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Thromb Haemost 2019; 119(09): 1433-1440
DOI: 10.1055/s-0039-1692721
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Linking Complement Activation, Coagulation, and Neutrophils in Transplant-Associated Thrombotic Microangiopathy

Eleni Gavriilaki
1   Department of Hematology, BMT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
,
Akrivi Chrysanthopoulou
2   Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece
,
Ioanna Sakellari
1   Department of Hematology, BMT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
,
Ioannis Batsis
1   Department of Hematology, BMT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
,
Despina Mallouri
1   Department of Hematology, BMT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
,
Tasoula Touloumenidou
1   Department of Hematology, BMT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
,
Apostolia Papalexandri
1   Department of Hematology, BMT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
,
Alexandros Mitsios
2   Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece
,
Athanasios Arampatzioglou
2   Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece
,
Konstantinos Ritis
2   Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece
,
Robert Alan Brodsky
3   Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
,
Ioannis Mitroulis   *
2   Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece
4   Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
5   National Center for Tumor Diseases, Partner Site Dresden, of the German Cancer Research Center, Heidelberg and of the Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and of the Helmholtz Association/Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
,
Achilles Anagnostopoulos   *
1   Department of Hematology, BMT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
› Institutsangaben Funding E.G. was supported by the European Hematology Association Clinical Research Grant 2016. I.M. and A.C. were supported by BMBF/GSRT German-Greek Bilateral Research and Innovation Program, “BRIDGING,” grant no. T2DGED-0101. I.M. was supported by the National Center for Tumor Diseases, Dresden, Germany.
Weitere Informationen

Publikationsverlauf

05. Januar 2019

14. Mai 2019

Publikationsdatum:
02. Juli 2019 (online)

    Lizenzen und Reprints

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe and life-threatening complication of hematopoietic cell transplantation (HCT) that often coincides with graft-versus-host-disease (GVHD). Although endothelial damage seems to be the common denominator for both disorders, the role of complement system, neutrophils, and coagulation has not been clarified. In an effort to distinguish the pathogenesis of TA-TMA from GVHD, we evaluated markers of complement activation, neutrophil extracellular trap (NET) release, endothelial damage, and activation of coagulation cascade in the circulation of patients with these two disorders, as well as control HCT recipients without TA-TMA or GVHD. We observed that the terminal complement product C5b-9 levels, the levels of markers of NET formation, and thrombin–antithrombin complex levels were significantly increased in the TA-TMA group compared with patients without complications, whereas there was no significant difference between the GVHD and the control group. On the other hand, the levels of circulating thrombomodulin, an endothelial damage marker, were significantly increased in both TA-TMA and GVHD patients. These findings propose a role for the interplay between complement system, neutrophil activation through NET release, and activation of the coagulation cascade in TA-TMA.

Keywords

thrombotic microangiopathy - hematopoietic cell transplantation - graft-versus-host disease - complement - neutrophil extracellular traps

Authors' Contributions

E.G., K.R., R.A.B., I.M., and A.c.A were responsible for the study conception and design. E.G., I.S., I.B., and D.M. recruited study participants and collected clinical data. A.C., A.A., T.T., A.P., A.M., and A.l.A performed experiments and acquired data. E.G. and I.M. analyzed and interpreted the data. E.G., A.C., K.R., R.A.B., I.M., and A.c.A drafted the manuscript and performed critical revisions. All authors approved the final version of the manuscript.


* These authors share equal contribution.


Supplementary Material

 

  • References

  • 1 Gavriilaki E, Sakellari I, Batsis I. , et al. Transplant-associated thrombotic microangiopathy: Incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation. Clin Transplant 2018; 32 (09) e13371
    CrossrefPubMedGoogle Scholar
  • 2 Kraft S, Bollinger N, Bodenmann B. , et al. High mortality in hematopoietic stem cell transplant-associated thrombotic microangiopathy with and without concomitant acute graft-versus-host disease. Bone Marrow Transplant 2019; 54 (04) 540-548
    CrossrefPubMedGoogle Scholar
  • 3 Jodele S. Complement in pathophysiology and treatment of transplant-associated thrombotic microangiopathies. Semin Hematol 2018; 55 (03) 159-166
    CrossrefPubMedGoogle Scholar
  • 4 Jodele S, Zhang K, Zou F. , et al. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood 2016; 127 (08) 989-996
    CrossrefPubMedGoogle Scholar
  • 5 Jodele S, Licht C, Goebel J. , et al. Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood 2013; 122 (12) 2003-2007
    PubMedGoogle Scholar
  • 6 Brodsky RA. Complement in hemolytic anemia. Blood 2015; 126 (22) 2459-2465
    PubMedGoogle Scholar
  • 7 Vasu S, Wu H, Satoskar A. , et al. Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy. Bone Marrow Transplant 2016; 51 (09) 1241-1244
    CrossrefPubMedGoogle Scholar
  • 8 Bohl SR, Kuchenbauer F, von Harsdorf S. , et al. Thrombotic Microangiopathy after allogeneic stem cell transplantation: a comparison of eculizumab therapy and conventional therapy. Biol Blood Marrow Transplant 2017; 23 (12) 2172-2177
    CrossrefPubMedGoogle Scholar
  • 9 de Fontbrune FS, Galambrun C, Sirvent A. , et al. Use of eculizumab in patients with allogeneic stem cell transplant-associated thrombotic microangiopathy: a study from the SFGM-TC. Transplantation 2015; 99 (09) 1953-1959
    CrossrefPubMedGoogle Scholar
  • 10 Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant 2011; 46 (12) 1495-1502
    CrossrefPubMedGoogle Scholar
  • 11 Jodele S, Laskin BL, Dandoy CE. , et al. A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev 2015; 29 (03) 191-204
    CrossrefPubMedGoogle Scholar
  • 12 Zeigler ZR, Rosenfeld CS, Andrews III DF. , et al. Plasma von Willebrand factor antigen (vWF:AG) and thrombomodulin (TM) levels in adult thrombotic thrombocytopenic purpura/hemolytic uremic syndromes (TTP/HUS) and bone marrow transplant-associated thrombotic microangiopathy (BMT-TM). Am J Hematol 1996; 53 (04) 213-220
    CrossrefPubMedGoogle Scholar
  • 13 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 (09) 977-982
    CrossrefPubMedGoogle Scholar
  • 14 Salat C, Holler E, Kolb HJ, Pihusch R, Reinhardt B, Hiller E. Endothelial cell markers in bone marrow transplant recipients with and without acute graft-versus-host disease. Bone Marrow Transplant 1997; 19 (09) 909-914
    CrossrefPubMedGoogle Scholar
  • 15 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
    CrossrefPubMedGoogle Scholar
  • 16 von Brühl M-L, Stark K, Steinhart A. , et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
    CrossrefPubMedGoogle Scholar
  • 17 Kambas K, Chrysanthopoulou A, Vassilopoulos D. , et al. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease. Ann Rheum Dis 2014; 73 (10) 1854-1863
    CrossrefPubMedGoogle Scholar
  • 18 Massberg S, Grahl L, von Bruehl M-L. , et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16 (08) 887-896
    CrossrefPubMedGoogle Scholar
  • 19 Gloude NJ, Khandelwal P, Luebbering N. , et al. Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD. Blood 2017; 130 (10) 1259-1266
    CrossrefPubMedGoogle Scholar
  • 20 Arai Y, Yamashita K, Mizugishi K. , et al. Serum neutrophil extracellular trap levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19 (12) 1683-1689
    CrossrefPubMedGoogle Scholar
  • 21 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123 (18) 2768-2776
    CrossrefPubMedGoogle Scholar
  • 22 Fuchs TA, Kremer Hovinga JA, Schatzberg D, Wagner DD, Lämmle B. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood 2012; 120 (06) 1157-1164
    PubMedGoogle Scholar
  • 23 Sakellari I, Gavriilaki E, Chatziioannou K. , et al. Long-term outcomes of total body irradiation plus cyclophosphamide versus busulfan plus cyclophosphamide as conditioning regimen for acute lymphoblastic leukemia: a comparative study. Ann Hematol 2018; 97 (10) 1987-1994
    CrossrefPubMedGoogle Scholar
  • 24 Sakellari I, Batsis I, Bousiou Z. , et al. The role of low-dose anti-thymocyte globulin as standard prophylaxis in mismatched and matched unrelated hematopoietic peripheral stem cell transplantation for hematologic malignancies. Clin Lymphoma Myeloma Leuk 2017; 17 (10) 658-666
    CrossrefPubMedGoogle Scholar
  • 25 Przepiorka D, Weisdorf D, Martin P. , et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15 (06) 825-828
    PubMedGoogle Scholar
  • 26 Flowers ME, Kansu E, Sullivan KM. Pathophysiology and treatment of graft-versus-host disease. Hematol Oncol Clin North Am 1999; 13 (05) 1091-1112
    CrossrefPubMedGoogle Scholar
  • 27 Ruutu T, Barosi G, Benjamin RJ. , et al; European Group for Blood and Marrow Transplantation; European LeukemiaNet. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica 2007; 92 (01) 95-100
    CrossrefPubMedGoogle Scholar
  • 28 Vaught AJ, Gavriilaki E, Hueppchen N. , et al. Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome. Exp Hematol 2016; 44 (05) 390-398
    CrossrefPubMedGoogle Scholar
  • 29 Gavriilaki E, Yuan X, Ye Z. , et al. Modified Ham test for atypical hemolytic uremic syndrome. Blood 2015; 125 (23) 3637-3646
    CrossrefPubMedGoogle Scholar
  • 30 Raftery MJ, Lalwani P, Krautkrӓmer E. , et al. β2 integrin mediates hantavirus-induced release of neutrophil extracellular traps. J Exp Med 2014; 211 (07) 1485-1497
    CrossrefPubMedGoogle Scholar
  • 31 Caudrillier A, Kessenbrock K, Gilliss BM. , et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. The Journal of clinical investigation 2012; 122 (07) 2661-2771
    CrossrefPubMedGoogle Scholar
  • 32 Merrill SA, Brodsky RA. Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria. Hematology (Am Soc Hematol Educ Program) 2018; 2018 (01) 371-376
    CrossrefPubMedGoogle Scholar
  • 33 Shayani S, Palmer J, Stiller T. , et al. Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant 2013; 19 (02) 298-304
    CrossrefPubMedGoogle Scholar
  • 34 Nakamae H, Yamane T, Hasegawa T. , et al. Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation. Am J Hematol 2006; 81 (07) 525-531
    CrossrefPubMedGoogle Scholar
  • 35 Cutler C, Henry NL, Magee C. , et al. Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11 (07) 551-557
    CrossrefPubMedGoogle Scholar
  • 36 Ma Q, Li D, Nurieva R. , et al. Reduced graft-versus-host disease in C3-deficient mice is associated with decreased donor Th1/Th17 differentiation. Biol Blood Marrow Transplant 2012; 18 (08) 1174-1181
    CrossrefPubMedGoogle Scholar
  • 37 Cravedi P, Leventhal J, Lakhani P, Ward SC, Donovan MJ, Heeger PS. Immune cell-derived C3a and C5a costimulate human T cell alloimmunity. Am J Transplant 2013; 13 (10) 2530-2539
    CrossrefPubMedGoogle Scholar
  • 38 Kwan W-H, Hashimoto D, Paz-Artal E. , et al. Antigen-presenting cell-derived complement modulates graft-versus-host disease. J Clin Invest 2012; 122 (06) 2234-2238
    CrossrefPubMedGoogle Scholar
  • 39 Grkovic L, Baird K, Steinberg SM. , et al. Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity. Leukemia 2012; 26 (04) 633-643
    CrossrefPubMedGoogle Scholar
  • 40 Scambi C, La Verde V, De Franceschi L. , et al. Comparative proteomic analysis of serum from patients with systemic sclerosis and sclerodermatous GVHD. Evidence of defective function of factor H. PLoS One 2010; 5 (08) e12162
    CrossrefPubMedGoogle Scholar
  • 41 Cumpelik A, Gerossier E, Jin J. , et al. Mechanism of platelet activation and hypercoagulability by antithymocyte globulins (ATG). Am J Transplant 2015; 15 (10) 2588-2601
    CrossrefPubMedGoogle Scholar
  • 42 Horváth O, Kállay K, Csuka D. , et al. Early increase in complement terminal pathway activation marker sC5b-9 is predictive for the development of thrombotic microangiopathy after stem cell transplantation. Biol Blood Marrow Transplant 2018; 24 (05) 989-996
    CrossrefPubMedGoogle Scholar
  • 43 Rotz SJ, Luebbering N, Dixon BP. , et al. In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy. Blood Adv 2017; 1 (20) 1632-1634
    CrossrefPubMedGoogle Scholar
  • 44 Kennedy GA, Bleakley S, Butler J, Mudie K, Kearey N, Durrant S. Posttransplant thrombotic microangiopathy: sensitivity of proposed new diagnostic criteria. Transfusion 2009; 49 (09) 1884-1889
    CrossrefPubMedGoogle Scholar
  • 45 de Bont CM, Boelens WC, Pruijn GJM. NETosis, complement, and coagulation: a triangular relationship. Cell Mol Immunol 2019; 16 (01) 19-27
    Google Scholar
  • 46 Huang Y-M, Wang H, Wang C, Chen M, Zhao MH. Promotion of hypercoagulability in antineutrophil cytoplasmic antibody-associated vasculitis by C5a-induced tissue factor-expressing microparticles and neutrophil extracellular traps. Arthritis Rheumatol 2015; 67 (10) 2780-2790
    PubMedGoogle Scholar
  • 47 Wang H, Wang C, Zhao M-H, Chen M. Neutrophil extracellular traps can activate alternative complement pathways. Clin Exp Immunol 2015; 181 (03) 518-527
    CrossrefPubMedGoogle Scholar
  • 48 Guglietta S, Chiavelli A, Zagato E. , et al. Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis. Nat Commun 2016; 7: 11037
    CrossrefPubMedGoogle Scholar