Haptoglobin degradation product as a novel serum biomarker for hematopoietic stem cell transplant-associated thrombotic microangiopathy
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.
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.
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.
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.
KeywordsThrombotic microangiopathy Hematopoietic stem cell transplant Biomarker Haptoglobin
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.
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 was obtained from all individual participants included in the study.
- 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.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
- 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
- 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
- 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
- 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.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