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Transplantation associated Thrombotic microangiopathy (TA-TMA)

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Transplantation associated Thrombotic microangiopathy (TA-TMA)

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Bone marrow transplantation associated Thrombotic Microangiopathy - history, definition, epidemiology, risk factors, pathogenesis, clinical features, lab studies, diagnostic criteria, treatment, prognosis, differences from Idiopathic TTP

Bone marrow transplantation associated Thrombotic Microangiopathy - history, definition, epidemiology, risk factors, pathogenesis, clinical features, lab studies, diagnostic criteria, treatment, prognosis, differences from Idiopathic TTP

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Transplantation associated Thrombotic microangiopathy (TA-TMA)

  1. 1. By Jagjit Khosla By Dr. JAGJIT KHOSLA
  2. 2. History Definition Epidemio Risk Factors PathogenesisClinical FeaturesLab Studies Diagnostic Crieteria Treatment Prognosis By Dr. JAGJIT KHOSLA
  3. 3.  A syndrome of microangiopathic hemolytic anemia, renal dysfunction and neurological abnormalities was first noted in bone marrow transplant recipients 32 years ago 1 Powles, R. L., et al. "Cyclosporin A to prevent graft-versus-host disease in man after allogeneic bone-marrow transplantation. “ The Lancet 315.8164 (1980): 327-329 By Dr. JAGJIT KHOSLA
  4. 4.  TMA = Thrombosis + Small vessels (Capillaries, terminal arterioles)  2 proposed consensus definitions:  Blood and Marrow Transplant Clinical Trials Network (BMT CTN) toxicity committee consensus definition2  International Working Group Definition3  Fail to distinguish the primary syndrome from secondary causes such as infections or medication exposure Transplanted associated Thrombotic Microangiopathy (TA-TMA) Thrombotic Thrombocytopenic Purpura (TTP) after Hematopoietic Stem Cell Transplant By Dr. JAGJIT KHOSLA
  5. 5.  Incidence –  0.5% - 76%10  Allogeneic >> Autologous 5,6  Onset –  Usually within first 100 days after HSCT  Mortality –  60-90%  different diagnostic criteria  28 different definitions used in 35 reviewed reports 4  heterogeneity of the transplant population. By Dr. JAGJIT KHOSLA
  6. 6.  Older age  Female sex  African American race  Advanced primary disease  Unrelated donor transplants  HLA-mismatch (one or more loci)  Nonmyeloablative transplants (fludarabine-based regimens)  High-dose busulfan (16 mg/kg)  Total body irradiation  Calcineurin Inhibitors - Cyclosporine (CsA), Tacrolimus (FK506)  Calcineurin Inhibitors + sirolimus  Acute GVHD  Infections By Dr. JAGJIT KHOSLA
  7. 7.  Idiopathic TTP  Transplant-associated TMA By Dr. JAGJIT KHOSLA
  8. 8. Weibel-Palade Bodies Mature Von-Willebrand Factor Large Unfolded vWF Polymer By Dr. JAGJIT KHOSLA
  9. 9. Large Unfolded vWF Polymer Factor VIII Platelets Collagen (Endothelium) vWF Monomers ADAMTS13 By Dr. JAGJIT KHOSLA
  10. 10. Large Unfolded vWF PolymervWF Monomers ADAMTS13  Platelet aggregation By Dr. JAGJIT KHOSLA
  11. 11. Microthrombi formation RBC Schistocytes By Dr. JAGJIT KHOSLA
  12. 12.  Deficiency of ADAMTS13  33-100% have < 5% of ADAMTS13  Autoantibody against or deficiency of ADAMTS13 By Dr. JAGJIT KHOSLA
  13. 13.  Majority of patients with TA-TMA have only slightly reduced or normal levels of ADAMTS13 Normal ADAMTS13 Decreased ADAMTS13 Elliott et al. 2003 10/10 (100%) 0/10 Van der Plas et al. 1999 7/8 (88%) 1/8 Arai et al. 2001 5/6 (83%) 1/6 Vesely et al. 2003 7/7 (100%) By Dr. JAGJIT KHOSLA
  14. 14.  Majority of patients with TA-TMA have only slightly reduced or normal levels of ADAMTS13  Endothelial injury is critical to pathogenesis  Markers of Endothelial Injury  Absent Prostacyclin PGI2  Elevated vWF antigen levels with normal vWF multimer pattern  Elevated Thrombomodulin(TM), PAI-1, ICAM-1  Increased levels of Endothelial toxins  IL-1  TNFα  IL-8  IFNγ By Dr. JAGJIT KHOSLA
  15. 15. 1 2 3 5 4By Dr. JAGJIT KHOSLA
  16. 16.  Fatigue (due to anemia)  Petechiae / spontaneous bleeding  Neurologic manifestations  Altered mental status  Seizures  Hemiplegia  Paresthesias  Visual disturbances  Aphasia  Fever (50%) History By Dr. JAGJIT KHOSLA
  17. 17.  Pallor  Jaundice  Petechiae  Neurologic examination Examination By Dr. JAGJIT KHOSLA
  18. 18.  CBC -  Anemia  Thrombocytopenia  Peripheral blood smear  Fragmented RBCs (Schistocytes) By Dr. JAGJIT KHOSLA
  19. 19.  CBC -  Anemia  Thrombocytopenia  Peripheral blood smear  Fragmented RBCs (Schistocytes)  BUN/Creatinine  Cr ≥ 2.0, or > 50% increase in Cr from baseline  Increased to greater degree in HUS  Evidence of Intravascular hemolysis –  Increased Indirect Bilirubin  Increased LDH  Decreased haptoglobin By Dr. JAGJIT KHOSLA
  20. 20.  Coagulation profile (PT, PTT, Fibrinogen)  Normal (deranged in DIC)  D-dimer – Normal or slightly elevated (Rule out DIC)  Direct Coombs test (to rule out Autoimmune Hemolytic Anemia)  ADAMTS13 activity  Sample must be drawn before Plasma exchange started  May be low in other conditions but not <25% of normal  <5% suggest TTP  Anti-ADAMTS13 antibodies  Brain CT – Prognostic9 By Dr. JAGJIT KHOSLA
  21. 21.  Thrombocytopenia  Microangiopathic hemolytic anemia (MAHA)  Neurologic abnormalities  Renal abnormalities  Fever  Thrombocytopenia  MAHA  Neurologic abnormalities Pentad of Classic TTP Triad of TTP (40% patients) (70% patients) By Dr. JAGJIT KHOSLA
  22. 22. BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK (BMT CTN) TOXICITY COMMITTEE CONSENSUS DEFINITION2  RBC fragmentation and ≥ 2 schistocytes/hpf on peripheral film  Concurrent increased serum LDH above institutional baseline  Concurrent renal and/or neurologic dysfunction without other explanations  Negative direct and indirect Coomb’s test results INTERNATIONAL WORKING GROUP DEFINITION3  Increased percentage (> 4%) of schistocytes in the blood  De novo, prolonged or progressive thrombocytopenia (platelet count less than 5 x 109/l or a 50% or greater decrease from previous counts)  Sudden and persistent increase in LDH  Decrease in hemoglobin concentration or increased red blood cell transfusion requirement  Decrease in serum haptoglobin concentrationBy Dr. JAGJIT KHOSLA
  23. 23.  Poor Prognosis – high mortality rate (>60%)4  Causes :  Complications like  Renal failure  Myocardial ischemia  Brain ischemia  Serious concomitant disorders  GVHD  Infection By Dr. JAGJIT KHOSLA
  24. 24.  Age ≥ 18 years  Unrelated or haplo-identical donor  Elevated TMA index (LDH/platelet ratio)  Schistocyte count (45–10/hpf)  TMA in the absence of sirolimus exposure  Nephropathy Poor Prognostic Factors7 By Dr. JAGJIT KHOSLA
  25. 25.  Plasma exchange  Mechanism :  Removes autoantibodies against ADAMTS13  Restores ADAMTS13 levels  Not effective for Transplant associated TMA Ho, Vincent T., et al. "Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation.“ Biology of Blood and Marrow Transplantation 11.8 (2005): 571-575. By Dr. JAGJIT KHOSLA
  26. 26. Reason for High Mortality  Selection bias  Systemic Infection  Hemorrhage  Pneumothorax  Pericardial Tamponade  Hypoxia  Hypotension  Serum Sickness By Dr. JAGJIT KHOSLA
  27. 27.  Remove Medication Insult  Cyclosporine  Tacrolimus  Sirolimus  Treat underlying disorders  Infections  GVHD By Dr. JAGJIT KHOSLA
  28. 28. DACLIZUMAB  Mechanism :  Humanized monoclonal anti-CD25 antibody  Targets the α chain of IL-2 receptor on T cells  decreased IL-2 production  Uses :  Treatment of GVHD (Wolff et al. – Dose 1mg/Kg weekly)  Side effects :  Rash, infections By Dr. JAGJIT KHOSLA
  29. 29. DEFIBROTIDE  Mechanism :  Polydeoxyribonucleotide salt  Inhibits TNF-α mediated endothelial apoptosis  Decreases tissue factor expression by endothelial cells  Uses :  Recurrent TTP (dose – 40mg/Kg PO daily)  Post-transplant hepatic VOD By Dr. JAGJIT KHOSLA
  30. 30. OTHER AGENTS : • RITUXIMAB (Anti-CD20 antibody) • EPA (eicosapentaenoic acid) • Transdermal isosorbide By Dr. JAGJIT KHOSLA
  31. 31. Transplant associated TMA Idiopathic acquired TTP Etiology  Unknown  ADAMTS13 deficiency in many patients, caused by anti-ADAMTS13 autoantibodies Pathology  Thrombotic microangiopathy, primarily limited to the renal microvasculature  Systemic thrombotic microangiopathy Risk Factors  Female sex, acute graft-versus-host disease, unrelated or mismatched donor, and other transplant-related complications  Female sex, black race By Dr. JAGJIT KHOSLA
  32. 32. Transplant associated TMA Idiopathic acquired TTP Laboratory findings  Microangiopathic hemolytic anemia, LDH , thrombocytopenia, creatinine  in some  Microangiopathic hemolytic anemia, LDH , thrombocytopenia, creatinine  in some Diagnosis  Exclude other causes of MAHA and thrombocytopenia, diagnosis uncertain  Exclude other causes of MAHA and thrombocytopenia, diagnosis uncertain Treatment  Supportive care, withdraw or  calcineurin inhibitors  Plasma exchange, immunosuppressive agents Mortality  0–100%  15–20% By Dr. JAGJIT KHOSLA
  33. 33. 1. Powles, R. L., et al. "Cyclosporin A to prevent graft-versus-host disease in man after allogeneic bone-marrow transplantation." The Lancet 315.8164 (1980): 327-329 2. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005 Aug;11:571-5. 3. Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, Holler E, Iacobelli M, Kentouche K, Lammle B, Moake JL, Richardson P, Socie G, Zeigler Z, Niederwieser D, Barbui T. Diagnostic criteria for hematopoietic stem cell transplant- associated microangiopathy: results of a consensus process by an International Working Group. Haematologica 2007 Jan;92:95-100 4. George, James N., et al. "Thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma." Transfusion 44.2 (2004): 294-304. 5. Pettitt AR, Clark RE. Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant 1994 Oct;14:495-504. 6. Iacopino P, Pucci G, Arcese W, Bosi A, Falda M, Locatelli F, Marenco P, Miniero R, Morabito F, Rossetti F, Sica S, Uderzo C, Bacigalupo A. Severe thrombotic microangiopathy: an infrequent complication of bone marrow transplantation. Gruppo Italiano Trapianto Midollo Osseo (GITMO). Bone Marrow Transplant 1999 Jul;24:47-51. 7. Batts, E. D., and H. M. Lazarus. "Diagnosis and treatment of transplantation-associated thrombotic microangiopathy: real progress or are we still waiting?."Bone marrow transplantation 40.8 (2007): 709-719. 8. Kojouri, Kiarash, and James N. George. "Thrombotic microangiopathy following allogeneic hematopoietic stem cell transplantation." Current opinion in oncology 19.2 (2007): 148-154. 9. Kay, A. C., et al. "Prognostic significance of computed tomography of the brain in thrombotic thrombocytopenic purpura." Mayo Clinic proceedings. Mayo Clinic. Vol. 66. No. 6. 1991. 10. Ho, Vincent T., et al. "Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation." Biology of Blood and Marrow Transplantation 11.8 (2005): 571-575. By Dr. JAGJIT KHOSLA
  34. 34. By Dr. JAGJIT KHOSLA

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