Advertisement

Haptoglobin degradation product as a novel serum biomarker for hematopoietic stem cell transplant-associated thrombotic microangiopathy

  • Meredith P. SchuhEmail author
  • Michael R. Bennett
  • Adam Lane
  • Sonata Jodele
  • Benjamin L. Laskin
  • Prasad Devarajan
Original Article

Abstract

Background

Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a well-known complication of HSCT and carries high risk of morbidity and mortality. A lack of consistent non-invasive diagnostic criteria can delay diagnosis and lead to irreversible organ damage.

Methods

Serum samples of 100 patients that underwent HSCT at Cincinnati Children’s Hospital were serially collected. Unbiased proteomic profiling by SELDI-TOF-MS was performed on serum from TA-TMA patients at baseline (pre-HSCT), 2 weeks before TMA diagnosis (pre-TMA), and at clinical TMA diagnosis. Two proteins with mass to charge ratios of 12–13 kDa were consistently elevated at the 2 week pre-TMA time point by SELDI-TOF, compared to control samples. Potential peptides were isolated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the Linear Trap Quadropole (LTQ). A MASCOT search identified haptoglobin fragments in the 12–17-kDa range. Western blot was performed to validate haptoglobin fragments as a potential biomarker.

Results

Western blot of TA-TMA patients showed haptoglobin fragments at 12, 14, and 17 kDa that varied between baseline, pre-TMA, and TMA time points for each patient. By densitometric analysis, the 17-kDa fragment in the pre-TMA samples differed significantly from TMA diagnosis (p < 0.0001). There was no significant difference in the concentrations of the 12-kDa and 14-kDa fragments.

Conclusion

The 17-kDa haptoglobin degradation product may represent a novel early serum biomarker for TA-TMA that could potentially allow for earlier diagnosis and intervention.

Keywords

Thrombotic microangiopathy Hematopoietic stem cell transplant Biomarker Haptoglobin 

Notes

Funding

This study was supported by NIH P50 DK096418.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

This was an analysis of a previously collected, prospective study that was approved by the institutional review board.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Laskin BL, Goebel J, Davies SM, Jodele S (2011) Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood 118:1452–1462CrossRefGoogle Scholar
  2. 2.
    Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, Bleesing J, El-Bietar J, Wallace G, Chima RS, Paff Z, Laskin BL (2014) Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood 124:645–653CrossRefGoogle Scholar
  3. 3.
    Glezerman IG, Jhaveri KD, Watson TH, Edwards AM, Papadopoulos EB, Young JW, Flombaum CD, Jakubowski AA (2010) Chronic kidney disease, thrombotic microangiopathy, and hypertension following T cell-depleted hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 6:976–984CrossRefGoogle Scholar
  4. 4.
    Hoffmeister PA, Hingorani SR, Storer BE, Baker KS, Sanders JE (2010) Hypertension in long-term survivors of pediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant 16:515–524CrossRefGoogle Scholar
  5. 5.
    Hingorani S (2016) Renal complications of hematopoietic-cell transplantation. N Engl J Med 374:2256–2267CrossRefGoogle Scholar
  6. 6.
    Laskin BL, Maisel J, Goebel J, Yin HJ, Luo G, Khoury JC, Davies SM, Jodele S (2013) Renal arteriolar C4d deposition: a novel characteristic of hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Transplantation 96:217–223CrossRefGoogle Scholar
  7. 7.
    Cho BS, Min CK, Eom KS, Kim YJ, Kim HJ, Lee S, Cho SG, Kim Y, Kim DW, Lee JW, Min WS, Kim CC (2008) Clinical impact of thrombotic microangiopathy on the outcome of patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 41:813–820CrossRefGoogle Scholar
  8. 8.
    Tsai HM (2013) Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome. Am J Med 126:200–209CrossRefGoogle Scholar
  9. 9.
    Jodele S, Fukuda T, Vinks A, Mizuno K, Laskin BL, Goebel J, Dixon BP, Teusink A, Pluthero FG, Lu L, Licht C, Davies SM (2014) Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood Marrow Transplant 20:518–525CrossRefGoogle Scholar
  10. 10.
    Jodele S, Laskin BL, Dandoy CE, Myers KC, El-Bietar J, Davies SM, Goebel J, Dixon BP (2014) A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev 29:191–204CrossRefGoogle Scholar
  11. 11.
    Kim SS, Patel M, Yum K, Keyzner A (2015) Hematopoietic stem cell transplant-associated thrombotic microangiopathy: review of pharmacologic treatment options. Transfusion 55:452–458CrossRefGoogle Scholar
  12. 12.
    De Fontbrune FS, Galambrun C, Sirvent A, Huynh A, Faguer S, Nguyen S, Bay JO, Neven B, Moussi J, Simon L, Xhaard A, Resche-Riggon M, O’Meara A, Fremeaux-Bacchi V, Veyradier A, Socié G, Coppo P, de Latour RP (2015) Transplantation 99:953–1959CrossRefGoogle Scholar
  13. 13.
    Khosla J, Yeh AC, Spitzer TR, Dey BR (2017) Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies. Bone Marrow Transplant 53:129–137CrossRefGoogle Scholar
  14. 14.
    Jodele S, Fukuda T, Mizuno K, Vinks AA, Laskin BL, Goebel J, Dixon BP, Chima RS, Hirsch R, Teusink A, Lazear D, Lane A, Myers KC, Dandoy CE, Davies SM (2016) Variable eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 22:307–315CrossRefGoogle Scholar
  15. 15.
    Shih AWY, Mcfarlane A, Verhovsek M (2014) Haptoglobin testing in hemolysis: measurement and interpretation. Am J Hematol 89:443–447CrossRefGoogle Scholar
  16. 16.
    Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS, Park CW (2010) Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation 90:918–926CrossRefGoogle Scholar
  17. 17.
    Uderzo C, Bonanomi S, Busca A, Renoldi M, Ferrari P, Iacobelli M, Morreale G, Lanino E, Annaloro C, Volpe AD, Alessandrino P, Longoni D, Locatelli F, Sangalli H, Rovelli A (2006) Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation 82:638–644CrossRefGoogle Scholar
  18. 18.
    Arredouani M, Matthijs P, Van Hoeyveld E, Kasran A, Baumann H, Ceuppens JL, Stevens E (2003) Haptoglobin directly affects T cells and suppresses T helper cell type 2 cytokine release. Immunology 108:144–151CrossRefGoogle Scholar
  19. 19.
    Wang Y, Kinzie E, Berger FG, Lim SK, Baumann H (2001) Haptoglobin, an inflammation-inducible plasma protein. Redox Rep 6:379–385CrossRefGoogle Scholar
  20. 20.
    Robert L (2013) Serum haptoglobin in clinical biochemistry: change of a paradigm. Pathol Biol 61:277–279CrossRefGoogle Scholar
  21. 21.
    Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, Lane A, Meller J, Medvedovic M, Chen J, Davies SM (2016) The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood 27:989–996CrossRefGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  1. 1.Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical CenterUniversity of CincinnatiCincinnatiUSA
  2. 2.Division of Bone Marrow Transplantation, Cincinnati Children’s Hospital Medical CenterUniversity of CincinnatiCincinnatiUSA
  3. 3.Division of Nephrology, The Children’s Hospital of Philadelphia and the Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations