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. 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. 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. 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
12. Deficiency of ADAMTS13
33-100% have < 5% of ADAMTS13
Autoantibody against or deficiency of ADAMTS13
By Dr. JAGJIT KHOSLA
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. 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
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. Pallor
Jaundice
Petechiae
Neurologic examination
Examination
By Dr. JAGJIT KHOSLA
18. CBC -
Anemia
Thrombocytopenia
Peripheral blood smear
Fragmented RBCs (Schistocytes)
By Dr. JAGJIT KHOSLA
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. 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. 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. 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. 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. 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. 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. Reason for High Mortality
Selection bias
Systemic Infection
Hemorrhage
Pneumothorax
Pericardial Tamponade
Hypoxia
Hypotension
Serum Sickness
By Dr. JAGJIT KHOSLA
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. 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. OTHER AGENTS :
• RITUXIMAB (Anti-CD20 antibody)
• EPA (eicosapentaenoic acid)
• Transdermal isosorbide
By Dr. JAGJIT KHOSLA
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. 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. 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