Decreased ADAMTS13 Activity Levels in Patients with a Bleeding Tendency of Unknown Origin

ADAMTS13 (A Disintegrin-like And Metalloproteinase domain with ThromboSpondin type 1 domains) is a 190 kDa glycosylated protein, which cleaves ultra-large vWF multimers, reduces platelet adhesion and aggregation and down regulates thrombus formation and inflammation. This metalloproteinase is synthesized in the liver and the vascular endothelium. Reduction or absence of ADAMTS13 activity is associated with impaired degradation of ultra-large vWF multimers and excessive vWF-induced platelet aggregation on the vascular endothelium, as seen in thrombotic thrombocytopenic purpura (TTP). An imbalance in the size of vWF multimers causes thrombosis in the microvasculature, but has also been reported to be associated with bleeding. No physiological regulative mechanism of ADAMTS13 activity is known so far. Proteolysis of ADAMTS13 in vivo has just been reported in sepsis or a rare case of α2-antiplasmin deficiency, in which plasmin cleaves ADAMTS13, and ADAMTS13 levels in patients with a bleeding tendency has not been investigated so far: This study aimed to investigate ADAMTS13 levels in pediatric and adult patients with a bleeding tendency of unknown origin.

Patients and Methods: 250 white patients [150 children & 100 adults] with a median (min-max) age of 14.0 (0.1–85.0) years [female: 56.4%] with a bleeding tendency of unknown origin and 232 age- and sex-matched healthy controls [130 children & 102 adults], were enrolled at the University of Münster (Germany) and the Department of Medicine I, Division of Hematology and Hemostaseology at the Medical University of Vienna. Patients with established bleeding disorders, such as hemophilia A and B, von Willebrand syndrome, thrombocytopenia or severe platelet function disorders were not included. Further exclusion criteria were abnormal global clotting tests, severe anemia, acute infection/sepsis or liver disease. The investigation was performed according to the Declaration of Helsinki and all participants and/or their parents gave written informed consent before study inclusion. ADAMTS13 activity was determined by ELISA (Technozym®, Technoclone, Vienna, Austria) beyond the acute bleeding episode. Non-parametric statistics were performed for descriptive analysis [median (min-max) values] and inter-group comparisons [Mann-Whitney U test]. Odds ratios [ORs] with corresponding 95% confidence intervals [CIs] were estimated by multivariate analysis using a logistic regression model, adjusted for age at blood sampling, FVIII, vWF antigen and blood group. For all analyses, a two-sided P-value <0.05 was considered as statistically significant.

ADAMTS13 activity levels [%] were significantly lower in patients compared to controls (p<0.001) with median [min-max] levels of 102.1% [36.5–198.0 %] in patients and 114.0% [46.0–201.1 %] in controls. The proportion of ADAMTS13 activity levels below the 25^th percentile was 36.4% [children 33.3%; adults 41%] in patients compared to 23.3% [children 22.3%; adults 24.5%] in the control group [p=0.001]. In multivariate analysis, the association of ADAMTS13 levels <25th percentiles with bleeding of unknown origin was statistically significant after adjustment for age at blood sampling, factor VIII, vWF and ABO-blood groups (OR [95% CI]: 2.0 [1.28–2.95]).

ADAMTS13 activity levels are significantly lower in patients with bleeding of unknown origin compared to healthy controls. The results were consistent in pediatric and adult patients. A possible protective counter-regulation of ADAMTS13 levels to reduce vWF cleavage may be speculated. However, the underlying mechanisms still have to be elucidated.

No relevant conflicts of interest to declare.