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 6

Lung injury improved with TM rescue.

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Lung injury improved with TM rescue. (A and B) Acute lung injury by hist...
(A and B) Acute lung injury by histopathology elicited after cell-free hemoglobin challenge was improved with TM rescue at 2 or 24 hours after the challenge (n = 8, 4 male, 4 female at 2 hours per condition; n = 6, 3 male, 3 female at 24 hours per condition; Mann-Whitney U test) (original magnification, ×400). (C) Lung wet-to-dry ratios increased with cell-free hemoglobin challenges and improved with TM rescue (n = 6, 3 male, 3 female per condition at 2 and 24 hours; Mann-Whitney U test). Biomarkers of (D) neutrophil activity (myeloperoxidase [MPO]) and (E and F) inflammation (IL-6, TNF-α) increased after cell-free hemoglobin exposure and were improved with TM rescue in lung lysates from the SCD mice (n = 8, 4 male, 4 female per condition at 2 and 24 hours; 1-way ANOVA). Mice were challenged with cell-free hemoglobin (0.24 g/kg i.v.) and rescued with TM (5 mg/kg s.c. + 1 mg/kg i.v.) under the respective conditions, and samples and tissue were harvested 24 hours after the TM rescue (26 hours for the 2-hour TM rescue and 48 hours for the 24-hour TM rescue after cell-free hemoglobin challenges). Median and IQR values provided in Supplemental Table 2; *P < 0.05, **P < 0.01, ***P < 0.001.