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Xenotransplants

Porcine hematopoietic cell xenotransplantation in nonhuman primates is complicated by thrombotic microangiopathy

Bone Marrow Transplantation volume 27, pages 1227–1236 (2001)Cite this article

Abstract

Thrombotic microangiopathy (TM) is a serious complication of bone marrow transplantation (BMT) that resembles thrombotic thrombocytopenic purpura (TTP). In attempting to achieve hematopoietic cell chimerism in the pig-to-baboon model, we have observed TM following infusion of high doses (>1010 cells/kg) of porcine peripheral blood mobilized progenitor cells (PBPC) into baboons. We performed investigations to analyze the pathobiology of this TM and to test therapeutic interventions to ameliorate it. PBPC were obtained by leukapheresis of cytokine-stimulated swine. The initial observations were made in two baboons that underwent a non-myeloablative regimen (NMR) prior to PBPC transplantation (TX) (group 1). We then studied three experimental groups. Group 2 (n = 2) received NMR without PBPC TX. Group 3 (n = 2) received PBPC TX alone. Group 4 (n = 6) received NMR + PBPC TX combined with prostacyclin, low-dose heparin, methylprednisolone, and cyclosporine was replaced by anti-CD40L mAb in five cases. Baboons in groups 1 and 3 developed severe thrombocytopenia (<10 000/mm3), intravascular hemolysis with schistocytosis (>10/high powered field (hpf)), increase in plasma lactate dehydrogenase (LDH) (2500–9000 U/l), transient neurologic changes, renal insufficiency, and purpura. Autopsy on two baboons confirmed extensive platelet thrombi in the microcirculation, and, similar to clinical BMT-associated TM/TTP, no unusually large vWF multimers or changes in vWF protease activity were observed in the plasma of baboons with TM. In group 2, self-limited thrombocytopenia occurred for 10–15 days following NMR. Group 4 baboons developed thrombocytopenia (<20 000/mm3) rarely requiring platelet transfusion, minimal schistocytosis (<3/hpf), minor increase in LDH (<1000 U/l), with no clinical sequelae. We conclude that high-dose porcine PBPC infusion into baboons induces a microangiopathic state with vWF biochemical parameters resembling clinical BMT-associated TM/TTP and that administration of antithrombotic and anti-inflammatory agents can ameliorate this complication. Bone Marrow Transplantation (2001) 27, 1227–1236.

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Acknowledgements

We thank Drs J Fishman and T Spitzer for their considerable advice throughout this study, Drs C Ferran and T Spitzer for their review of the manuscript, A Watts, S Treter and K Nash for excellent technical assistance and Mrs Lisa Bernardo for help in manuscript preparation. We also wish to record our gratitude to Ms Stephanie Spaide of Abbott Laboratories for making available additional Omniflow 4000 infusion pumps on several occasions, and to the following companies for generous gifts of their products: Abbot Laboratories (Hetastarch 6%), Baxter Healthcare (Albumin 5%), Novartis Pharmaceuticals (Sandimmune iv), Glaxo-Wellcome (Zantac iv), and Roche Laboratories, Inc. (CellCept iv). This work was supported in part by National Institutes of Health grant No. 5P01 AI39755 and by a Sponsored Research Agreement between the Massachusetts General Hospital and BioTransplant, Inc.

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Author notes

  1. L Bühler and C Goepfert: The first two authors contributed equally to this paper

  2. SC Robson and R Sackstein: The last two authors are joint senior authors

Authors and Affiliations

  1. Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

    L Bühler, M Basker, S Gojo, IPJ Alwayn, DH Sachs & DKC Cooper

  2. Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

    H Kitamura

  3. Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

    R Sackstein

  4. Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA

    C Goepfert & SC Robson

  5. BioTransplant, Inc., Charlestown, MA, USA

    Q Chang & JD Down

  6. Division of Hematology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA

    H Tsai

  7. Department of Hematology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA

    R Wise

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Bühler, L., Goepfert, C., Kitamura, H. et al. Porcine hematopoietic cell xenotransplantation in nonhuman primates is complicated by thrombotic microangiopathy. Bone Marrow Transplant 27, 1227–1236 (2001). https://doi.org/10.1038/sj.bmt.1703067

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