ADAMTS13 Activity and Autoantibodies Subclasses as Recurrency Risk Predictors In Acquired Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease characterized by acute episodes of thrombocytopenia and microangiopathic hemolytic anemia due to disseminated microvascular thrombosis. Up to 40% of patients with TTP who survive the first acute disease episode develop one or more recurrent episodes. The severe deficiency of the von Willebrand factor (VWF) cleaving protease ADAMTS13 in plasma and the presence of anti-ADAMTS13 autoantibodies during both acute presentation and disease remission are associated with increased risk for recurrence. However, additional markers are needed for an accurate prediction of the risk for recurrent disease. Anti-ADAMTS13 autoantibodies of different immunoglobulin (Ig) subclass, specificity and mechanisms of action have been described in patients with the autoimmune form of TTP.

We sought to determine the relationships between anti-ADAMTS13 Ig subclasses and risk for recurrence in a large cohort of TTP patients.

TTP was defined using commonly accepted criteria (microangiopathic hemolytic anemia, thrombocytopenia and exclusion of alternative explanation for the disease symptoms). Anti-ADAMTS13 IgM, IgA, IgG and IgG1, IgG2, IgG3 and IgG4 subclasses were measured by ELISA in plasma samples obtained from a total of 115 patients with TTP referred to the Milan TTP registry. Plasma samples had been collected during acute disease presentation (n=60), disease remission (n=92) or both (n=37). ADAMTS13 activity and inhibitor were also measured. The levels of different Ig subclasses were compared between two groups of patients with or without recurrence during follow-up. Patients with a follow-up <24 months were excluded from analysis. Statistical analysis was performed using random effect linear regression models.

TTP patients had a median follow-up of 64 months (range 0–399). A total of 11 patients (9.5% of all patients) were followed-up for less than 24 months and excluded from further analysis.

Of patients with a follow-up >24 months, 53 (50%) developed recurrences, whereas 51 did not.

Recurrences occurred at a median of 24 months (45 days to 11 years) after the first episode and were more common in the first three years (n=35, 67%). Comparison of anti-ADAMTS13 Ig subclasses measured during acute disease presentation in TTP patients with recurrence and in patients without recurrence revealed lower levels of IgA (0.017 vs 0.243, p=0.05), IgG1 (0.076 vs 0.234, p=0.01) and IgG3 (0.126 vs 0.385, p=0.002) in recurrent patients, whereas IgG4 were higher in recurrent TTP (0.712 vs 0.289, p<0.0005).

Notably, levels of IgA (random effect, p=0.018), IgG1 (random effect, p=0.005) and IgG3 (random effect, p=0.006) were also associated with lower platelet counts at presentation of acute TTP and IgG3 levels were associated with the number of plasma exchange procedures performed until remission/death.

In TTP patients during remission lower levels of ADAMTS13 antigen (49.3 vs 69.5 p<0.0005) and activity (41.4 vs 75.5 p<0.0005) as well as high levels of anti-ADAMTS13 total IgG (21.93 vs 5.13 p=0.007) were confirmed to be predictors of recurrent disease. Other Ig subclasses, measured during remission were not associated with a history of recurrent TTP.

The logistic analysis showed an odds of relapse of 4.2 (range 1.5–12 p=0.008) at remission in patients with reduced ADAMTS13 and of 4.4 (range 1.7–11.3; p=0.002) in patients with high levels of IgG, but not in the acute phase.

Low values of ADAMTS13 and anti-ADAMTS13 autoantibodies showed and association with a fourfold increase of recurrency risk, while the same result is not confirmed for the acute phase.

Anti-ADAMTS13 IgA, IgG1, 3 and 4 subclasses, measured at acute TTP presentation, showed association with recurrent disease in a retrospective cohort study of TTP patients. Ig subclass measurement might be useful to improve recurrence risk prediction in patients with TTP.

No relevant conflicts of interest to declare.