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. Disclosures No relevant conflicts of interest to declare.
Background Historically a diagnosis of thrombotic thrombocytopenic purpura (TTP) was made on autopsy. Following the identification of ADAMTS13 deficiency as central to the pathophysiology of TTP, measurement of the enzyme became a vital diagnostic tool. ADAMTS13 activity can be measured using fluorescence resonance energy transfer (FRET), immunoblotting (IB) or enzyme-linked immunosorbent assay (ELISA). However, such assays have traditionally been performed in only a few selective laboratories nationally. ADAMTS13 testing serves as both a diagnostic investigation for those with suspected TTP, as well as a method of monitoring those at risk of relapse. Due to the diversity in local practice, availability, and reporting of both acute and serial ADAMTS13 measurements, it remains unclear as to what constitutes best practice with regards to frequency of testing and how the test can result best support clinical decision making. Aim To review changing trends and patterns in ADAMTS13 testing before and after the set-up of a regional TTP Specialist Centre. To evaluate how this might inform future practice with regards to regional testing provision, patient monitoring and elective Rituximab. Methods This was a retrospective study of ADAMTS13 testing from 2011-18. Data was collected using the Trust electronic laboratory software system, instituted in 2011. The data was reviewed to identify serial trends in testing and in relation to the set-up of a regional TTP Specialist Service provision in 2013. Results A total of 2140 ADAMTS13 activity requests for 464 individual patients were performed between January 2011 and January 2018 using the Technoclone ELISA ADAMTS13 activity assay. A review of the number of ADAMTS13 activity tests performed demonstrated a serial annual rise with total tests per year- 2011: 39, 2012: 88, 2013: 137, 2014: 301, 2015: 401, 2016: 494, 2017: 679. This equated to a 17-fold increase in testing from 2011 compared to 2017, and 5-fold increase from 2013 to 2018 since the set-up of the regional Specialist Service. External referrals for testing constituted 14% of all ADAMTS13 activity requests with a significant 600% rise in all external requests between 2013 and 2018. These included external requests for analysis from 23 different hospital trusts, with the furthest requesting trust being 54 miles from the regional centre. 65% of external requests represented acute referrals with 35% representing monitoring requests for patients receiving shared care between their local hospital and Specialist Centre. Of all internal requests, 82% were from haematology followed by critical care and nephrology. In contrast to external requesting, of the internal requests only 5% were for acute diagnosis compared with 95% of requests made for monitoring purposes. ADAMTS13 activity for monitoring in this patient cohort represented a combination of assessing response to treatment following an acute diagnosis, as well as long term monitoring in remission to identify potential relapse. Internal requests for both acute and monitoring purposes rose annually, with a 20-fold increase in monitoring requests from 2011 to 2017, and a 3-fold increase in acute requests over the same time period. Conclusions ADAMTS13 testing has continued to significantly increase annually suggesting a combination of improved diagnostic awareness and increased disease monitoring. The setup of a regional clinical service including laboratory diagnostics results in a significant increase in acute testing requests serving a wide geographic area. In an era where agents are available to potentially avoid acute relapse, more patients are being monitored using serial ADAMTS13 measurements during follow-up. Although avoiding acute clinical relapse has significant implications for the health service and patient mortality, the economics of serial testing in a condition where the enzyme activity is so unpredictable, remains unclear. There is wide variation globally in ADAMTS13 testing and hence a wider evaluation of current practice and outcomes would not only be valuable in establishing greater consensus on best practice, but also inform us more of the natural history of this condition. Disclosures No relevant conflicts of interest to declare.
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