The document discusses thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). TMAs are caused by endothelial cell damage and platelet activation leading to thrombosis. While plasma therapy can induce remission in some patients with aHUS, genetic mutations affecting complement regulatory factors often result in poor long-term outcomes of end-stage renal disease or death despite treatment.

1. Thrombotic Microangiopathies:
Diagnosis, Pathophysiology,
Treatment
Jeffrey Laurence, M.D.
Professor of Medicine
Division of Hematology and Medical
Oncology
Weill Cornell Medical College

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5. CASE 1:
A TMA Occurring in the Setting of
Pregnancy and Sepsis
24 y.o. g2p1 female, 16 weeks pregnant, presents
to her OB with a 2 day history of fever, marked
fatigue, and diffuse abdominal pain. BP 90/60.
Fluids administered.
The next day her OB f/u failed to detect a fetal
heartbeat; pt. referred to ED. Temp. 40.3, BP
94/58, RUQ abd. pain/tenderness, vaginal
bleeding, respiratory distress noted. 1+ LE
edema, bibasilar opacities on CXR. Fluids and
antibiotics administered. Within 6 hours the
patient was hypotensive, intubated, on pressors.

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Initial primary dx: Sepsis and DIC
Secondary considerations: HELLP vs.
eclampsia vs. TTP
CVVP Hemodialysis
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RATIO
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Sepsis, DIC, and Liver Failure Resolve
but Renal Failure Remains Prominent
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Spontaneous
abortion
Skin biopsy
ADAMTS13
drawn
ADAMTS13
28%; no inhibitor
CVVP Hemodialysis
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Plasma exchange
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Lower limit

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Platelets Normalized but
Low Level Hemolysis Persists
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Diagnosis of aHUS Made: PEX and HD
Stopped, Eculizumab Initiated
1
Jan
2 3 4 5 6 7 8 9
10 11
16 23 30 6
Feb
13
PEX
No
PEX
Dialysis HD HD
Eculizumab 900mg 900mg 900mg 900mg 1200mg
LDH 328 284 307 298 279 285 290 255 223 164 136 137 139
Creatinine 4.9 5.85 7.02 4.22 4.61 4.33 4.11 3.16 2.52 2.14 1.63 1.42 1.04 1.04 0.91 0.85
Platelets 200 225 319 310 342 332 337 385 349 374 315 407 374 329 303 356
Hb 8 7.5 7.8 7.5 7.3 7.3 7.4 7.4 7.1 7.5 7.6 10.3 10 10.7 10.7 10.8
Discharge

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 TTP and aHUS are ultra-rare diseases (4/1 million incidence): lack of
clinical suspicion
 Clinical presentations are similar, if not identical, in TTP, aHUS and
STEC-HUS, as well as in other conditions characterized by TMA
 Coexisting disorders can unmask aHUS
 Diagnosis: Plasma intervention prior to ADAMTS13 blood draw
 Response: Defining a CR in TTP patients treated with plasma
 Response: Often diagnosed late when there is already organ damage
 Historically limited interest in differentiating aHUS from TTP as, until
September 2011, no specific treatment for aHUS
Challenges in Distinguishing Among the
TMAs

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Systemic Thrombotic Microangiopathy
Predisposing Conditions
• 10 genetic deficiency
• 10 or 20 complement activation
• Abnormal vWF-cleaving
protease activity (ADAMTS13)
• PNH
Triggers of Vascular Injury
• Shiga toxin
• Viruses
• Immune complexes
• Drugs
• Pregnancy
• Malignancy
Causes of Thrombotic Microangiopathy
Modified from Scheiring J, et al. Eur J Pediatr. 2010;169:7-13
Endothelial Cell Damage
Platelet Activation
WBC Recruitment & Activation

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TTP: Acquired anti-ADAMTS13 IgG

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Cell Destruction
Inflammation
Thrombosis
ConsequencesConsequences
aHUS: Congenital Loss of C Regulatory Proteins
ProximalTerminal
C3
C5
C5a
 Potent Anaphylatoxin
 Chemotaxis
 Proinflammatory
 Leukocyte Activation
 Endothelial Activation
 Prothrombotic
C5b-9
Membrane Attack Complex
 Cell Lysis
 Proinflammatory
 Platelet Activation
 Leukocyte Activation
 Endothelial Activation
 Prothrombotic
Amplification
Immune Complex Clearance
Microbial Opsonization
Anaphylaxis
Inflammation
Thrombosis
C3 + H2O - ALWAYS ACTIVE
(Chronic)
Lectin Pathway Alternative PathwayClassical Pathway
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.
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 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 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.
Natural Inhibitors:
Factor H, I, MCP,
CD55
Natural Inhibitor:
CD59

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aHUS: Devastating Prognosis
Despite Historical Supportive Care
 Despite intensive use of PE/PI:
– 33-40% of patients die or
progress to ESRD with the
first clinical manifestation1,2
– 65% of all patients die,
require dialysis, or have
permanent renal damage
within the first year after
diagnosis despite PE/PI 1
 Platelet activation demonstrated
to persist during PE/PI3,4
 Chronic uncontrolled
complement activation causes
complement-mediated TMA
in aHUS2
1. Caprioli et al Blood. 2006; 108:1267-1272. 2. Noris M, et al. N Engl J Med. 2009;361:1676-1687. 3. Stahl A et al. Blood. 2008;111:5307-5315.
4. Licht C et al. Blood. 2009;114:4538-4545.
1.00
0.75
0.50
0.25
0.00
0 3 6 2512.5
CumulativeFractionofPatients
FreeofEvents
Follow-up (months)
Modified from Caprioli et al. 2006. CFH Mutation Depicted.

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Regulation of Complement Activation
 Complement activation has the potential to cause severe damage not only
to microbes but also to host cells and tissues1,2
 Strict regulation is needed to avoid unnecessary damage to self due to
overt or mistargeted activation1,2
– Tight control needed especially for the alternative pathway which is
continuously turned on
– The most critical steps are controlled by several regulators
Endothelial Cells Damaged by
Complement Attack
Photo: S. Meri, Univ. of Helsinki
Multimeric C9 Lesions on
PNH Erythrocyte
Photo: W Rosse
1. Holers VM et al. Immunol Rev. 2008;223:300-316. 2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;4:372-378.

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Complement-Mediated TMA Leads to the
Morbidities and Mortality in aHUS
1.Ohanian M et al. Clinical Pharmacology: Advances and Applications. 2011;3:5-12. 2. Hosler et al. Arch Pathol Lab Med. 2003;127:834-839. 3. Noris et al.
CJASN. 2010;10:1844-1859. 4. Neuhaus et al. Arch Dis Chilid. 1997;76:518-521. 5. Vesely et al Blood. 2003;102:60-68. 6. Sallee et al. Nephrol Dial Trans.
2010;25:2028-32. 7. Kose et al. Semin Thromb Hemost. 2010;36:669-672. 8. Davin et al. Am J Kid Dis. 2010;55:708-777. 9. Caprioli et al. Blood.
2006;108:1267-7. 10. Dragon-Durey et al. J Am Soc Nephrol. 2010;21:2180-2187. 11. Loirat et al. Pediatr Nephrol. 2008;23:1957-1972. 12. Stahl et al. Blood.
2008;111:5307-5315. 13. Chatelet V et al. Am J Transplant. 2009 Nov;9(11):2644-2645. 14. Sellier-Leclerc et al. J Am Soc Nephrol. 2007;18:2392-2400.
Renal7,8,9,11,12
Elevated creatinine
Edema
Malignant
hypertension
Renal failure
Dialysis
Transplant
Gastrointestinal2,3,5,10,11,12
Liver necrosis
Pancreatitis
Diabetes Mellitus
Colitis
Diarrhea
Nausea/vomiting
Abdominal pain
Blood11
Hemolysis
Decreased platelets
Fatigue
Transfusions
Impaired Quality of Life13
Fatigue
Pain/anxiety
Reduced mobility
Pulmonary1,6,14
Dyspnea
Pulmonary hemorrhage
Pulmonary edema
Cardiovascular2,3,4,6
Myocardial infarction
Thromboembolism
Cardiomyopathy
Diffuse vasculopathy
CNS1,2,3,4,5
 Confusion
 Seizures
 Stroke
 Encephalopathy
 Diffuse cerebral dysfunction
Complement-Mediated
Thrombotic
Microangiopathy
Systemic Organ Damage CNS Kidney GI System Heart Others

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Genetic mutation cannot be identified in 20%-30%
of patients with aHUS
Absence of identifiable genetic mutations does
not rule out aHUS. Results generally takes weeks to
months, and therefore do not impact initial clinical
management
Serum complement levels:
– C3 and C4 are normal in up to 80% of aHUS patients
– Complement Factor H (CFH) protein levels are normal in
87% of aHUS patients with a CFH mutation
aHUS: Diagnosis Does Not Require Identification
of a Genetic Mutation, and Serum-based
Complement Levels are Not Useful
1. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-1859.

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Affected Protein
Response to Short-term
Plasma Therapy
(remission rate, %)
Factor H 60%
CFHR1, R3 70%-80%
MCP
No definitive
indication for therapy
Factor I 30%-40%
Factor B 30%
C3 40%-50%
Thrombomodulin
(THBD)
60%
Noris M et al. N Engl J Med. 2009;361:1676-1687.
Initial Response
to Plasma Therapy in aHUS

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Affected Protein
Response to Short-term
Plasma Therapy
(remission rate, %)
Long-term Outcome
(rate of death or ESRD, %)
Factor H 60% 70%-80%
CFHR1, R3 70%-80% 30%-40%
MCP (CD46)
No definitive
indication for therapy
<20%
Factor I 30%-40% 60%-70%
Factor B 30% 70%
C3 40%-50% 60%
Thrombomodulin
(THBD)
60% 60%
Noris M et al. N Engl J Med. 2009;361:1676-1687.
Long-Term Outcome
With Plasma Therapy in aHUS
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1.00
0.75
0.50
0.25
0.00
0 3 6 2512.5
CumulativeFractionofPatientsFreeofEvents
Follow-up (months)
50 75
40 27 20 712 5 3No. at Risk
Up to 70% of patients
with aHUS who have the
most common mutation
die, require dialysis, or
have chronic renal
insufficiency
CFH mutation =
most common population
Modified from Caprioli et al. Blood. 2006;108(4):1267-1272.

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SUMMARY: Distinguishing Among the TMAs
 The three major forms of TMA, TTP, aHUS, and STEC-HUS, are
indistinguishable clinically: 50% of aHUS cases have prominent CNS
findings; 20% of aHUS cases present with normal serum creatinine; and
bloody diarrhea can occur in all TMAs. In general, with plts > 40K and/or
creatinine >1.7, think aHUS, not TTP.
 Up to 80% of aHUS cases will have a complete hematologic response to
PE, but tissue damage continues
 ADAMTS13 activity <5-10% defines most cases of TTP, with CR induced
after 20-40 liters of FFP via PE
 TTP is virtually always acquired, involving IgG anti-ADAMTS13 antibodies.
These antibodies are very difficult to deplete via PE. 1-2 PEs are unlikely to
raise an ADAMTS13 originally <5-10% to >10-20%
 aHUS is virtually always congenital, involving C regulatory factor mutations.
There is no role for plasma . Eculizumab is the only FDA-approved therapy.
 Diagnostic dilemmas may require tissue biopsy or C mutation analysis.