Thrombotische Mikroangiopathie nach Stammzelltransplantation

Zusammenfassung

Die Stammzelltransplantation-assoziierte thrombotische Mikroangiopathie (TA-TMA) tritt bei ca. 7% aller Transplantationen auf. Während sie alle Zeichen der idiopathischen TTP oder des HUS aufweist, zeigt die Plasmatherapie kaum Erfolg. Insgesamt versterben mehr als 80% der TA-TMA-Patienten. Der Vergleich von Fallberichten konnte Risikofaktoren für die Entwicklung einer TA-TMA aufdecken und unterschiedliche Varianten der Erkrankung anhand klinischer und labordiagnostischer Parameter sowie der therapeutischen Beeinflussbarkeit definieren. Es wird eine multifaktorielle Ätiologie angenommen, deren zentrale Gemeinsamkeit die Endothelschädigung ist. Das Gerinnungssystem wird durch intensive chemo- und strahlentherapeutische Konditionierungsbehandlung, Infektionen und Graft-versus-host-Reaktion in Verbindung mit der immunsuppressiven Therapie (v. a. Cyclosporin A) in Richtung prokoagulanter Status verschoben. Die bisherigen von der idiopathischen TTP übernommenen Therapieansätze verliefen enttäuschend. Das Absetzen von Cyclosporin ist der einzige Konsens in diesem Zusammenhang. Zukünftige Behandlungsansätze zielen auf Minimierung des Endothelschadens.

Summary

Stem cell transplantation associated microangiopathy (TA-TMA) occurs in about 7% of all transplantations. While it resembles in all its features idiopathic TTP or HUS, response to plasma therapy is poor. The overall mortality of patients afflicted with TA-TMA is about 80%. Comparative studies aimed at discovering risk factors for the development of TA-TMA and defined different entities according to clinical, laboratory and outcome parameters. It is thought to be of multifactorial aetiology with the central event of endothelial damage. Intensive chemotherapy and radiation for bmt-preparation, infection in the immunocompromised host and graft versus host disease in conjunction with immunosuppressive therapy i. e. cyclosporine turn the haemostatic balance into a procoagulant state. Therapeutic strategies deduced from idiopathic TTP were disappointing with the only consensus in the withdrawal of cyclosporine from TA-TMA patients. Future trials are directed to ameliorate endothelial dysfunction.

Schlüsselwörter

Thrombotische Mikroangiopathie - Stammzelltransplantation - Endothelschaden

Keywords

Thrombotic microangiopathy - stem cell transplantation - endothelial dysfunction

• Literatur

• 1 Alessandrino EP, Martinelli G, Canevari A. et al. Prompt response to high-dose intravenous immunoglobulins given as first-line therapy in post-transplant thrombotic thrombocytopenic purpura. Bone Marrow Transplant 2000; 25: 1217-8.
• 2 Alvarez-Larrán A, Petriz J, Martınez A. et al. Plasma from patients with thrombotic thrombocytopenic purpura induces activation of human monocytes and polymorphonuclear neutrophils. Br J Haematol 2003; 120: 129-34.
• 3 Anthony M, Zeigler ZR, Lister J. et al. Plasminogen activator inhibitor (PAI-1) antigen levels in primary TTP and secondary TTP post-bone marrow. Am J Hematol 1998; 59: 9-14.
• 4 Arai S, Carol A, Streiff M. et al. Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy. Hematol J 2001; 2: 292-9.
• 5 Arya M, Anvari B, Romo GM. et al. Ultralarge multimers of vonWillebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers. Blood 2002; 99: 3971-7.
• 6 Atkinson K, Biggs JC, Hayes J. et al. Cyclosporin A associated nephrotoxicity in the first 100 days after allogeneic bone marrow transplantation: three distinct syndromes. Br J Haematol 1983; 54: 59-67.
• 7 Bacigalupo A, Oneto R, Bruno B. et al. Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin. Bone Marrow Transplant 1999; 24: 653-9.
• 8 Bartynski WS, Zeigler Z, Spearman PM. et al. Etiology of cortical and white matter lesions in cyclosporin-A and FK-506 neurotoxicity. Am J Neuroradiol 2001; 22: 1901-14.
• 9 Bearman SI. Avoiding hepatic veno-occlusive disease: what do we know and where are we going?. Bone Marrow Transplant 2001; 27: 1113-20.
• 10 Blackall DP, Uhl L, Spitalnik SL. Cryoprecipitate-reduced plasma:rationale for use and efficacy in the treatment of thrombotic thrombocytopenic purpura. Transfusion 2001; 41: 840-4.
• 11 Bosch T, Cuhmann R, Lennertz A. et al. Therapeutic plasma exchange in patients suffering from thrombotic microangiopathy after allogeneic bone marrow transplantation. Ther Apher 1999; 3: 252-6.
• 12 Brown SA, Davies SV, Fegan C. et al. Haemostatic and fibrinolytic responses to bone marrow transplantation. Br J Haematol 1999; 104: 468-74.
• 13 Bruno B, Gooley T, Sullivan KM. et al. Secondary failure of platelet recovery after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001; 7: 154-62.
• 14 Chappell ME, Keeling DM, Prentice HG. et al. Haemolytic uraemic syndrome after bone marrow transplantion: an adverse effect of total body irradiation?. Bone Marrow Transplant 1988; 3: 339-47.
• 15 Cohen H, Bull HA, Seddon A. et al. Vascular endothelial cell function and ultrastructure in thrombotic microangiopathy following allogeneic bone marrow transplantation. Eur J Haematol 1989; 43: 207-14.
• 16 Cohen JA, Brecher ME, Bandarenko N. Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. J Clin Apheresis 1998; 13: 16-9.
• 17 Coppo P, Adrie C, Azoulay E. et al. Infectious diseases as a trigger in thrombotic microangiopathies in intensive care unit (ICU) patients?. Int Care Med 2003; 29: 564-9.
• 18 Corti P, Uderzo C, Tagliabue A. et al. Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation. Bone Marrow Transplant 2002; 29: 542-3.
• 19 Daly AS, Xenocostas A, Lipton JH. Transplantation-associated thrombotic microangiopathy: twenty-two years later. Bone Marrow Transplant 2002; 30: 709-15.
• 20 De la Rubia J, Plumé G, Arriaga F. et al. Platelet transfusion and thrombotic thrombocytopenic purpura. Transfusion 2002; 42: 1384-5.
• 21 Elliott ME, Nichols JR WL, Plumhoff EA. et al. Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review. Mayo Clin Proc 2003; 78: 421-30.
• 22 Evans G, Llewelyn C, Luddington R. et al. Solvent detergent fresh frozen plasma as primary treatment of acute thrombotic thrombocytopenic purpura. Clin Lab Haem 1999; 21: 119-23.
• 23 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.
• 24 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 (22) 1578-84.
• 25 Furlong T, Storb R, Anasetti C. et al. Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities. Bone Marrow Transplant 2000; 26: 985-91.
• 26 Gharpure VS, Devine SM, Holland HK. et al. Thrombotic thrombocytopenic purpura associated with FK 506 following bone marrow transplantation. Bone Marrow Transplant 1995; 16: 715-6.
• 27 Iacopino P, Pucci G, Arcese W. et al. Severe thrombotic microangiopathy: an infrequent complication of bone marrow transplantation. Bone Marrow Transplant 1999; 24: 47-51.
• 28 Imbert-Marcille BM, Tang XW, Lepelletier AD. et al. Human herpesvirus 6 infection after autologous or allogeneic stem cell transplantation: a single-center prospective longitudinal study of 92 patients. Clin Inf Dis 2000; 31: 881-6.
• 29 Kahan B. Cyclosporine. N Engl J Med 1989; 321 (25) 1725-38.
• 30 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: 705-9.
• 31 Kfoury Baz EM, Mikati ARA, Kanj NA. Reactive hemophagocytic syndrome associated with thrombotic thrombocytopenic purpura during therapeutic plasma exchange. Ther Apher 2002; 6: 159-62.
• 32 Kondo M, Kojima S, Horibe K. et al. Hemolytic uremic syndrome after allogeneic or autologous hematopoetic stem cell transplantation for childhood malignancies. Bone Marrow Transplant 1998; 21: 281-6.
• 33 Lecornu-Heuze L, Ducloux D, Rebibou J-M. et al. Mycophenolate mofetil in cyclosporine-associated thrombotic microangiopathy. Nephrol Dial Transplant 1998; 13: 3212-3.
• 34 Lee JH, Lee KH, Kim S. et al. Relevance of proteins C and S, antithrombin III, von Willebrand factor, and factor VIII for the development of hepatic veno-occlusive disease in patients undergoing allogeneic bone marrow transplantation: a prospective study. Bone Marrow Transplant 1998; 22: 883-8.
• 35 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: 305-6.
• 36 Lugassy G, Ducach A, Blumenthal R. Fatal chronic relapsing thrombotic thrombocytopenic purpura following autologous bone marrow transplantation for chronic myeloid leukemia. Bone Marrow Transplant 1998; 21: 859-60.
• 37 Mannucci PM, Canciani MT, Forza I. et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98: 2730-5.
• 38 Marshall RJ, Sweny P. Haemolytic-uremic syndrome in recipients of bone marrow transplants not treated with cyclosporin A. Histopathology 1986; 10: 953-62.
• 39 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: 977-82.
• 40 Matsuda Y, Hara J, Miyoshi Y. et al. Thrombotic microangiopathy associated with reactivation of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young children. Bone Marrow Transplant 1999; 24: 919-23.
• 41 Mielcarek M, Zaucha JM, Sandmaier B. et al. Type of post-grafting immunosuppression after non-myeloablative blood cell transplantation may influence risk of delayed haemolysis due to minor AB0 incompatibility. Br J Haematol 2002; 116: 500-1.
• 42 Milone J, Napal J, Bordone J. et al. Complete response in severe thrombotic microangiopathy post bone marrow transplantation (BMT-TM) after multiple plasmaphereses. Bone Marrow Transplant 1998; 22: 1019-21.
• 43 Milone J, Napal J, Etchegoyen O. et al. Response: Prompt response to high-dose intravenous immunoglobulins given as first-line therapy in post-transplant thrombotic thrombocytopenic purpura. Bone Marrow Transplant 2000; 25: 1218.
• 44 Mitra D, Jaffe EA, Weksler B. et al. Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome. Plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells. Blood 1997; 89: 1224-34.
• 45 Moake JE. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589-600.
• 46 Mori Y, Wada H, Gabazza EC. et al. Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of von Willebrand factor cleaving protease activity. Transfusion 2002; 42: 572-80.
• 47 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: 815-9.
• 48 Nevo S, Enger C, Hartley E. et al. Acute bleeding and thrombocytopenia after bone marrow transplantation. Bone Marrow Transplant 2001; 27: 65-72.
• 49 Niederwieser D. Workshop Thrombotische Mikroangiopathien. Jena: 9./10. 5. 2003. (persönliche Mitteilung).
• 50 Ohno E, Ohtsuka E, Iwashita T. et al. Hemolytic uremic syndrome following autologous peripheral blood stem cell transplantation in a patient with malignant lymphoma. Bone Marrow Transplant 1997; 19: 1045-7.
• 51 Paquette RL, Tran L, Landaw EM. Thrombotic microangiopathy following allogenic bone marrow transplantation is associated with intensive graft-versus-host disease prophylaxis. Bone Marrow Transplant 1998; 22: 351-7.
• 52 Park YD, Yoshioka A, Kawa K. et al. Impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurence of hepatic veno-occlusive disease after stem cell transplantation. Bone Marrow Transplant 2002; 29: 789-94.
• 53 Perrault C, Moog S, Rubinstein E. et al. A novel monoclonal antibody against the extracellular domain of GPIb modulates VWF mediated platelet adhesion. Thromb Haemost 2001; 86: 1238-48.
• 54 Pettitt AR, Clark RE. Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant 1994; 14: 495-504.
• 55 Pihusch R, Wegner H, Salat C. et al. Flow cytometric findings in platelets of patients following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 30: 381-7.
• 56 Plews DE, Turner ML, Wallace WHB. Plasma exchange as successful treatment of thrombotic thrombocytopenic purpura post autologous bone marrow transplant in a child. Bone Marrow Transplant 2000; 25: 679-80.
• 57 Powles RL, Clink HM, Spence D. et al. Cyclosporine to prevent graft-versus-host disease in man after allogenic bone marrow transplantation. Lancet 1980; 1: 327-9.
• 58 Proesmans W, Van Geet C. Fibrinolysis in the hemolytic uremic syndrome. Pediatr Nephrol 2002; 17: 871-2.
• 59 Richardson PG, Murakami C, Jin Z. et al. Multiinstitutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002; 100: 4337-43.
• 60 Roy V, Rizvi MA, Vesely SK. et al. Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes. Bone Marrow Transplant 2001; 27: 641-6.
• 61 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: 1112-9.
• 62 Salat C, Holler E, Kolb HJ. et al. Endothelial cell markers in bone marrow transplant recipients with and without acute graft-versus-host disease. Bone Marrow Transplant 1997; 19: 909-14.
• 63 Sarkodee-Adoo C, Sotirescu D, Sensenbrenner L. et al. Thrombotic microangiopathy in blood and marrow transplant patients receiving tacrolimus or cyclosporin A. Transfusion 2003; 43: 78-84.
• 64 Schriber JR, Herzig GP. Transplantation-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol 1997; 34: 126-33.
• 65 Shankaran H, Alexandridis P, Neelamegham S. Aspects of hydrodynamic shear regulating shear-induced platelet activation and self-association of vonWillebrand factor in suspension. Blood 2003; 101: 2637-45.
• 66 Spruce WE, Forman SJ, Blume KG. et al. Hemolytic uremic syndrome after bone marrow transplantion. Acta Haematol 1982; 67: 206-10.
• 67 Srivastava A, Gottlieb D, Bradstock KF. Diffuse alveolar haemorrhage associated with microangiopathy after allogeneic bone marrow transplantation. Bone Marrow Transplant 1995; 15: 863-7.
• 68 Takatsuka H, Takemoto Y, Okamoto T. et al. Thrombotic microangiopathy following allogeneic bone marrow transplantation. Bone Marrow Transplant 1999; 24: 303-6.
• 69 Takatsuka H, Takemoto Y, Yamada S. et al. Complications after bone marrow transplantation are manifestations of systemic inflammatory response syndrome. Bone Marrow Transplant 2000; 26: 419-26.
• 70 Takatsuka H, Wakae T, Mori A. et al. Endothelial damage caused by cytomegalovirus and human herpesvirus-6. Bone Marrow Transplant 2003; 31: 475-9.
• 71 Takatsuka H, Takemoto Y, Iwata N. et al. Oral eicosapentaenoic acid for complications of bone marrow transplantation. Bone Marrow Transplant 2001; 28: 769-74.
• 72 Teruya J, Styler M, Verde S. et al. Questionable efficacy of plasma exchange for thrombotic thrombocytopenic purpura after bone marrow transplantation. J Clin Apheresis 2001; 16: 169-74.
• 73 Tezcan H, Zimmer W, Fenstermaker R. et al. Severe cerebellar swelling and thrombotic thrombocytopenic purpura associated with FK506. Bone Marrow Transplant 1998; 21: 105-9.
• 74 Tokimasa S, Hara J, Osugi Y. et al. Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogeneic stem cell transplantation. Bone Marrow Transplant 2002; 29: 595-8.
• 75 Tsai HM, Lian CY. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339 (22) 1585-94.
• 76 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: 1005-9.
• 77 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 (11) 3798-802.
• 78 Vantelon JM, Munck JN, Bourhis JH. et al. Thrombotic microangiopathy: a new dose-limiting toxicity of high-dose sequential chemotherapy. Bone Marrow Transplant 2001; 27: 531-6.
• 79 Wang FZ, Larsson K, Linde A. et al. Human herpesvirus 6 infection and cytomegalovirus-specific lymphoproliferative responses in allogeneic stem cell transplant recipients. Bone Marrow Transplant 2002; 30: 521-6.
• 80 Zager RA. Acute renal failure in the setting of bone marrow transplantation. Kidney Int 1994; 46: 1443-58.
• 81 Zeigler ZR, Shadduck RK, Nemunaites J. et al. Bone marrow transplant-associated thrombotic microangiopathy: a case series. Bone Marrow Transplant 1995; 15: 247-53.
• 82 Zeigler ZR, Kelton JG, Moore JC. et al. Calpain activity in bone marrow transplant-associated thrombotic thrombocytopenic purpura. Bone Marrow Transplant 1999; 24: 641-5.
• 83 Zomas A, Saso R, Powles R. et al. Red cell fragmentation (schistocytosis) after bone marrow transplantation. Bone Marrow Transplant 1998; 22: 777-80.