Giles Jason B, Martinez Kiana L, Steiner Heidi E, Klein Andrew, Ooi Aikseng, Pryor Julie, Sweitzer Nancy, Fuchs Deborah, Karnes Jason H
Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, 1295 N Martin AVE, Tucson, AZ, 85721, USA.
Cardiovasc Toxicol. 2024 Sep;24(9):968-981. doi: 10.1007/s12012-024-09895-w. Epub 2024 Jul 17.
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD] of 0.93 (SD = 1.21) units, and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody-negative patients. We observed statistical differences between antibody-positive and -negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody-positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including in vitro binding studies and larger observational cohorts.
肝素诱导的血小板减少症（HIT）是一种针对肝素与血小板因子4（PF4）复合物的抗体介导的免疫反应。肝素与PF4之间的静电相互作用对于HIT中所见的抗PF4/肝素抗体反应至关重要。金属阳离子与肝素的结合会诱导肝素分子的构象变化和电荷中和，并且阳离子-肝素结合可以调节对肝素结合伙伴的特异性和亲和力。然而，在抗PF4/肝素抗体反应的背景下，金属阳离子与肝素结合的影响尚未确定。在此，我们利用电感耦合等离子体质谱法（ICP-MS）对患者血浆中的16种金属阳离子进行定量，并在一组接受肝素治疗的患者临床怀疑HIT后，测试其与抗PF4/肝素IgG水平和血小板计数的相关性。该队列（n = 32）的平均年龄为60.53岁（标准差= 14.31），抗PF4/肝素抗体光密度[OD]平均值为0.93（标准差= 1.21）单位，且主要为女性（n = 23）。与抗体阴性患者相比，抗PF4/肝素抗体检测结果为阳性（OD≥0.5单位）的患者更年轻，体重和BMI增加，且血清素释放试验（SRA）结果更可能为阳性。我们观察到抗体阳性和阴性组之间在钠和铝方面存在统计学差异，并且抗PF4/肝素抗体水平与钠和银之间存在显著相关性。虽然钠浓度的差异与抗体阳性状态相关且与抗体水平相关，但未进行重复实验。有必要进行更多研究以证实我们观察到的关联，包括体外结合研究和更大规模的观察性队列研究。
