Temporality of heparin-induced antibodies: a retrospective study in outpatients undergoing hemodialysis on unfractionated heparin

Abstract

Background: Heparin-induced antibodies (HIA) are responsible for causing heparin-induced thrombocytopenia and thrombosis. Research has shown that the temporality of heparin-induced antibodies does not follow the classic immunologic response. The immunobiology of HIA generation remains unclear with varying in vitro and in vivo data. Outpatients undergoing hemodialysis (HD) are exposed to heparin chronically. The HIA immune response can therefore be investigated in vivo in this population.

Methods: We examined the time between the start of HD using unfractionated heparin and HIA levels in 212 outpatients during a 6-year period. Antibodies were detected on enzyme-linked immunosorbent assay. HIA levels were analyzed to determine significance of the trend over time. HIA subgroups were also analyzed for correlation with subsequent thrombotic events and platelet count during follow up.

Results: Overall, the HIA response in HD was found to peak early with waning antibody response despite continued exposure to heparin. The peak prevalence of a strong immune response (optical density > 1.000) was early and short lived, while weaker immune response (optical density 0.400-1.000) persisted for the first 6 months then declined. The mean follow-up time per patient was 2.3 ± 1.4 years. Despite circulating HIA, including high titers, no patients developed HIT in this sample. There was no association between HIA and thrombocytopenia. There was increased incidence of thrombosis in patients with strong HIA compared to other groups, but this did not achieve statistical significance.

Conclusions: The data suggest a significant temporal pattern of HIA in outpatients undergoing HD using unfractionated heparin. Positive HIA was not found to be significantly associated with thrombocytopenia or thrombosis risk in these patients. However, while not achieving statistical significance, subsequent thrombotic events occurred most frequently in the strong positive HIA group (optical density > 1.000). Further research into HIA and risk of thrombosis in this population is needed.

Keywords: Antibodies; HIT; Hemodialysis; Heparin; Thrombocytopenia; Thrombosis.

Fig. 1

Distribution of HIA in chronic hemodialysis using unfractionated heparin. The antibody responses demonstrate continuous unimodal distribution skewed to the right with high OD outliers

Fig. 2

Temporality of positive HIA in hemodialysis using UFH. Anti-PF4/heparin antibodies are produced along a continuum, but there is waning of the immune response with increased time on hemodialysis. The strongest antibody generation is within the first 6 months

Fig. 3

Plot of all HIA levels (OD) stratified by time and compared for significance. The box plots show the 25th percentile to the 75th percentile, with the midline representing the median and separating the two quartiles. The first whisker (below) shows the lowest 25%; while the second whisker (upper) shows the top 25%, excluding outliers. The mean OD is denoted by the “X” marker. Outliers are designated by values greater than 1.5 times the interquartile range. A significant decline in OD was noted after 6 months