Abstract

Abstract Background Antithrombin (AT) deficiency is considered to be the primary cause of heparin resistance (HR); however, some patients with HR have normal AT activity (non-AT-mediated HR). Supplementation with concentrated human AT is recommended for patients with AT-deficient HR (AT-mediated HR), whereas treatment has not been established for non-AT-mediated HR. Interestingly, the efficacy of concentrated human AT for non-AT-mediated HR has recently been reported. Therefore, this study aimed to investigate the effect of AT in non-AT-mediated HR by developing experimental models using platelet factor 4 (PF4), a potent heparin inhibitor and potential risk factor for non-AT-mediated HR. Methods Normal human plasma, mice, and whole blood samples were treated with recombinant PF4 (rPF4), heparin, and AT. Coagulation parameters, including activated partial thromboplastin time (APTT) and clotting time (CT) on rotational thromboelastometry, were assessed. In addition, AT activity of the rPF4-containing plasma was measured, and the interaction of rPF4 or AT with heparin was evaluated. Results Treatment with rPF4 shortened APTT and CT prolonged by heparin without reducing AT activity, and AT ameliorated this shortening in a dose-dependent manner. Furthermore, the binding affinity of AT for heparin was weaker than that of rPF4. Conclusions We experimentally verified that AT ameliorated non-AT-mediated HR. The potential mechanism was considered to be via increased absolute numbers of AT-heparin complexes. This report provides evidence for therapeutic strategies for non-AT-mediated HR. Trial registration Not applicable.