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C5b-9 and MASP2 deposition in skin and bone marrow microvasculature characterize hematopoietic stem cell transplant-associated thrombotic microangiopathy

Bone Marrow Transplantation volume 57, pages 1445–1447 (2022)Cite this article

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Thrombotic microangiopathies (TMA) complicate 3–30% of allogeneic hematopoietic stem cell transplants (alloHSCT) in adults and children [1, 2]. Lack of uniform diagnostic criteria and validated biomarkers for a transplant associated (TA)-TMA may account for the wide disparity in published incidence and survival rates. Complement involvement in those TA-TMAs accompanied by persistent organ, particularly renal, dysfunction, has been established utilizing multiple methods in pediatric cohorts [3]. The anti-complement C5 monoclonal antibody (mAb) eculizumab has markedly improved response rates and survival in those individuals, although these were single center, non-randomized studies [4]. But association of complement with TA-TMAs in adults is less clear. In a previous report we confirmed the elevation of terminal complement pathway membrane attack complex sC5b-9 in plasmas of adults with TA-TMA vs. healthy controls [5], as initially documented in pediatric TA-TMA [3], and extended that observation to changes in levels of the lectin pathway of complement enzyme MBL-associated serine protease 2 (MASP2) [5]. However, we failed to find an association between sC5b-9 or MASP2 levels in adult TA-TMA patients vs. alloHSCT patients without TMA [5]. Indeed, a recent study found no link between TA-TMA and sC5b-9 levels until 2–6 weeks after TMA development [6], and though another study did link sC5b-9 levels to TA-TMA recognition, longitudinal specimens were not available to assess their predictive value [7]. We hypothesize that assessment of complement deposition in the microvasculature of easily accessible tissues such as bone marrow and skin could help identify individuals with persistent TA-TMAs.

This prospective, observational study was approved by the Weill Cornell Institutional Review Board and registered with the National Clinical Trials network (NCT02604420). Informed consent was obtained from all subjects. Inclusion criteria for a TA-TMA consisted of five peripheral markers: microangiopathic changes, based upon a persistent increase over baseline of peripheral schistocytes; serum lactate dehydrogenase levels exceeding the upper limit of normal; haptoglobin levels <50 mg/dL; de novo thrombocytopenia, based on a platelet count <50 ×109/L or a ≥ 25% decrease from baseline; absence of disseminated intravascular coagulation (DIC); and a negative direct Coombs test. TA-TMA patients were then sub-divided into two categories based on presence or absence of acute kidney injury (AKI), as recognized by an increase in serum creatinine over baseline. Per protocol, it was recommended that calcineurin inhibitors (CNI) and mTOR inhibitors (mTORi) be held upon TMA diagnosis, and glucocorticoids and mycophenolate mofetil substituted. At baseline, defined as between the time of consent and the beginning of the conditioning regimen (within days -14 to 0 of transplant), at each regularly scheduled visit post-transplant—day 28 ± 5 days; day 100 ± 28 days; day 180 ± 28 days; and day 365 ± 28 days—and at the time of development of a TMA, the following studies were performed: complete blood count; red cell morphology; standard metabolic and hepatic function panels; and bone marrow aspirate and biopsy.

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Fig. 1: Description of alloHSCT subjects and documentation of complement deposition in cutaneous and bone marrow microvasculature in those with and without TMA.

Data availability

Data used and/or analyzed during this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Daniel Greenberg, Sharon Barouk-Fox, Paula Bertram, Beatriz Lorenzo, Levi Y. Elhadad, and Yuzhou Zhang in the laboratory of Dr. Richard Smith of the University of Iowa for expert technical work. This work was supported by funds from: Omeros (JL), Jazz Pharmaceuticals (JL), and the NIH (RO1 HL148123 and HL123605 (JA), and R01 GM099111 (JPA.) and U54 HL112303 (JPA and EDOR)).

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Author notes

  1. John Chapin

    Present address: CRISPR Therapeutics, Cambridge, MA, USA

  2. Lizamarie Bachier Rodriguez

    Present address: Montefiore Medical Center, New York, NY, USA

  3. Usama Gerghis

    Present address: Thomas Jefferson University Hospital, Philadelphia, PA, USA

Authors and Affiliations

  1. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY, USA

    Sonia Elhadad, Koen Van Besien, Hunter Terry, June Greenberg, Whitney Reid, John Chapin, Dennis Copertino, Sahar Geramfard, Lizamarie Bachier Rodriguez, Nina Orfali, Usama Gerghis, Tsiporah Shore, Sebastian Mayer & Jeffrey Laurence

  2. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

    Amy Chadburn & Cynthia Magro

  3. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA

    Elisha D. O. Roberson

  4. Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA

    John P. Atkinson

  5. Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Jasimuddin Ahamed

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Contributions

JL conceived the study and wrote the paper. SE, KVB, AC, EDOR, EO, and JPA edited the manuscript and provided important insights. JPA and EDOR performed the genetic analyses. CM performed the skin biopsy analyses. AC performed the bone marrow analyses. SE, DC, SG, and JA performed select studies, provided insights and help edit the manuscript. SE, DC, and SG did the statistical analyses. WR, JG, and JC coordinated patient studies. LBR, UG, SM, and TS treated these patients and obtained the blood and bone marrow aspirate samples.

Corresponding author

Correspondence to Jeffrey Laurence.

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Competing interests

JL has received a research grant and JL and UG have received speaker fees from Alexion. JL and SM have current research grants from Omeros, Inc., and JL from Jazz Pharmaceuticals. These entities did not have input in the study design, analysis, manuscript preparation, or decision to submit for publication. The remaining authors declare no competing financial interests.

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Elhadad, S., Chadburn, A., Magro, C. et al. C5b-9 and MASP2 deposition in skin and bone marrow microvasculature characterize hematopoietic stem cell transplant-associated thrombotic microangiopathy. Bone Marrow Transplant 57, 1445–1447 (2022). https://doi.org/10.1038/s41409-022-01723-5

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