ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor–Induced Thrombotic Microangiopathy

Abstract

Thrombotic microangiopathy (TMA) is a life-threatening condition that affects some, but not all, recipients of vascular endothelial growth factor (VEGF) inhibitors given as part of chemotherapy. TMA is also a complication of preeclampsia, a disease characterized by excess production of the VEGF-scavenging soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1; sFlt-1). Risk factors for VEGF inhibitor-related TMA remain unknown. We hypothesized that deficiency of the VWF-cleaving ADAMTS13 endopeptidase contributes to the development of VEGF inhibitor-related TMA. ADAMTS13 2/2 mice overexpressing sFlt-1 presented all hallmarks of TMA, including thrombocytopenia, schistocytosis, anemia, and VWF-positive microthrombi in multiple organs. Similar to VEGF inhibitor-related TMA in humans, these mice exhibited severely impaired kidney function and hypertension. In contrast, wild-type mice overexpressing sFlt-1 developed modest hypertension but no other features of TMA. Recombinant ADAMTS13 therapy ameliorated all symptoms of TMA in ADAMTS13 2/2 mice overexpressing sFlt-1 and normalized BP in wild-type mice. ADAMTS13 activity may thus be a critical determinant for the development of TMA secondary to VEGF inhibition. Administration of recombinant ADAMTS13 may serve as a therapeutic approach to treat or prevent thrombotic complications of VEGF inhibition.

Endothelial Dysfunction

“…8,9 ADAMTS13 is a protease that cleaves large vWf multimers that are released from activated endothelial cells, thereby blocking local platelet aggregation and thrombosis. Erpenbeck et al 6 show that overexpression of sFLT-1 in control mice induced mild manifestations of TMAs, which has been previously reported, whereas a lack of ADAMTS13 resulted in no manifestations of TMAs. However, the combination resulted in a lesion that greatly resembled preeclampsia, with thrombocytopenia, hemolytic anemia, glomerular endotheliosis, and marked proteinuria and hypertension.…”

“…Although exciting, the study would have been stronger if Erpenbeck et al 6 had shown this synergy in pregnant mice. In addition, Erpenbeck et al 6 showed the synergy in mice that were null for the ADAMTS13 gene, thereby having no ADAMTS13 activity at all.…”

“…Although exciting, the study would have been stronger if Erpenbeck et al 6 had shown this synergy in pregnant mice. In addition, Erpenbeck et al 6 showed the synergy in mice that were null for the ADAMTS13 gene, thereby having no ADAMTS13 activity at all. Although this is clinically relevant to subjects with hereditary TTP who also have ,10% ADAMTS13 activity, it may or may not be relevant to subjects with preeclampsia who have partial reductions (20%-40%) in ADAMTS13 activity.…”

“…The study by Erpenbeck et al, 6 thus, suggests that a reduction in ADAMTS13 activity might be a synergistic factor to the pathogenesis of preeclampsia. Although exciting, the study would have been stronger if Erpenbeck et al 6 had shown this synergy in pregnant mice.…”

“…In this issue of JASN, Erpenbeck et al 6 investigate the role of ADAMTS13 deficiency as a synergistic factor with sFLT-1 in inducing a preeclampsia-like lesion. sFLT-1 is a circulating inhibitor for vascular endothelial growth factor and placental growth factor that is expressed at high levels in the circulation and placenta of subjects with preeclampsia.…”