Thrombomodulin protects against acute vascular and multiorgan injury in sickle cell disease
Guohui Ren, Dustin R. Fraidenburg, Suman Setty, Jiwang Chen, Janae Gonzales, Maria Armila Ruiz, Zalaya Ivy, Najmeh Eskandari, Richard D. Minshall, James P. Lash, Victor R. Gordeuk, Santosh L. Saraf
Guohui Ren, Dustin R. Fraidenburg, Suman Setty, Jiwang Chen, Janae Gonzales, Maria Armila Ruiz, Zalaya Ivy, Najmeh Eskandari, Richard D. Minshall, James P. Lash, Victor R. Gordeuk, Santosh L. Saraf
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Research Article Hematology Nephrology

Thrombomodulin protects against acute vascular and multiorgan injury in sickle cell disease

Abstract

Vaso-occlusive episodes (VOEs) in the setting of hyperhemolysis can rapidly evolve into multiorgan failure in sickle cell disease (SCD). Although the mechanisms for rapid progression to multiorgan failure are unclear, a systemic vasculopathy with thrombotic microangiopathy–type features has been described. Reduced thrombomodulin (TM) function is implicated in some thrombotic microangiopathy syndromes. We observed a greater decline in platelet count and hemoglobin concentration and an increase in vascular injury biomarkers within 24 hours of admission for a VOE in 12 patients with SCD with multiorgan failure versus 12 patients without multiorgan failure. We observed decreased TM expression on the lung and kidney vasculature of 3 additional patients with SCD with multiorgan failure compared with a control patient without SCD. Transgenic SCD mice challenged with cell-free hemoglobin had reduced TM function, increased vascular injury biomarkers, and reduced renal cortical blood flow. Infusion of recombinant TM 2 or 24 hours after the challenge restored cortical blood flow and mitigated increases in vascular injury, complement activation, and tubular injury biomarkers, and protected against acute kidney and lung injury. We demonstrated that impaired TM function may be involved in the systemic vasculopathy of SCD-related multiorgan failure, and infusion of recombinant TM may restore vascular function and protect against acute organ damage.

Authors

Guohui Ren, Dustin R. Fraidenburg, Suman Setty, Jiwang Chen, Janae Gonzales, Maria Armila Ruiz, Zalaya Ivy, Najmeh Eskandari, Richard D. Minshall, James P. Lash, Victor R. Gordeuk, Santosh L. Saraf

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Figure 2

Cell-free hemoglobin reduces TM expression and increases circulating concentrations of soluble TM and neutrophil elastase in SCD mice.

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Cell-free hemoglobin reduces TM expression and increases circulating con...
(A and B) TM expression was reduced in the glomerular endothelium relative to CD31 expression (n = 8; 4 male, 4 female mice per condition) (original magnification, 600×) by the test for linear trend while (C) increased concentrations of soluble TM were released in circulation from control to 26 and 48 hours after cell-free hemoglobin exposure (n = 6; 3 male, 3 female mice per condition; Mann-Whitney U test). (D) Circulating concentrations of neutrophil elastase (ELANE) were increased at 26 hours and trended higher at 48 hours after the cell-free hemoglobin challenge (n = 4; 2 male, 2 female mice per condition; 1-way ANOVA). (E) Administration of sivelestat, an ELANE inhibitor, led to retained TM on the vasculature by fluorescent intensity at 48 hours after cell-free hemoglobin challenge (1-way ANOVA) and (F) reduced soluble TM released into circulation (n = 6; 3 male, 3 female mice per condition; Mann-Whitney U test). Mice were challenged with a cell-free hemoglobin dose of 0.24 g/kg, and samples and tissue were harvested 26 and 48 hours later. Scale bars: 50 μm. *P < 0.05, **P < 0.01.