Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-Versus-Tumor Effects

Transplant-associated microangiopathy (TAM) in recipients of allogeneic hematopoietic stem cell transplants

Summary:

We studied occurrence, risk factors and outcome of patients with transplant-associated microangiopathy (TAM) after allogeneic stem cell transplantation (HSCT). A total of 221 consecutive patients were transplanted between 1995 and 2002. TAM is defined as evidence of hemolysis and schistocytes in the first 100 days. Outcomes analyzed included TAM and overall survival. Of 221 patients, 68 had TAM. The cumulative incidence was 31 (25–38)% at 100 days. Patients with TAM had higher LDH, higher bilirubin, higher creatinine and more often neurologic symptoms. TAM was not associated with stem cell source, cyclosporine levels and was not more frequent in recent years. In multivariate analysis, risk factors for TAM included donor type, age, gender, ABO-incompatibility and acute graft-versus-host disease (aGvHD). In patients with TAM, 1-year survival was lower than in patients without TAM (27±18% for TAM with high schistocyte counts; 53±15% for TAM with low schistocyte counts; vs 78±7% in patients without TAM; P<0.0001). TAM was independently associated with mortality adjusting for donor type, age and aGvHD occurrence and severity. TAM is frequent after HSCT and is associated with mortality even after adjustment for aGvHD grade. Risk factors of TAM are similar to aGvHD. TAM may represent endothelial damage driven by donor–host interactions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Uderzo C, Fumagalli M, De Lorenzo P et al. Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation. Bone Marrow Transplant 2000; 26: 1005–1009.

    Article  CAS  PubMed  Google Scholar 

  2. Kanamori H, Maruta A, Sasaki S et al. Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy. Bone Marrow Transplant 1998; 21: 705–709.

    Article  CAS  PubMed  Google Scholar 

  3. Natazuka T, Kajimoto K, Ogawa R et al. Coagulation abnormalities and thrombotic microangiopathy following bone marrow transplantation from HLA-matched unrelated donors in patients with hematological malignancies. Bone Marrow Transplant 1998; 21: 815–819.

    Article  CAS  PubMed  Google Scholar 

  4. Paquette RL, Tran L, Landaw EM . Thrombotic microangiopathy following allogeneic bone marrow transplantation is associated with intensive graft-versus-host disease prophylaxis. Bone Marrow Transplant 1998; 22: 351–357.

    Article  CAS  PubMed  Google Scholar 

  5. Takatsuka H, Takemoto Y, Okamoto T et al. Thrombotic microangiopathy following allogeneic bone marrow transplantation. Bone Marrow Transplant 1999; 24: 303–306.

    Article  CAS  PubMed  Google Scholar 

  6. Roy V, Rizvi MA, Vesely SK, George JN . Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes. Bone Marrow Transplant 2001; 27: 641–646.

    Article  CAS  PubMed  Google Scholar 

  7. Shimoni A, Yeshurun M, Hardan I et al. Thrombotic microangiopathy after allogeneic stem cell transplantation in the era of reduced-intensity conditioning: the incidence is not reduced. Biol Blood Marrow Transplant 2004; 10: 484–493.

    Article  PubMed  Google Scholar 

  8. Ruutu T, Hermans J, Niederwieser D et al. Thrombotic thrombocytopenic purpura after allogeneic stem cell transplantation: a survey of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2002; 118: 1112–1119.

    Article  PubMed  Google Scholar 

  9. Takatsuka H, Wakae T, Mori A et al. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome following allogeneic bone marrow transplantation. Bone Marrow Transplant 2002; 29: 907–911.

    Article  CAS  PubMed  Google Scholar 

  10. George JN, Selby GB . Thrombotic microangiopathy after allogeneic bone marrow transplantation: a pathologic abnormality associated with diverse clinical syndromes. Bone Marrow Transplant 2004; 33: 1073–1074.

    Article  CAS  PubMed  Google Scholar 

  11. Iacopino P, Pucci G, Arcese W et al. Severe thrombotic microangiopathy: an infrequent complication of bone marrow transplantation. Gruppo Italiano Trapianto Midollo Osseo (GITMO). Bone Marrow Transplant 1999; 24: 47–51.

    Article  CAS  PubMed  Google Scholar 

  12. Zeigler ZR, Shadduck RK, Nemunaitis J et al. Bone marrow transplant-associated thrombotic microangiopathy: a case series. Bone Marrow Transplant 1995; 15: 247–253.

    CAS  PubMed  Google Scholar 

  13. Chemnitz J, Fuchs M, Blau W et al. Fatal thrombotic thrombocytopenic purpura as a rare complication following allogeneic stem cell transplantation. Ann Hematol 2000; 79: 527–529.

    Article  CAS  PubMed  Google Scholar 

  14. George JN, Li X, McMinn JR et al. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion 2004; 44: 294–304.

    Article  PubMed  Google Scholar 

  15. Daly AS, Xenocostas A, Lipton JH . Transplantation-associated thrombotic microangiopathy: 22 years later. Bone Marrow Transplant 2002; 30: 709–715.

    Article  CAS  PubMed  Google Scholar 

  16. Fuge R, Bird JM, Fraser A et al. The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation. Br J Haematol 2001; 113: 58–64.

    Article  CAS  PubMed  Google Scholar 

  17. Pettitt AR, Clark RE . Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant 1994; 14: 495–504.

    CAS  PubMed  Google Scholar 

  18. Matsumoto T, Wada H, Nishiyama H et al. Hemostatic abnormalities and changes following bone marrow transplantation. Clin Appl Thromb Hemost 2004; 10: 341–350.

    Article  PubMed  Google Scholar 

  19. Hahn T, Alam AR, Lawrence D et al. Thrombotic microangiopathy after allogeneic blood and marrow transplantation is associated with dose-intensive myeloablative conditioning regimens, unrelated donor, and methylprednisolone T-cell depletion. Transplantation 2004; 78: 1515–1522.

    Article  PubMed  Google Scholar 

  20. Daly AS, Hasegawa WS, Lipton JH et al. Transplantation-associated thrombotic microangiopathy is associated with transplantation from unrelated donors, acute graft-versus-host disease and venoocclusive disease of the liver. Transfus Apheresis Sci 2002; 27: 3–12.

    Article  Google Scholar 

  21. Galbusera M, Noris M, Rossi C et al. Increased fragmentation of von Willebrand factor, due to abnormal cleavage of the subunit, parallels disease activity in recurrent hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and discloses predisposition in families. The Italian Registry of Familial and Recurrent HUS/TTP. Blood 1999; 94: 610–620.

    CAS  PubMed  Google Scholar 

  22. Knovich MA, Craver K, Matulis MD et al. Simplified assay for VWF cleaving protease (ADAMTS13) activity and inhibitor in plasma. Am J Hematol 2004; 76: 286–290.

    Article  CAS  PubMed  Google Scholar 

  23. Moake JL . Thrombotic microangiopathies. N Engl J Med 2002; 347: 589–600.

    Article  CAS  PubMed  Google Scholar 

  24. Remuzzi G, Galbusera M, Noris M et al. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood 2002; 100: 778–785.

    Article  CAS  PubMed  Google Scholar 

  25. van der Plas RM, Schiphorst ME, Huizinga EG et al. von Willebrand factor proteolysis is deficient in classic, but not in bone marrow transplantation-associated thrombotic thrombocytopenic purpura. Blood 1999; 93: 3798–3802.

    CAS  PubMed  Google Scholar 

  26. Furlan M, Robles R, Galbusera M et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339: 1578–1584.

    Article  CAS  PubMed  Google Scholar 

  27. Veyradier A, Obert B, Houllier A et al. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 2001; 98: 1765–1772.

    Article  CAS  PubMed  Google Scholar 

  28. Vesely SK, George JN, Lammle B et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003; 102: 60–68.

    Article  CAS  PubMed  Google Scholar 

  29. Llamas P, Romero R, Cabrera R et al. Management of thrombotic microangiopathy following allogeneic transplantation: what is the role of plasma exchange? Bone Marrow Transplant 1997; 20: 305–306.

    Article  CAS  PubMed  Google Scholar 

  30. Biedermann BC, Sahner S, Gregor M et al. Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft-versus-host disease. Lancet 2002; 359: 2078–2083.

    Article  PubMed  Google Scholar 

  31. Holler E, Kolb HJ, Hiller E et al. Microangiopathy in patients on cyclosporine prophylaxis who developed acute graft-versus-host disease after HLA-identical bone marrow transplantation. Blood 1989; 73: 2018–2024.

    CAS  PubMed  Google Scholar 

  32. Chappell ME, Keeling DM, Prentice HG, Sweny P . Haemolytic uraemic syndrome after bone marrow transplantation: an adverse effect of total body irradiation? Bone Marrow Transplant 1988; 3: 339–347.

    CAS  PubMed  Google Scholar 

  33. Champlin RE, Schmitz N, Horowitz MM et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT). Blood 2000; 95: 3702–3709.

    CAS  PubMed  Google Scholar 

  34. Kondo M, Kojima S, Horibe K et al. Hemolytic uremic syndrome after allogeneic or autologous hematopoietic stem cell transplantation for childhood malignancies. Bone Marrow Transplant 1998; 21: 281–286.

    Article  CAS  PubMed  Google Scholar 

  35. Carlson K, Smedmyr B, Hagberg H et al. Haemolytic uraemic syndrome and renal dysfunction following BEAC (BCNU, etoposide, ara-C, cyclophosphamide) ±TBI and autologous BMT for malignant lymphomas. Bone Marrow Transplant 1993; 11: 205–208.

    CAS  PubMed  Google Scholar 

  36. van der Lelie H, Baars JW, Rodenhuis S et al. Hemolytic uremic syndrome after high dose chemotherapy with autologous stem cell support. Cancer 1995; 76: 2338–2342.

    Article  CAS  PubMed  Google Scholar 

  37. Sarkodee-Adoo C, Sotirescu D, Sensenbrenner L et al. Thrombotic microangiopathy in blood and marrow transplant patients receiving tacrolimus or cyclosporine A. Transfusion 2003; 43: 78–84.

    Article  CAS  PubMed  Google Scholar 

  38. Cutler C, Kim HT, Hochberg E et al. Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2004; 10: 328–336.

    Article  CAS  PubMed  Google Scholar 

  39. Nash RA, Pineiro LA, Storb R et al. FK506 in combination with methotrexate for the prevention of graft-versus-host disease after marrow transplantation from matched unrelated donors. Blood 1996; 88: 3634–3641.

    CAS  PubMed  Google Scholar 

  40. Mbonu CC, Davison DL, El-Jazzar KM, Simon GL . Clostridium difficile colitis associated with hemolytic-uremic syndrome. Am J Kidney Dis 2003; 41: E14.

    Article  PubMed  Google Scholar 

  41. Matsuda Y, Hara J, Osugi Y et al. Serum levels of soluble adhesion molecules in stem cell transplantation-related complications. Bone Marrow Transplant 2001; 27: 977–982.

    Article  CAS  PubMed  Google Scholar 

  42. Dignat-George F, Sampol J, Lip G, Blann AD . Circulating endothelial cells: realities and promises in vascular disorders. Pathophysiol Haemost Thromb 2003; 33: 495–499.

    Article  PubMed  Google Scholar 

  43. Pihusch R, Salat C, Schmidt E et al. Hemostatic complications in bone marrow transplantation: a retrospective analysis of 447 patients. Transplantation 2002; 74: 1303–1309.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J R Passweg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martinez, M., Bucher, C., Stussi, G. et al. Transplant-associated microangiopathy (TAM) in recipients of allogeneic hematopoietic stem cell transplants. Bone Marrow Transplant 36, 993–1000 (2005). https://doi.org/10.1038/sj.bmt.1705160

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705160

Keywords

This article is cited by

Search

Quick links