Involvement of the ADAMTS13-VWF axis in acute Kawasaki disease and effects of intravenous immunoglobulin

Nobuyuki Tsujii; Keiji Nogami; Masanori Matsumoto; Hiroyuki Yoshizawa; Toshio Takase; Ichiro Tanaka; Toshiyuki Sakai; Kazuyoshi Fukuda; Masaki Hayakawa; Kazuya Sakai; Ayami Isonishi; Kayoko Matsuura; Yoshihiro Fujimura; Midori Shima

doi:10.1016/j.thromres.2019.04.026

Involvement of the ADAMTS13-VWF axis in acute Kawasaki disease and effects of intravenous immunoglobulin

Thromb Res. 2019 Jul:179:1-10. doi: 10.1016/j.thromres.2019.04.026. Epub 2019 Apr 24.

Affiliations

¹ Department of Pediatrics, Nara Medical University, Kashihara, Nara 634-8522, Japan.
² Department of Pediatrics, Nara Medical University, Kashihara, Nara 634-8522, Japan. Electronic address: roc-noga@naramed-u.ac.jp.
³ Department of Blood Transfusion Medicine, Nara Medical University, Nara, Japan.
⁴ Pediatrics, Yao Municipal Hospital, Osaka, Japan.
⁵ Pediatrics, Kokuho Central Hospital, Nara, Japan.
⁶ Pediatrics, Saiseikai Chuwa Hospital, Nara, Japan.
⁷ Japanese Red Cross Kinki Block Blood Center, Osaka, Japan.

PMID: 31055186
DOI: 10.1016/j.thromres.2019.04.026

Abstract

Introduction: ADAMTS13 modulates shear-dependent platelet thrombus formation (PTF) by limited proteolysis of von Willebrand factor (VWF). A high-plasma-ratio of VWF antigen to ADAMTS13 activity (VWF:Ag/ADAMTS13:AC) promotes PTF and aggravates shear-induced inflammation mediated by VWF. A role of ADAMTS13 in Kawasaki disease (KD) remains unknown, however. We investigated the involvement of ADAMTS13-VWF axis in the acute-phase of KD (acute-KD).

Methods: VWF:Ag and ADAMTS13:AC in 77 KD infants were measured at three time-points; immediately before (Pre), one-week (1 W) and one-month (1 M) after intravenous-immunoglobulin (IVIG) treatment. VWF multimer (VWFM) distribution and ADAMTS13-isoelectrofocusing (IEF) patterns were compared between the responders and non-responders to IVIG.

Results: A high VWF:Ag (195.7 ± 85.6%, p < 0.05), low ADAMTS13:AC (60.3 ± 23.8%, p < 0.05) and high VWF:Ag/ADAMTS13:AC ratio (3.70 ± 2.12, p < 0.05) at Pre were seen compared to control plasmas. These parameters returned to normal levels time-dependently after IVIG treatment. Non-responders to IVIG demonstrated high VWF:Ag and low ADAMTS13:AC at Pre, and high VWF:Ag/ADAMTS13:AC ratio at 1 W compared to responders, but there were no significant differences in VWFM distribution between both groups. IEF analyses revealed the decreased free form of ADAMTS13 and increased complex form with ADAMTS13 and high-molecular-weight-VWFM at Pre in non-responders. A high VWF:Ag/ADAMTS13:AC ratio was associated with increased white blood cell counts, together with decreased serum albumin and sodium at Pre and 1 W.

Conclusions: A high VWF:Ag/ADAMTS13:AC ratio in acute-KD persisted after primary treatment in non-responders, and unbalanced substrate-to-enzyme ratio appeared to associate with vascular endothelial damage. Analysis of existing mode of ADAMTS13 may help to clarify pathogenesis of IVIG resistance in acute-KD.

Keywords: ADAMTS13; Intravenous immunoglobulin; Isoelectro-focusing analysis; Kawasaki disease; von Willebrand factor.

MeSH terms

ADAMTS13 Protein / blood*
Acute Disease
Aspirin / administration & dosage
Case-Control Studies
Child
Child, Preschool
Female
Humans
Immunoglobulins, Intravenous / administration & dosage*
Infant
Male
Mucocutaneous Lymph Node Syndrome / blood*
Mucocutaneous Lymph Node Syndrome / drug therapy*
Platelet Aggregation Inhibitors / administration & dosage
Signal Transduction / drug effects
von Willebrand Factor / metabolism*

Substances

Immunoglobulins, Intravenous
Platelet Aggregation Inhibitors
von Willebrand Factor
ADAMTS13 Protein
ADAMTS13 protein, human
Aspirin