Do Immune-Mediated TTP Patients Presenting with No Detectable ADAMTS13 Antibody Represent a Unique Clinical Phenotype?

Background:

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterised by antibody mediated activity against ADAMTS13. Prompt diagnosis and treatment is critical in this rare condition which has an untreated mortality of around 90%. An ADAMTS13 activity level of <10% is consistent with a diagnosis of TTP and for a significant proportion of patients, ADAMTS13 antibodies can also be demonstrated, confirming iTTP. Recent literature suggests that the sub-group of patients with low ADAMTS13 antigen levels and high ADAMTS13 antibody have the highest mortality (Ferras et al., Blood 2017.); however, the sub-group of patients who have never had a detectable inhibitor remain poorly defined. With therapies becoming increasingly available as adjuvants to plasma exchange, in addition to elective agents for suspected relapsing disease, there is a need to better risk stratify this heterogeneous patient group and identify which patients may benefit most from additional therapies. In most literature to date, patients with low ADAMTS13 inhibitor levels have been excluded from further data analysis and therefore remain an under-represented population. Aim: To define the characteristics of the iTTP patient sub-group where an ADAMTS13 inhibitor has never been demonstrated throughout their clinical course Methods: This was retrospective study of data from a single UK TTP tertiary referral centre from 2011 to 2018. Inclusion criteria for patients with iTTP included ADAMTS13 activity ≤10% at acute presentation. Patients with congenital TTP were excluded from data analysis. A positive ADAMTS13 antibody was defined as >12 U/ml using the Technoclone ADAMTS13 inhibitor ELISA assay. Data collected included patient demographics, presenting symptoms, laboratory markers at first presentation, ADAMTS13 activity and antibody and number of relapses. Clinical relapse was defined as reappearance of clinical manifestations or laboratory parameters consistent with acute TTP and serological relapse was defined as ADAMTS13 activity of <15%. Patients with no detectable antibody were compared with a like group of TTP patients with a detectable ADAMTS13 antibody. Results: A total of 61 patients and 72 acute patient episodes were analysed, of which 7 patients had never demonstrated an ADAMTS13 inhibitor in 10 acute episodes. This sub-group was subsequently compared to an equal sample size of patients with a detectable ADAMTS13 antibody and similar demographics. The average antibody level for the antibody negative group was 5.8 U/ml (range 3 - 10 U/ml) compared to 98.7 U/ml (range 37 - 147U/ml) in the antibody positive group. The respective average ADAMTS13 activity was 4.5% (0-10%), compared with 0.3% (0-1%). 100% of the patients in the antibody positive group had neurological symptoms at presentation compared with 43% of the patients with no detectable antibody. The average presenting platelet count and Troponin T for the antibody negative cohort was 27 x 109/L and 21 ng/L respectively; compared with 10 x 109/L and 206 ng/L in the antibody positive group. 43% of patients in the antibody negative group had multiple acute clinical relapses (1-3) compared with 0% patients presenting with a detectable antibody. 14% of the antibody positive group had a serological relapse treated with elective Rituximab compared with 43% of the patients in the antibody negative group. Conclusion: This data specifically reports the apparent characteristics of patients with ADAMTS13 antibody negative iTTP. Up to 10% of patients may never demonstrate an inhibitor against ADAMTS13 and appear to have a less severe clinical presentation with fewer neurological and cardiac manifestations. This study further suggests that this sub-group may represent a more 'grumbling'/ relapsing phenotype with a tendency for more frequent clinical or serological relapse of TTP. Although TTP is rare, further study of this sub-population of iTTP patients is important in risk stratification, and to support treatment decisions, in particular towards preventing future relapse.