In recent years, diagnostic tests for ADAMTS-13 and respective autoantibodies became available and are routinely used to support thrombotic thrombocytopenic purpura (TTP) diagnosis and therapy. ADAMTS-13 abnormalities have also been described in other pathological situations such as liver cirrhosis (Uemura, 2008), sepsis- induced DIC (Ono, 2006) or inflammatory bowel disease (Feys, 2009), where the relationship between ADAMTS13 parameters and state of disease is less clear than in TTP.
A clear-cut distinction between normal and pathologic levels of ADAMTS-13 parameters (activity, antigen and autoantibodies) is only available in most TTP, with ADAMTS-13 activity levels < 10% and antibody titers well above normal levels. Pathological ranges for other diseases are not yet well defined. As normal ranges for ADAMTS-13 levels seem to be very broad, differentiation between normal and pathologic levels in cases other than TTP will depend on the size of the population used to establish the normal range and presumably also on age, gender, and likely also on other parameters present in this population.
The aim of this study was therefore to establish normal values for ADAMTS-13 parameters by analyzing normal populations in five different European laboratories using the same commercial assays.
ADAMTS-13 autoantibodies were measured using the TECHNOZYM®ADAMTS-13 INH ELISA (anti-IgG). ADAMTS-13 activity and antigen concentrations were measured using TECHNOZYM®ADAMTS-13 ELISA, a combined assay for activity and antigen. Samples were frozen citrated plasma samples used in the respective laboratories as normal controls (approximately 40 in each laboratory; all together 193 normal controls).
The normal range for anti-ADAMTS-13 IgG was compared between the 5 different labs. For ADAMTS-13 INH, the median in these different populations varied between 6 and 9 U/ml which is well below the previously defined borderline value of 12 – 15 U/ml in this assay. The median for all samples was 6.7 U/ml; the number of “false-positives” (>15U/ml) varied from 5 to 10%. To analyze a possible age dependency, three groups were considered : <30 y.o., 31-50 y.o. and >50 y.o. No age dependent differences between these groups could be found (p>0.6). No significant differences were either found between male and female controls (p=0.55). For ADAMTS-13 activity and antigen only data from 140 normal subjects and 60 TTP patients are currently available. For normal subjects, the median for ADAMTS-13 activity was 103%, for antigen 101%. Both parameters showed a wide distribution of values between 53% and 205% for activity and 34% and 217% for antigen. In comparison, the median values in TTP patients were significantly lower (activity 12%, antigen 49%).
We can show that a substantial variation in normal values for ADAMTS-13 activity and antigen exists in normal subjects, while the range for ADAMTS-13 autoantibodies is rather narrow. All values in normal subjects are well separated from those obtained in TTP patients. The broad range of ADAMTS-13 activity and antigen in normal subjects has to be considered when these parameters are measured in diseases other than TTP.
Geiter:Technoclone GmbH: Employment. Graf:Technoclone GmbH: Employment. Tschokert:Technoclone GmbH: Employment. Vetr:Technoclone GmbH: Employment.
Asterisk with author names denotes non-ASH members.