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

Abstract

BackgroundHeparin-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.MethodsWe 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.ResultsOverall, 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.ConclusionsThe 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.

Heparin‐induced thrombocytopenia in end‐stage renal disease: Reliability of the PF4‐heparin ELISA

“…There are few a small, observational studies examining the diagnosis of HIT in ESRD. 9 , 19 , 20 Maharaj et al 9 examined 212 outpatients receiving hemodialysis with UFH as the intracatheter anticoagulant agent over 6 years. This study used an OD of >0.4 as the cutoff for a positive PF4 and classified a “strong” immune response as having an OD ≥ 1.0 and a “weak” immune response as having an OD between 0.4 and 1.0.…”

“…In patients with renal disease, the prevalence of HIT antibodies may overestimate the number of patients with pathogenic antibodies that result in platelet activation and increased risk of thrombosis. 8 , 9 , 10 , 11 While the exact incidence of HIT with thrombosis in ESRD is unknown, one large, observational study determined an incidence of 0.26 per 100 patients in their cohort of 13 682 patients. 12 There is also a chance for a false‐negative SRA with an estimated specificity of 98% and a sensitivity of 95%; therefore, clinical judgment is crucial in determining whether to treat for HIT.…”

“…In addition to the difficulty in diagnosing HIT using validated pretest probability scores in this population, antigen tests may also overestimate the number of patients with confirmed HIT by identifying IgG PF4‐heparin antibodies that are not causing pathologic platelet activation. In patients with renal disease, the prevalence of HIT antibodies may overestimate the number of patients with pathogenic antibodies that result in platelet activation and increased risk of thrombosis 8–11 . While the exact incidence of HIT with thrombosis in ESRD is unknown, one large, observational study determined an incidence of 0.26 per 100 patients in their cohort of 13 682 patients 12 .…”

Anticoagulation in hemodialysis: A narrative review

“…Small, cross‐sectional, and cohort studies have detected subacute HIT (positive antibodies without thrombocytopenia) in 1.3%–35.7% of HD patients 51–57 . The wide variability is attributable to assay technique and dialysis vintage, as there appears to be a strong temporal pattern of antibody seroconversion related to dialysis initiation, wherein titers are highest within the first 6 months of treatment 58 . Outcomes in patients with isolated PF4‐H antibodies reveal no increased risk of thrombosis, 57,59 but increased risk of mortality 55,60–63 .…”

“…[51][52][53][54][55][56][57] The wide variability is attributable to assay technique and dialysis vintage, as there appears to be a strong temporal pattern of antibody seroconversion related to dialysis initiation, wherein titers are highest within the first 6 months of treatment. 58 Outcomes in patients with isolated PF4-H antibodies reveal no increased risk of thrombosis, 57,59 but increased risk of mortality. 55,[60][61][62][63] This mortality effect has been demonstrated with detection of IgG-specific PF4-H antibodies alone and in combination with a platelet serotonin release assay, 60 as well as a dose-response effect in those with highest PF4-H titers.…”