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Pooled MSCs for treatment of severe hemorrhage

Bone Marrow Transplantation volume 46, pages 1158–1160 (2011)Cite this article

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MSCs have attracted great interest in regenerative medicine because they can differentiate into several tissues of mesenchymal origin, such as bone, cartilage, tendon and cardiomyocytes.1 Infused MSCs improve the outcome of acute renal, neural and lung injury, possibly by promoting a shift from production of proinflammatory cytokines to antiinflammatory cytokines at the site of injury.2, 3 MSCs also have immunomodulatory effects and they reduce alloreactive T-cell responses and mitogenic responses in vitro.4, 5, 6 We investigated the use of MSCs for immunomodulation in patients with acute GVHD of the gastrointestinal tract, liver and skin, and were able to demonstrate MSC donor DNA in the target organ.7 Subsequently, MSCs were also used for tissue toxicity such as hemorrhagic cystitis, pneumomediastinum and perforated colon.8 Responses were seen in half of the patients, although many subsequently died from infection. MSCs reduced alloreactivity in MLCs in vitro equally effectively, irrespective of whether they were autologous or HLA mismatched.5 This has also been confirmed in vivo, in which responses in GVHD were the same regardless of whether the MSCs were HLA identical, HLA haploidentical or HLA mismatched.

Here, we report a patient with myelofibrosis who was treated with MSCs for severe hemorrhage. This 61-year-old male underwent allogeneic hematopoietic SCT from an HLA-A, -B and -DRb1 genomically identical unrelated donor. He received conditioning with fludarabine (30 mg/m2) for 6 consecutive days, followed by BU (4 mg/kg/day) for 2 consecutive days and antithymocyte globulin (5.5 mg/kg). He received a BM graft containing 1.8 × 108 nucleated cells per kg and 1.8 × 106 CD34+ cells per kg. He received CYA and ‘short’ MTX as immunosuppressive treatment. His total WBC count fell below 0.1 × 109 cells per L on day +11. Except for an increase in bilirubin on day +4, thought to be due to hepatotoxicity, his post transplant course was uneventful. On day +12, he started to bleed from the nose and gastrointestinal tract. During the next 5 days, he received in total 17 U of erythrocytes, 7 U of fresh frozen plasma and 12 U of platelets, and had a constant platelet level below 5 × 109 cells per L. Hb level was maintained between 73 and 97 g/L. On day +16, he was also given a G-CSF-mobilized granulocyte transfusion without any increment in neutrophil count. He had constant melena and an abdominal computed tomography scan revealed diffuse hemorrhaging from the proximal jejunum. Owing to previous portal and mesenteric thrombosis, he had undergone surgery, receiving a mesenteric caval shunt in the year 2000 and developing several varicose mesenteric veins. On this occasion, surgery to stop the bleeding was not possible for technical reasons and the platelet levels were <5 × 109 cells per L. He had multispecific anti-HLA antibodies and was refractory to platelets. Because of life-threatening hemorrhage and no other treatment option, MSCs at 2 × 106 cells per kg (pooled from two donors) were given on day +18.

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Acknowledgements

We thank Maivor Hoglund-Lindecrantz for help with data collection and Inger Hammarberg for excellent typing of the paper. The study was supported by grants from the Swedish Cancer Society, the Children's Cancer Foundation, the Swedish Research Council, the Tobias Foundation, the Cancer Society in Stockholm, the Swedish Society of Medicine, the Stockholm County Council, the Sven and Ebba-Christina Hagbergs Foundation and Karolinska Institutet.

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  1. Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet and Karolinska University Hospital, Huddinge, Stockholm, Sweden

    O Ringdén

  2. Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet and Karolinska University Hospital, Huddinge, Stockholm, Sweden

    O Ringdén & K LeBlanc

  3. Hematology Center, Karolinska Institutet and Karolinska University Hospital, Huddinge, Stockholm, Sweden

    K LeBlanc

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  1. O Ringdén
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Correspondence to O Ringdén.

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Ringdén, O., LeBlanc, K. Pooled MSCs for treatment of severe hemorrhage. Bone Marrow Transplant 46, 1158–1160 (2011). https://doi.org/10.1038/bmt.2010.262

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