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.
11. Confidential – For Educational Purposes Only 11
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
13. Confidential – For Educational Purposes Only 13
TTP: Acquired anti-ADAMTS13 IgG
14. Confidential – For Educational Purposes Only 14
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
15. Confidential – For Educational Purposes Only 15
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.
16. Confidential – For Educational Purposes Only 16
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.
18. Confidential – For Educational Purposes Only 18
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
19. Confidential – For Educational Purposes Only 19
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.
21. Confidential – For Educational Purposes Only 21
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
22. Confidential – For Educational Purposes Only 22
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
Confidential – For Internal Use Only 22
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.
34. Confidential – For Educational Purposes Only 34
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.
