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

1. By Jagjit Khosla
By Dr. JAGJIT KHOSLA

2. History Definition Epidemio
Risk
Factors
PathogenesisClinical FeaturesLab Studies
Diagnostic
Crieteria Treatment Prognosis
By Dr. JAGJIT KHOSLA

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

7.  Idiopathic TTP
 Transplant-associated TMA
By Dr. JAGJIT KHOSLA

8. Weibel-Palade Bodies
Mature Von-Willebrand Factor
Large Unfolded
vWF Polymer
By Dr. JAGJIT KHOSLA

9. Large Unfolded
vWF Polymer
Factor VIII
Platelets
Collagen (Endothelium)
vWF Monomers
ADAMTS13
By Dr. JAGJIT KHOSLA

10. Large Unfolded
vWF PolymervWF Monomers
ADAMTS13

Platelet
aggregation
By Dr. JAGJIT KHOSLA

11. Microthrombi
formation
RBC Schistocytes
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

15. 1
2
3
5
4By 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

27.  Remove Medication Insult
 Cyclosporine
 Tacrolimus
 Sirolimus
 Treat underlying disorders
 Infections
 GVHD
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

34. By Dr. JAGJIT KHOSLA