# Zebrafish model reveals developmental and hematopoietic functions of ADAMTS13

## TL;DR

A zebrafish model shows that ADAMTS13 is important for blood vessel development and blood cell balance, beyond its role in preventing blood clots.

## Contribution

The study introduces a zebrafish model to uncover new roles of ADAMTS13 in vascular development and hematopoiesis.

## Key findings

- ADAMTS13 deficiency in zebrafish causes prothrombotic responses and disrupted vascular patterning.
- Loss of ADAMTS13 leads to myeloid expansion and lymphoid depletion in adult hematopoiesis.
- The adamts13i5 zebrafish model recapitulates features of congenital thrombotic thrombocytopenic purpura.

## Abstract

ADAMTS13 is a metalloprotease that cleaves the von Willebrand factor and prevents pathological thrombosis. Severe genetic deficiency of ADAMTS13 causes congenital thrombotic thrombocytopenic purpura, a life-threatening thrombotic microangiopathy. Increasing evidence suggests that ADAMTS13 contributes to physiological processes beyond hemostasis, including vascular development and tissue homeostasis, but these functions remain poorly understood. To address this gap, we generated a transparent, multitransgenic adamts13i5 zebrafish model and began investigating the developmental and disease-related roles of ADAMTS13 in vivo.

The adamts13i5 mutants recapitulated hallmark features of congenital thrombotic thrombocytopenic purpura, including erythrocyte fragmentation and schistocyte formation in adults. In larvae, ADAMTS13 loss unveiled a prothrombotic response to vascular injury, a phenotype masked in patients by thrombocytopenia. Mechanistically, ADAMTS13 deficiency impaired developmental vascular patterning, suppressed vegfa expression, and reduced macrophage number, accompanied by diminished inflammatory and pro-angiogenic signaling. ADAMTS13 loss disrupted hematopoietic homeostasis in adulthood, with myeloid expansion and lymphoid depletion in the kidney marrow. These findings establish ADAMTS13 as a multifaceted regulator of thrombosis, vascular development, inflammation, and hematopoietic lineage specification. The adamts13i5 zebrafish provides a powerful vertebrate model for dissecting the mechanisms of thrombotic thrombocytopenic purpura pathogenesis and identifying therapeutic strategies extending beyond hemostasis.

Summary: This study uses the zebrafish animal model to uncover the developmental roles of ADAMTS13 in vascular patterning and hematopoietic lineage balance.