1. Case presentation
 42 y/o man. No prior medical problems. Evaluated due to leg celulitis.
 6/2011-
 AML-biphenotypic. FLT-3 mutated.
 Induction: Ara-C/Ida (7+3). Persistent blasts.
 Re-induction with High dose Ara-C. Clinical remission.
 8/16/2011-
 Allograft-
 Preparative regimen: Busulfan/Cytoxan.
 Donor : HLA matched brother. Blood type: O/O

2. Laboratories Flow Sheet
Date 8/30 9/9 9/16 9/20 9/30 10/7 10/14 10/21 10/28
Post BMT
+14 +24 +31 +35 +45 +52 +59 +66 +73
WBC 20.6 7.4 6.1 10.4 5.8 12.8 10.5 8.8 6.5
Hgb 9.1 11.3 11.6 11.6 9.2 12.1 14.2 11.4 10.7
Hct 25.6 32.5 33.5 33.3 27.5 36.8 42.8 32.0 29.7
Plt 287 122 23 10 62 17 34 35 19
Schistocytes 0 0 0 0 2+ 2+ 2+
NRBC 1 0 5 4 1 14
BUN 11 12 10 33 103 60 72 68 110
Creat 1.0 0.9 0.9 1.9 2.2 1.5 1.6 1.2 2.0
Bili 0.3 0.5 0.5 2.2 17.6 24.9 23.8 22.5 24.8
Alk phos 124 101 106 92 66 82 100 110 186
SGOT 54 57 68 3169 89 50 39 71 102
SGPT 56 101 96 2827 123 52 41 44 91
LDH 1392 491 320 1620 945 435 333 325 349
Haptoglobin <1 <1 2 4 25

3. Case
 9/20- Admission
 Acute liver injury. Hepatology consult. Viral studies: negative. Given Mucomyst for possible
Acetaminophen toxicity. Sonogram: Non-revealing. Not suggestive of VOD. +Ascites. Transjugular
liver biopsy: - GVHD. Areas of necrosis. Extramedullary hematopoiesis? Therapeutic paracentesis.
 9/26
 Renal insufficiency- Renal consult. Hepatorenal syndrome?
 9/28
 Altered mental status- hepatic encephalopathy? Sepsis? Hypotensive/Hypoxic/Agitated. Transferred
to ICU. Abdominal pain. GI bleeding. Treated with broad spectrum antibiotics/pressors. Abdomen CT
scan: pancreatitis. Amylase and lipase elevated. Pneumatosis intestinales. Surgery consult.
 9/29
 Exploratory laparotomy- hemicolectomy for necrotic bowel. Extensive ischemic damage. No GVHD
Liver biopsy: no change. Immature hematopoietic cells seen ? BM biopsy and flow: negative for
leukemia. Chimeric studies: 100% donor cells.
 10/1
 2nd look laparotomy. Anastomosis. Liver biopsy: flow negative for leukemia. No GVHD. Pulmonary
consult.
 10/3
 Clinical improvement

4. Laboratories Flow Sheet
Date 8/30 9/9 9/16 9/20 9/30 10/7 10/14 10/21 10/28
Post BMT
+14 +24 +31 +35 +45 +52 +59 +66 +73
WBC 20.6 7.4 6.1 10.4 5.8 12.8 10.5 8.8 6.5
Hgb 9.1 11.3 11.6 11.6 9.2 12.1 14.2 11.4 10.7
Hct 25.6 32.5 33.5 33.3 27.5 36.8 42.8 32.0 29.7
Plt 287 122 23 10 62 17 34 35 19
Schistocytes 0 0 0 0 2+ 2+ 2+
NRBC 1 0 5 4 1 14
BUN 11 12 10 33 103 60 72 68 110
Creat 1.0 0.9 0.9 1.9 2.2 1.5 1.6 1.2 2.0
Bili 0.3 0.5 0.5 2.2 17.6 24.9 23.8 22.5 24.8
Alk phos 124 101 106 92 66 82 100 110 186
SGOT 54 57 68 3169 89 50 39 71 102
SGPT 56 101 96 2827 123 52 41 44 91
LDH 1392 491 320 1620 945 435 333 325 349
Haptoglobin <1 <1 2 4 25

5. Case
 10/7
 Eculizumab treatment initiated. Bacteremia. Fungemia.
 10/9
 Re-intubation. Pressors.Sepsis- enterococcus faecium
 10/11
 Extubated. CMV +. Clinical improvement. BK viruria. + galactomanan assay. Peritonitis. ID consult
 10/27
 Progressive renal insufficiency. Hypotension. Hypoxemia.
 10/31
 Re-intubation. Withdrawal of support.
 AUTOPSY
 Heart: sub-endocardial hemorrhage
 Lungs: Organizing acute lung injury. Negative for fungal elements/cultures. Cultures: enterococcus faecium
 Liver:Centrilobular perivenular and sinusoidal fibrosis.---VOD. No GVHD
 Bowel: Microvascular thrombosis.
 Pancreas: interstitial fibrosis. Enzymatic necrosis
 Kidneys: Recent ischemic changes.
 Spleen: Intravascular thrombi.
 BM: NO leukemia

6. Moschcowitz’ Disease
 1924-
 Girl who presented with an
abrupt onset of petechiae and
pallor followed rapidly by
paralysis, coma and death.
 Pathological examination
revealed small arterioles and
capillaries with thrombi
consisting mainly of platelets
 “a powerful poison which has
both agglutinative and
hemolytic properties”
 Proceedings of the New York Pathological Society 1924,24:21
 Archives of Internal Medicine 1925, 36:89

7.  1959-blood exchange
 1976-plasma exchange
History 

albumin
plasma
 1977-plasma infusion
 1924-Moschowitz  washed RBC +albumin
 fresh plasma
 1936-hyaline occlusion
of small vessels
 1958- Term TTP
 1966- Clinical pentad
 Microangiopathic hemolytic anemia
 Thrombocytopenia
 Neurological abnormalities
 Renal involvement
 Fever

8. Cleavage of Unusually Large Multimers of von Willebrand Factor on Endothelial Cells by the von
Willebrand Factor–Cleaving Metalloprotease, ADAMTS 13.
(A Disintegrin-like And Metalloprotease w Thrombospondin Type 1 motif 13)
Moake JL. N Engl J Med 2002;347:589-600.

9. Proposed Relation among the Absence of ADAMTS 13 Activity in Vivo, Excessive Adhesion and
Aggregation of Platelets, and Thrombotic Thrombocytopenic Purpura.
Moake JL. N Engl J Med 2002;347:589-600.

10. Relation between Defects in Plasma von Willebrand Factor–Cleaving Metalloprotease, ADAMTS
13, and Thrombotic Thrombocytopenic Purpura (TTP).
(Upshaw-Schulman Syndrome)
Moake JL. N Engl J Med 2002;347:589-600.

11. Treatment
Replacement of a deficient component
Plasma infusion


 Metalloprotease
 Plasma exchange  Normal vWF multimers
 Immunosuppressants  Removal of a harmful plasma
component
 Steroids  Auto antibodies
 Rituximab  Unusually high multimers vWF
 Immune regulation

12. (A) Effect of treatment on median ADAMTS13 activity and IgG antibody levels in box-
whisper format from admission to 1 year of follow-up in the rituximab group.
Scully M et al. Blood 2011;118:1746-1753
©2011 by American Society of Hematology

13. The clinical course of patients with TTP may be complex and cannot be easily
represented by a single diagram.
Baylor 2010
Plasma exchanges: 616
TTP: 292
35% at .3-13.9 yrs
Mortality 20%
George J N Blood 2010;116:4060-4069
©2010 by American Society of Hematology

14. Clinical Presentation
1925-1964 1964-1980 1982-1989
Microangiopathic 96 98 100
Hemolytic Anemia
Thrombocytopenia 96 96 100
Neurologic Symptoms 92 84 63
Renal Disease 88 76 59
Fever 98 59 24

15. Clinical categories of TTP and reduced ADAMTS 13 activity
 Allogeneic stem cell transplant 10 1 (10%)
 Pregnancy/postpartum 15 3 (21%)
 Drug associated
 Quinine 20 0
 Chemotherapy/calcineurin inh 12 0
 Other 6 0
 Bloody diarrhea 25 2 (8%)
 Other disorders
 SLE 21 2 (10%)
 Other autoimmune 16 1 (7%)
 Infectious 23 4 (17%)
 Malignancies 10 1 (10%)
 Hypertension 6 0
 Other 12 0
 Idiopathic 107 51 (48%)
All patients: 283. Only 65 (23%) w ADAMTS 13 <10% Blood 116:4060, 2010

16. Thrombotic Microangiopathies.
TTP/HUS
Moake JL. N Engl J Med 2002;347:589-600.

17. Proposed Mechanisms of Platelet–Fibrin Formation in the Hemolytic–Uremic Syndrome.
Moake JL. N Engl J Med 2002;347:589-600.

18. aHUS:
A Rare, Genetic, Devastating and
Life-threatening Disease
 Many patients cannot have a specific mutation identified and all still have
chronic uncontrolled complement activation
 Complement-mediated TMA leads to systemic, progressive organ damage and
sudden death
 One year after diagnosis, >50% of all patients have died, require dialysis, or
have permanent renal damage despite plasma exchange
 Diagnosis of early signs and symptoms is the critical first step to fundamentally
transform the lives of aHUS patients
 Genetic deficiency in complement regulatory genes causes chronic uncontrolled
complement activation

19. Genetic Loss of Natural Inhibitors Leads to Chronic Uncontrolled
Complement Activation
Lectin Pathway Classical Pathway Alternative Pathway
Proximal
C3 + H2O - ALWAYS ACTIVE
Immune Complex Clearance
Microbial Opsonization C3 (Chronic)
Amplification
Natural
–
Inhibitors
Terminal
C5
C5a C5b-9
Membrane Attack
Complex
 Potent
Anaphylaxis  Cell Lysis Cell Destructio
Anaphylatoxin
 Proinflammatory
Inflammation Consequences  Chemotaxis ConsequencesInflammation
 Platelet Activation
 Proinflammatory
Thrombosis  Leukocyte/Monocyt Thrombosis
 Leukocyte/Monocy
e Activation
te Activation
 Endothelial
 Endothelial
Activation
Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4:359-395; Walport MJ. N Engl J Med. 2001;344:1058-1066; Rother RP et al. Nature Biotech. 2007;25:1256-1264; Meyers G et al. Blood.
Activation
2007;110:Abstract 3683; Hill A et al. Br. J. Hematol. 2010;149:414-425; Hillmen P et al. Am J Hematol 2010; 85:553-559, International PNH Interest Group. Blood. 2005;106:3699-3709; Hillmen P et
 Prothrombotic
al. N Engl J Med. 1995;333:1253; Nishimura J et al. Medicine.2004;83:193-207; Caprioli J et al. Blood 2006;108:1267-1279; Noris M, et al. Clin J Am Soc Nephrol. 2010;5:1844-1859; George JN et
 Prothrombotic
al. Blood. 2010;116:4060-4069; Loirat C, et al. Pediatr Nephrol. 2008;23:1957-1972; Stahl A, et al Blood. 2008;111:5307-5315; Hosler GA, et al Arch Pathol Lab Med. 2003; 127;834-839; Ariceta G
et al. Pediatr Nephrol. 2009; 24:687-696.

20. Alternative Pathway of Complement Activation and Regulation.
Membrane Attack Complex
Delvaeye M et al. N Engl J Med 2009;361:345-357.

21. Model for the Mechanisms Leading from Impaired Regulation of the Alternative Pathway to
Thrombotic Microangiopathy.
Noris M, Remuzzi G. N Engl J Med 2009;361:1676-1687.

22. Classification of Atypical Hemolytic–Uremic Syndrome.
Noris M, Remuzzi G. N Engl J Med 2009;361:1676-1687.

23. Genetic Abnormalities and Clinical Outcome in Patients with Atypical Hemolytic–Uremic
Syndrome.
Noris M, Remuzzi G. N Engl J Med 2009;361:1676-1687.

24. Chronic Uncontrolled Complement Activation Causes
Platelet, Endothelial, Leukocyte/Monocyte Activation Leading to
Inflammation and Systemic Small Vessel Occlusion
Endothelial Platelet
Swelling and Consumption
Disruption
Mechanical
Hemolysis
Uncontrolled
Complement Endothelium (Schistocytes)
Activation Activation
Platelet
Activation Neutrophil
Platelet Platelet
Activation Aggregation
Blood Clots
Inflammation
Neutrophil
Occlusion
Ischemia
Hypoxia
Modified from Desch K et al. JASN. 2007;18:2457-60. Modified from Licht C et al. Blood. 2009;114:4538-4545. Modified from Noris M et al. NEJM. 2009;
361:1676-87. Modified from Stahl A, et al. Blood 2008;111:5307-15. Modified from Camous L et al. Blood. 2011;117:1340-9.

25. Systemic Organ Damage
Systemic Organ Damage CNS
CNS Kidney
Kidney GI System
GI System Heart
Heart Others
Others
Complement-Mediated TMA Leads to the
Morbidities and Mortality in aHUS
Cardiovascular2,3,4,6 CNS1,2,3,4,5
Myocardial infarction Confusion
Thromboembolism Seizures
Cardiomyopathy Stroke
Diffuse vasculopathy Encephalopathy
Complement-
Renal 7,8,9,11,12
Mediated Gastrointestinal2,3,5,10,11,12
Elevated creatinine Thrombotic Liver necrosis
Edema, malignant Pancreatitis, DM
Microangiopathy Colitis, Diarrhea
hypertension
Nausea/vomiting
Renal failure Abdominal pain
Dialysis, transplant
Pulmonary1 Impaired Quality of Life1
Dyspnea Blood11 Fatigue
Pulmonary edema Hemolysis Pain/Anxiety
Pulmonary embolism Decreased platelets Reduced mobility
Fatigue
Transfusions
1. George et al. Blood. 2010;116:4060-69. 2. Hosler et al. Arch Pathol Lab Med. 2003;127:834-39. 3. Noris et al. CJASN. 2010;10:1844-59. 4. Neuhaus et al.
Arch Dis Chilid. 1997;76:518-21. 5. Vesely et al Blood. 2003;102:60-8. 6. Sallee et al. Nephron Dial Trans. 2010; 25:2028-32. 7. Kose et al. Semin Thromb
Hemost. 2010;36:669-72. 8. Davin et al. Am J Kid Dis. 2010;55:708-77. 9. Caprioli et al. Blood. 2006;108:1267-7. 10. Dragon-Durey et al. J Am Soc Nephrol.
2010;21:2180-87. 11. Loirat et al. Pediatr Nephrol. 2008;23:1957-72. 12. Stahl et al. Blood. 2008;111:5307-15.

26. Early Signs and Symptoms of aHUS Signal the
Underlying Threat of Catastrophic Consequences
Platelet1,2
Platelet Confusion4 Edema5
Proteinuria 2
Early Signs
LDH / Haptoglobin
LDH Haptoglobin Diarrhea3 Fatigue6
of TMA
Anemia / Schistocytes
1
Nausea5 / Vomiting
Elevated creatinine3
Abdominal pain
Encephalopathy4
Acute
renal failure1
Pulmonary
complications4
Complications
ERSD1
Clinical TMA
Transplant failure1 Liver necrosis1,4
Death1
Pancreatitis7
Stroke 1
Seizures12 Malignant
hypertension4
Ischemic bowel11
Myocardial infarction10
1. Loirat C et al. Pediatr Nephrol. 2008;23:1957-1972. 3. Stahl A, et al Blood. 2008;111:5307-5315. 4. Hosler GA, et al. Arch Pathol Lab Med. 2003;127:834-839. 6. Ariceta G et al. Pediatr Nephrol. 2009;24:687-696. 7.
Caprioli J et al. Blood. 2006;108:1267-1279. 8.Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-1859. 9. George JN et al. Blood. 2010;116:4060-4069. 10. Sallee et al. Nephron Dial Trans. 2010;25:2028-2032. 11.
Ohanian M et al. Clinical Pharmacology: Advances and Applications. 2011:3 5–12 . 12. Davin et al. Am J Kid Dis. 2010;55:708-777.

27. Differential Diagnosis for Thrombotic Microangiopathies (TMAs)
Thrombocytopenia1,7 Microangiopathic Hemolysis2,7
Platelet count <150,000 Elevated LDH and/or
Or
>25% Decrease from baseline ± Decreased Haptoglobin and/or
Schistocytes and/or
Decreased Hemoglobin
Plus One or More of the Following:
Neurological Symptoms3,4,9,12 Renal Impairment5,6,7 Gastrointestinal Symptoms7,8,9
Confusion3,4 and/or Elevated Creatinine6 and/or Diarrhea +/- Blood8 and/or
Seizures9,12 and/or Decreased eGFR6,7 and/or Nausea/Vomiting9 and/or
Cerebral convulsions3 Abnormal Urinalysis5 Abdominal Pain9and/or
Gastroenteritis7,8
Evaluate ADAMTS13 Activity and Shiga-toxin/EHEC*Test10,11
≤5% ADAMTS13 Activity >5% ADAMTS13 Activity Shiga-toxin/EHEC Positive
TTP aHUS STEC-HUS**
*Shiga-toxin/EHEC test is warranted in history/presence of GI symptoms
**Need for high clinical suspicion of aHUS in all patients with systemic TMA, even if shiga-toxin positive
1. Data on file. Alexion Pharmaceuticals, Inc. 2. Noris et al. NEJM. 2009;361:1676-1687. 3. Neuhaus et al. Arch Dis Chilid. 1997;76:518-21. 4. Noris et al. JASN. 2005;16:
1177-1183. 5. Al-Akash et al. Pediatr Nephrol. 2011;26:613-619. 6. Sellier-Leclerc AL. JASN. 2007;18:2392-2400. 7. Caprioli et al Blood. 2006; 108(4)1267-7. 8. Noris M et al.
Clin J Am Soc Nephrol. 2010;5:1844-1859. 9. Dragon-Durey et al. J Am Soc Nephrol. 2010;21:2180-2187. 10.Tsai H-M. Int J Hematol. 2010;91:1-19.11. Bitzan M. Semin Thromb
Hemost. 2010;36:594-610. 12. Davin et al. Am J Kid Dis. 2010;55:708-777.

31. aHUS
Trigger
aHUS
Common Genetic Variants Rare Genetics Variant

32. Response to Eculizumab Therapy in Three Children with STEC-HUS and Progressive Central
Nervous System Involvement.
Lapeyraque A et al. N Engl J Med 2011;364:2561-2563.