Positive Direct Antiglobulin Test Predicts Development of Chronic Immune Thrombocytopenia and Treatment with Second Line Therapy in Pediatric ITP Patients

Background: ITP is the most common acquired bleeding disorder in children. For many children with ITP, thrombocytopenia resolves spontaneously, however, ~25% of affected children develop chronic ITP, with thrombocytopenia persisting >1 year. The predictors for the development of chronic ITP are not well understood. The direct antiglobulin test (DAT) is frequently tested at the time of ITP presentation to assess for concomitant antibody production against red cell antigens as well as for safety using Rh immune globulin therapy. In 2009, an International Working Group recommended screening DAT in all patients with ITP.

Objective: To identify characteristics that predict clinical course and duration of thrombocytopenia in a cohort of pediatric ITP patients.

Methods: From a multi-institutional pediatric ITP cohort, 186 consecutive patients were identified from July 2015 to July 2017. Characteristics including age, gender, ethnicity, presence of concurrent autoimmune disease, and treatment data were collected. Baseline laboratory investigation included complete blood count and absolute reticulocyte count, immunoglobulin levels, and DAT. A bleeding score at the time of diagnosis was defined using the Buchanan and Adix Bleeding Score. First line therapies were defined as intravenous immunoglobulin (IVIG), Rh immune globulin and/or corticosteroids. Rituximab, thrombopoietin agonists, immunosuppressive agents, and splenectomy were second line agents used in this cohort. The Mann-Whitney U-test was used to compare nonparametric continuous data, while chi-squared test or Fisher's exact test were utilized to compare nonparametric categorical data. A multivariate logistic regression model was conducted to determine independent associations with the development of chronic ITP and the requirement for second line therapy. Statistical analyses were performed using SPSS Statistics 24 (IBM, Armonk, NY). A p<0.05 was defined as statistically significant.

Results: The cohort included patients age 0.2 - 17.7 years at the time of diagnosis with median age of 5 years (IQR: 2.5-10.3 years). Median platelet count at diagnosis was 8 x10⁹/L (IQR: 4-19 x10⁹/L). 48% were male. Primary ITP was diagnosed in 88% of patients. Patients at all stages of ITP were enrolled. 45% had chronic ITP. Univariate analysis identified positive DAT (32.9% vs.15.4, p=0.013) and low IgA (13.9% vs. 4.8%, p=0.052),) to be associated with development of chronic ITP. There was a trend for a presenting platelet count <20 x10⁹/L (69.1% vs. 81.3%, p=0.074) and bleeding score ≥4 (2.8% vs. 11.0%, p=0.051) to be associated with resolution of ITP. Subsequent multivariate analysis identified positive DAT (OR: 3.34, p=0.010) as independently associated with the development of chronic ITP. This finding is independent of presence of Evans syndrome by multivariate analysis. Presenting platelet count <20 x10⁹/L (OR:0.419, p=0.043) was associated with a decreased rate of chronic ITP by multivariate analysis.

Among the 186 patients, 16.5% of patients were treated with second line therapies. A positive DAT (59.6% vs. 15.3%, p<0.001), low IgM (23.0% vs. 7.19%, p=0.012) and bleeding score ≥3 (55.6% vs. 36.5%, p=0.062) were more prevalent in patients treated with second line therapies. Subsequent multivariate analysis identified a positive DAT as independently associated with treatment with second line therapy (OR: 8.57, p<0.001). Additionally, a positive DAT was independently associated with requiring 3 or more modalities of therapy (OR: 4.82, p=0.008).

Conclusions: This study is the first to show that DAT positivity is independently associated with the development of chronic ITP as well as the need for second line treatment. This finding supports the hypothesis that generalized immune dysregulation plays a role in propagating chronic ITP and provides further rationale for the recommendation of routine DAT testing in all newly diagnosed ITP patients.