Trigger Viral/Bacterial infection Immuncomplex induced Hormones Drugs

Transcription

1 TMA post SCT Régis Peffault de Latour Bone Marrow Transplant Unit, Saint Louis Hospital, Paris, France 1

2 TMA post SCT 1. Pathophysiology 2. Clinical characteristics 3. Diagnostic criteria 4. Treatment (if any) 5. Perspectives 2

3 Pathophysiology Thrombotic Microangiopathy Endothelial damage Trigger Viral/Bacterial infection Immuncomplex induced Hormones Drugs Promoting Factor Dysfunction of complement regulatory proteins Abnormal big vwillebrand multimere

4 TMA post SCT Pathophysiology Thrombotic Microangiopathy Endothelial damage Trigger Conditioning regimen - TBI, Busulfan Infections - Aspergillus, Herpes Virus, Adenovirus ( ) Calcineurine & mtor inhibitors Graft versus host disease Promoting Factor (rare)

5 TMA post SCT Pathophysiology Trigger Conditioning regimen - TBI, Busulfan Infections - Aspergillus, Herpes Virus, Adenovirus ( ) Calcineurine & mtor inhibitors Graft versus host disease Consequencies Increased ADAMS 13 activity, Tissue Factor and Microparticules Prothrombotic and procoagulant state

6 TMA post SCT Pathophysiology TMA post-sct (Kidney) Multifactorial systemic endothelitis Trigger Conditioning regimen - TBI, Busulfan Infections - Aspergillus, Herpes Virus, Adenovirus ( ) Calcineurine & mtor inhibitors Graft versus host disease Consequencies Increased ADAMS 13 activity, Tissue Factor and Microparticules Prothrombotic and procoagulant state

7 Clinical Characteristics First described in 1978 (TBI) and 1981 (CSA) Kamil et al, Kidney Int 1978; Shulman et al, N Engl J Med 1981

8 Clinical Characteristics First described in 1978 (TBI) and 1981 (CSA) Risk Factors Female Gender & Age TBI, Busulfan, CNI Unrelated donor (mismatch) Graft versushost disease (II to IV) Kamil et al, Kidney Int 1978; Shulman et al, N Engl J Med 1981; Fuge et al, BJH 2001; Ruutu et al, BJH 2002; Roy et al, Bone Marrow Transplant 2001; Nakamae et al, Am J Hematol 2006; Uderzo et al, Transplantation 2006

9 Clinical Characteristics First described in 1978 (TBI) and 1981 (CSA) Risk Factors Female Gender & Age TBI, Busulfan, CNI Unrelated donor (mismatch) Graft versushost disease (II to IV) Mediantime of onset: 44 d (13-319) 319) post-sct Kamil et al, Kidney Int 1978; Shulman et al, N Engl J Med 1981; Fuge et al, BJH 2001; Ruutu et al, BJH 2002; Roy et al, Bone Marrow Transplant 2001; Nakamae et al, Am J Hematol 2006; Uderzo et al, Transplantation 2006

10 Clinical Characteristics First described in 1978 (TBI) and 1981 (CSA) Risk Factors Female Gender & Age TBI, Busulfan, CNI Unrelated donor (mismatch) Graft versushost disease (II to IV) Mediantime of onset: 44 d (13-319) 319) post-sct Probably underestimated (6% to 25%) Kamil et al, Kidney Int 1978; Shulman et al, N Engl J Med 1981; Fuge et al, BJH 2001; Ruutu et al, BJH 2002; Roy et al, Bone Marrow Transplant 2001; Nakamae et al, Am J Hematol 2006; Uderzo et al, Transplantation 2006

11 Clinical Characteristics Whyitissoso difficultto to identify TMA post SCT? Creatinine isa poormarker of kidneyfunction Laskin et al, Blood 2011

12 Clinical Characteristics Whyitissoso difficultto to identify TMA post SCT? Creatinine isa poormarker of kidneyfunction LDH always elevated Laskin et al, Blood 2011

13 Clinical Characteristics Whyitissoso difficultto to identify TMA post SCT? Creatinine isa poormarker of kidneyfunction LDH always elevated Schizocytesremaina a non specific finding after SCT Laskin et al, Blood 2011

14 Clinical Characteristics Whyitissoso difficultto to identify TMA post SCT? Creatinine isa poormarker of kidneyfunction LDH always elevated Schizocytesremaina a non specific finding after SCT Haptoglobin change and Inflammation Laskin et al, Blood 2011

15 Clinical Characteristics Whyitissoso difficultto to identify TMA post SCT? Creatinine isa poormarker of kidneyfunction LDH always elevated Schizocytesremaina a non specific finding after SCT Haptoglobin change and Inflammation Thrombocytopenia and SCT Laskin et al, Blood 2011

16 Clinical Characteristics Whyitissoso difficultto to identify TMA post SCT? Creatinine isa poormarker of kidneyfunction LDH always elevated Schizocytesremaina a non specific finding after SCT Haptoglobin change and Inflammation Thrombocytopenia and SCT Blood pressure Laskin et al, Blood 2011

17 Clinical Characteristics Whyitissoso difficultto to identify TMA post SCT? Creatinine isa poormarker of kidneyfunction LDH always elevated Schizocytesremaina a non specific finding after SCT Haptoglobin change and Inflammation Thrombocytopenia and SCT Blood pressure / Laskin et al, Blood 2011

18 Laskin et al, Blood 2011 Diagnostic Criteria

19 Treament Withdrawalof offending causative agents Best supportive care ( ) No real reference treatment Plasmapheresis Defibrotide Mabthera Sarode et al, BMT 1995; Roy et al, BMT 2001; Holler et al, Blood 1989; Fuge et al, BJH 2001 Corti et al, BMT 2002; Au et al, BJH 2007

20 Conclusions TMA post SCT is a very severe complication TMA post SCT is difficult to diagnose outside a carefull and regular basis follow-up TMA post SCT need explorations to find a cause (trigger) All putative agents need to be stopped No reference treatment until now What about complement blockers in this indication? 20

21 Perspective - complement blockers Complement Cascade Eculizumab oximal Pr C3 C3b C3a Eculizumab binds with high affinity to C5 Terminal complement - C5a and C5b-9 activity blocked Terminal C5 C5b C5a C5b-9 Proximal functions of complement remain intact Weak anaphylatoxin Immune complex clearance Microbial opsonization Eculizumab (Soliris ). Alexion Inc Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3): Walport MJ. N Engl J Med. 2001;344(14): Soliris (eculizumab) [package insert]. Alexion Pharmaceuticals; Rother RP et al. Nature Biotech. 2007;25(11):

22 One paper