ADAMTS‐13 and bleeding phenotype in von Willebrand disease

Abstract

Background The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF multimers into smaller, less active multimers, ADAMTS‐13 is an important regulator of VWF activity. However, it is unknown what the role of ADAMTS‐13 is in individuals with VWD. Objectives We therefore studied how ADAMTS‐13 activity is associated with the laboratory and bleeding phenotype in individuals with VWD. Methods We measured ADAMTS‐13 activity using the fluorescence resonance energy transfer substrate VWF 73 assay in 638 individuals with VWD in the nationwide cross‐sectional Willebrand in the Netherlands study and in 36 healthy controls. The bleeding phenotype was assessed using the Tosetto bleeding score. Results ADAMTS‐13 activity was similar in individuals with VWD (109% ± 20.6%) and controls (110% ± 19.7%). ADAMTS‐13 activity was higher in individuals with VWD with type 3 than those with type 1 (mean difference, 11.8%; 95% confidence interval [CI], 2.9%‐20.8%) or type 2 (mean difference, 16.1%; 95% CI, 7.1%‐25.1%). ADAMTS‐13 activity was not associated with the Tosetto bleeding score (0.1 Tosetto bleeding score increase per 10% ADAMTS‐13 increase, 95% CI, −0.2 to 0.3). Furthermore, ADAMTS‐13 activity did not differ between individuals with and without a bleeding event during the year preceding blood sampling (mean difference, 1.4%; 95% CI, −2.1% to 4.9%). Conclusion ADAMTS‐13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS‐13 activity does not influence the bleeding phenotype in individuals with VWD.

Platelet degranulation and bleeding phenotype in a large cohort of Von Willebrand disease patients

“…Intriguingly, we found that type 2A patients with A2 mutations had high PF4 levels, which might indicate a similar interaction in vivo . We did not find an association between ADAMTS13 activity and PF4 levels (data not shown), but the assay for ADAMTS13 activity is not suited to determine how PF4 affects ADAMTS13‐mediated VWF proteolysis 15 . Thus, our data cannot decisively answer if PF4 plays a role in VWF interactions and ADAMTS13‐mediated proteolysis in vivo yet, but suggests this could ultimately be relevant to type 2A patients.…”

Compound heterozygosity for novel von Willebrand factor genetic variants associated with von Willebrand disease in two Chinese patients

“…This cleavage is mediated by ADAMTS 13 [14]. ADAMTS 13 binds and cleaves cell-bound UL-VWF strings at the Tyr 1605 -Met 1606 bond, thereby eliminating the UL-VWF from the endothelial surface and resulting in the fragmentation of the VWF strings, to prevent VWF-induced platelet over-aggregation and thrombosis, thus playing a role in maintaining clotting homeostasis [15]. The mutation of VWF protein at amino acid 1606 in patient 2 may impact the ADAMTS13 cleavage site, which results in an increase in the amount of UL-VWF strings, leading to coagulation dysfunction.…”