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Mechanisms of vascular permeability in the Systemic Capillary Leak Syndrome (Clarkson disease)

Wednesday, October 10, 2012 — Poster Session II

Noon – 2:00 p.m

Natcher Conference Center, Building 45




  • Z Xie
  • C.C Ghosh
  • R Patel
  • S Iwaki
  • D Gaskins
  • C Nelson
  • N Jones
  • P.R. Greipp
  • S.M. Parikh
  • K.M. Druey


The systemic capillary leak syndrome (SCLS) is an extremely rare disorder characterized by transient episodes of hypotensive shock due to reversible vascular hyper-permeability. Although the high prevalence of monoclonal immunoglobulins (IgG) in SCLS has been reported, mechanisms of SCLS pathogenesis are unknown. Herein, we report clinical and molecular findings on 23 subjects, the largest SCLS case series to date. Application of episodic SCLS sera, but neither purified IgG nor sera obtained from subjects during remission, to human microvascular endothelial cells caused vascular endothelial cadherin (VE-Cad) internalization, disruption of cell-cell adherens junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. Intravenous immunoglobulin (IVIG), one promising therapy for SCLS, mitigated the permeability effect of episodic sera. Two circulating permeability factors, VEGF and Angiopoietin 2 (Ang2), were significantly elevated in episodic SCLS sera. Antibody-based inhibition of Ang2 counteracted permeability induced by episodic sera. Our results support a model of SCLS pathogenesis in which canonical permeability mediators such as VEGF and Angiopoietin 2, but not immunoglobulins, transiently activate pathogenic endothelial contraction pathways, suggesting a molecular mechanism and novel potential targets for this highly lethal disorder.

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