1. Assessing the Evidence and Implications for Clinical Practice
aHUS:
Assessing the Evidence and Implications for Clinical Practice
Lilian Monteiro Pereira Palma, MD State University of Campinas (UNICAMP) Brazil

2. aHUS: Diagnosis and Management
Thrombocytopenia
Platelet count <150 x 109/L
or >25% decrease from baseline
and
Microangiopathic hemolysis
Schistocytes and/or
elevated LDH and/or
decreased haptoglobin and/or
decreased hemoglobin
Plus one or
more of the following:
Neurological symptoms
Confusion and/or
seizures and/or
other cerebral
abnormalities
Renal symptoms
Elevated creatinine and/or
decreased eGFR and/or
elevated blood pressure and/or abnormal urinalysis
GI symptoms
Diarrhea ± blood and/or
nausea/vomiting and/or
abdominal pain and/or
gastroenteritis
Peripheral symptoms
Ischemia and/or
necrosis and/or
gangrene
Establishing a diagnosis of TTP, HUS, or aHUS
What is the molecular cause of the disease? Intrinsic Mechanisms
What has triggered the disease?
Extrinsic Mechanisms
Evaluate ADAMTS13 = TTP
Evaluate Shiga-toxin = STEC-HUS
By exclusion = aHUS
(complement factors?, functional tests?)
Infection, inflammation, malignancy
Medication (CsA, chemotherapy, VEGF-TK)
Immune complexes, autoantibodies, phospholipids
Pregnancy, "malignant" hypertension, scleroderma
Establishing the clinical severity of the disease (organ failure)
Individualized treatment strategy (eculizimab, plasmapheresis, clinical care)
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome; CsA, cyclosporin A; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; LDH, lactate dehydrogenase; STEC, Shiga toxin-producing Escherichia coli; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura; VEGF-TK, vascular endothelial growth factor tyrosine kinase inhibitor.
Reproduced with permission by Haller H.

3. Uncontrolled Complement Activation Is Strongly Linked to the Development of aHUS1-3
Spontaneous hydrolysis,
bacteria, viruses
Neutrophils C3
Platelets
C3 convertases
CFH C3
C3a
CFB
PMP
C3b
C3a
Anaphylatoxins
Coagulation
C5a
TAFIa
Proteinases
Oxygen radicals TM
CFI
TAFI
CFH
C5 convertase
MAC
GAG
C3b C5 Bb Bb
Thrombus
formation TM
MCP
C3b
FC notes: Noris, p1680A; Soliris PI, p4A (eculizumab MOA)
C3b
C3b
Endothelial cell
P-selectin
Endothelial-cell damage and retraction
Subendothelial matrix
In 30–40% of patients with aHUS, no complement abnormality could be identified
Cartoon: Noris, Remuzzi. N Engl J Med. 2009;361:
1. Noris et al. Clin J Am Soc Nephrol. 2010;5:1844– Maga et al. Hum Mutat. 2010;31:E1445– Fremeaux-Bacchi et al. Clin J Am Soc Nephrol. 2013;8:554–62.

4. Complement Abnormality May Inform Long-Term Prognosis
Native Kidney
Kidney Transplant
MCP
CFI
Not identified
C3-CFB
CFH
100 80 60 40 20
Modified from Frémeaux-Bacchi V, et al.1
survival without ESRD (%)
Overall renal 1 5
Time since first presentation (years)
No mutation and no at risk CFH haplotypes, n=16
No mutation but 2 at risk CFH haplotypes, n=7
CFH mutation, n=22
C3/CFB gain of function mutation, n=7
Graft survival without TMA (%)
CFI mutation, n=11
Post-renal transplantation follow-up (years) 1 5
100 50
Modified from Le Quintrec M, et al.2
FC notes: Slide library aHUS and Complement (deck received from ALXN), slide 14
Outcomes are poor: overall 7% death and 50% graft failure at 5 years post-transplant3
TMA generally presents rapidly after transplantation3
65% of all patients die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion1
CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; ESRD, end-stage renal disease; MCP, membrane cofactor protein; TMA, thrombotic microangiopathy.
1. Frémeaux-Bacchi et al. Clin J Am Soc Nephrol. 2013;8:554– Le Quintrec et al. Am J Transpl. 2013;13:663– Caprioli et al. Blood. 2006;108:1267–79.

5. Death-censored graft survival (%)
Graft Loss Is Significantly Higher in Patients with aHUS Experiencing Subsequent TMA Manifestations Than in Those Without
Post-transplant TMA manifestations are the leading cause of graft loss in patients with aHUS1,2
Death-censored graft survival (%)
Time (months)
100 80 60 40 20
120
140
160
No subsequent
TMA manifestations
P=0.0001, log rank
Subsequent
TMA manifestations
No subsequent
TMA manifestations
Number at risk 27 25 21 20 15 9 3 1 44 28 16 6 4
Subsequent
French registry of patients with aHUS: At 5 years post-transplant, graft loss was 70% in patients with subsequent TMA manifestations compared with 32% in patients without TMA complications
FC notes:
Le Quintrec, p5A
Bresin, p480A
Caprioli, p1274B
In the Italian aHUS registry, 86% (6/7) of patients with post-transplant TMA manifestations and complement abnormalities lost their grafts within 1 year3
aHUS, atypical hemolytic uremic syndrome; ESRD, end-stage renal disease; TMA, thrombotic microangiopathy.
In renal-transplant recipients with aHUS-related ESRD, with or without mutations; death censored data.
1. Le Quintrec et al. Am J Transplant. 2013;13: Bresin et al. Clin J Am Soc Nephrol. 2006;1: Caprioli et al. Blood. 2006;108:

6. Death-censored graft survival
Use of Plasma Exchange/Plasma Infusion (PE/PI) Does Not Improve Graft Survival
100%
80%
60%
Death-censored graft survival
40%
PE/PI
20%
No PE/PI
(P=0.9) 0%
Number at risk
Time (months)
No PE/PI
PE/PI
Le Quintrec et al. Am J Transplant. 2013;13:
TMA, thrombotic microangiopathy.

7. Poor Prognosis of aHUS in the Era of Plasma Exchange
High risk of rapid progression to ESRD
100
Pediatric onset, n=89
Adult onset, n=125
French cohort: N=214 80
1-Year mortality:
7% in children, 1% in adults 60
Overall renal survival (%) 40
ESRD or death
Children
Adults
First episode
17%
46%
1-year follow-up
29%
56%
5-year follow-up
36%
64% 20
P<0.001
FC notes: Fremeaux-Bacchi, p557AB, 558C 5 10 15 20
Years
Number of aHUS patients at risk
Pediatric onset 89 34 17 13 6
Adult onset
125 18 7 2
aHUS, atypical hemolytic uremic syndrome; ESRD, end-stage renal disease.
Frémeaux-Bacchi et al. Clin J Am Soc Nephrol 2013;8: 7 7 7 7

8. Patients With aHUS Show Chronic, Uncontrolled Complement Activity With or Without Identified Mutation
Complement depositions on activated endothelium were observed in patients with aHUS without overt TMA manifestation regardless of mutation status
10000
8000
6000
4000
2000
CFH
CFI C3
CFB
anti
CFH Ab No
mutation
C5b-9 deposition on activated endothelial cell in patients with aHUS without overt TMA
(pixel2)
C5b-9 deposition on endothelial cell is a sensitive tool to monitor complement activation
To find out a sensitive test of complement activation on endothelium, human microvascular endothelial cells (HMEC-1) were incubated for 4 hours with serum from the 36 aHUS patients not treated with Eculizumab with or without identified complement gene mutations/anti-CFH antibodies. Thereafter HMEC-1 were stained with anti-human C5b-9 antibodies and complement deposits were analyzed by confocal microscopy
Serum from patients “without overt TMA” was used
“There are still unrecognized genetic complement abnormalities leading to aHUS”
FC notes: Noris, p1719E
Range of C5b-9 deposition induced by healthy control serum (mean+/-SE)
Adapted from Noris et al., Blood, 2014
(n=4)
(n=10)
(n=3)
(n=1)
(n=2)
(n=7)
aHUS, atypical hemolytic uremic syndrome; CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; SE, standard error; TMA, thrombotic microangiopathy.
Noris et al. Blood. 2014;124:

9. Eculizumab: Terminal Blockade of the Alternative Complement Pathway
Spontaneous hydrolysis,
bacteria, viruses
Neutrophils C3
Platelets
C3 convertases
CFH C3
C3a
CFB
PMP
C3b
C3a
Anaphylatoxins
Coagulation
C5a
TAFIa
Proteinases
Oxygen radicals TM
CFI
TAFI
CFH
C5 convertase
Eculizumab
MAC
GAG
C3b C5 Bb
C5b
Thrombus
formation Bb TM
MCP
C3b
FC notes: Noris, p1680A; Soliris PI, p4A (eculizumab MOA)
C3b
C3b
Endothelial cell
P-selectin
Endothelial-cell damage and retraction
Subendothelial matrix
Noris, Remuzzi. N Engl J Med. 2009;361:

10. Eculizumab aHUS Dosing Schedule
Administration
Eculizumab should be administered at the recommended dosage regime time points, or within 2 days of these time points
Soliris SmPC, p1, col 1,
para 11; p2, Table
aHUS Dosing Schedule for Adults (18 years of age)
2 weeks before induction
Week 1 2 3 4 5 6 7 8 9+
Neisseria meningitidis vaccination
Soliris Dose
900 mg
1200 mg –
Soliris SmPC, p3, col 1,
para 7-8
Pretreatment
Induction Phase
Maintenance Phase
Soliris SmPC, p1, col 1,
para 9-11
Q2W
Soliris SmPC, p1, col 1,
para 9-11; p2, Table
aHUS Weight-based Dosing Schedule for Patients < 18 Years
40 kg and over
900 mg weekly  4 doses
1200 mg at week 5; then 1200 mg every 2 weeks (Q2W)
30 kg to <40 kg
600 mg weekly  2 doses
900 mg at week 3; then 900 mg Q2W
20 kg to <30 kg
600 mg at week 3; then 600 mg Q2W
10 kg to <20 kg
600 mg weekly  1 dose
300 mg at week 2; then 300 mg Q2W
5 kg to <10 kg
300 mg weekly  1 dose
300 mg at week 2; then 300 mg Q3W
Body Weight
Induction Phase
Maintenance Phase
FC notes: Soliris EMA, p3A, 4A
aHUS, atypical hemolytic uremic syndrome; Q2W, once every 2 weeks; Q3W, once every 3 weeks.
US Food and Drug Administration. Soliris (eculizumab) [prescribing information]. New Haven, CT: Alexion Pharmaceuticals, Inc., 2016.
Please See Summary of Product Characteristics for Soliris, including Special Warnings and Precautions for use. Alexion 2015.

11. Safety Profile of Eculizumab in the 100 Trial Patients With aHUS1-4
No unexpected safety signals
Most TEAEs were mild/moderate
1 death deemed unrelated to eculizumab (adult)
2 meningococcal infections (adults; both recovered)
1 patient had low positive values for human anti-human antibodies to eculizumab (pediatric)
Overall, there has been no observed correlation of antibody development to clinical response or adverse events
Adverse events were reported with less frequency over time from week 26 to the 2-year update in studies C and C08-003
FC Notes:
Legendre, p2177A, supplemental p18-19A
Licht, p9A, 10A
Greenbaum, Table 5, p6A, 8A
Fakhouri, p7A
aHUS, atypical hemolytic uremic syndrome; TEAEs, treatment-emergent adverse events.
1. Legendre et al. N Engl J Med. 2013;369(14): Licht et al. Kidney Int. 2015;87(5): Greenbaum et al. Kidney Int. 2016;89(3): Fakhouri et al. Am J Kidney Dis. 2016;68(1):84-93.

12. Eculizumab Clinical Development Program (2011–Ongoing)
A total of 100 patients in prospective clinical trials
Legendre N Engl J Med 2013– Page 2169 and 2172
Prospective1,2 (26 weeks)
Long-term extension studies1,2 86% (32/37) of patients continued chronic eculizumab treatment in extension studies
Trial 1 (C08-002) Adult/adolescent
Progressive TMA
(N=17)
Trial 2 (C08-003) Adult/adolescent
Long disease
duration and CKD
(N=20)
Study C Pediatrics (N=22)
Study C Adults (N=41)
Prospective (26 weeks)
Study C Patients <12 years of age (N=15)
Retrospective5
Licht ASH Annual Meeting 2012 Poster- Figure 2; Greenbaum ASH Annual Meeting 2012 Poster – Figure 2
Soliris (PI) Alexion Pharma Inc 2012– Page 5 Study C09-001 = aHUS Study 3
Long-term Follow-up Study
C ,7: 5 years
(Mar 2012– Dec 2017)
FC notes:
Legendre, p2169A, 2170A, 2171AB
Licht (Kidney Int), p2A
Greenbaum, p2A, 8A
Fakhouri, p2A, 3A
Eculizumab SmPC, p18 (Table 9)
Menne, p458A
Licht (BMC Nephrol), p1A, 3A
(study numbers not in publications but are correct)
aHUS Registry M ,9: treated and not treated
(Apr 2012–ongoing)
>1000 aHUS patients globally
aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; TMA, thrombotic microangiopathy.
1. Legendre et al. N Engl J Med. 2013;368:2169– Licht et al. Kidney Int. 2015;87: Greenbaum et al. Kidney Int. 2016;89: Fakhouri et al. Am J Kidney Dis. 2016;68: Eculizumab Summary of Product Characteristics. Alexion Europe SAS, Menne et al. J Am Soc Nephrol. 2015;26:458A.
Licht et al. BMC Nephrol. 2015;16:

13. Hematologic Normalization Achieved With Ongoing Eculizumab
Hematologic normalization: Normal platelet and LDH levels (≥2 consecutive measurements, ≥4 weeks apart)
C ,2 (N=17):
Progressing TMA
C (N=22):
Pediatric
C ,2 (N=20):
Long Duration of aHUS and CKD
C (N=41): Adult 90
(68–99)a
(at 26 weeks)
88b
(64–99)a
88b
(64–99)a 76
(50–93)a
Patients (%)
Patients (%)
FC notes:
GMA aHUS Expanded Continuation of Treatment MSL Slide Deck FINAL MLR Approved , slides 24, 25
Greenbaum, p3A
Fakhouri, p5A
Eculizumab increased TMA event-free status and reduced the TMA intervention rate in children and adolescents years with aHUS.
13/19 patients (68%) treated with eculizumab achieved TMA event-free status.
TMA event-free status was defined as the proportion of patients who did not have a decrease in platelet count > 25% for 12 consecutive weeks and no PE/PI and no new dialysis.
26 Weeks
1 Yearc
2 Yearsd
26 Weeks
1 Yearc
2 Yearsd
In all studies, hematologic normalization was achieved regardless of the identification of a complement abnormality
a95% CI. bThe 2 patients from C who did not achieve hematologic normalization at years 1 and 2 were those who withdrew from the study within the initial 26-week treatment period. cMedian duration 64 weeks. dMedian duration 100 weeks. aHUS, atypical hemolytic uremic syndrome; CI, confidence interval; CKD, chronic kidney disease; LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy.
1. Legendre et al. N Engl J Med. 2013;369(14): Licht et al. Kidney Int. 2015;87(5): Greenbaum et al. Kidney Int. 2016;89(3): Fakhouri et al. Am J Kidney Dis. 2016;68(1):84-93.

14. Improvement in eGFR Over 26 Weeks With Eculizumab
In Pediatric and Adult Patients
C (N=22): Pediatric
Median (range) time from TMA manifestation to eculizumab initiation: 0.2 (0–4) months
Mean (SD) eGFR at baseline: 33 (30) mL/min/1.73 m2 ‡ † *
*P≤0.01
†P≤0.001
‡P≤0.0001
Dialysis at baseline in
11 (50%)
Mean change from baseline at week 27:
64 mL/min/1.73 m2
(P<0.0001)
n =
C (N=41): Adult
Median (range) time from TMA manifestation to eculizumab initiation: 0.5 (0–19) months
Mean (SD) eGFR at baseline: 17 (12) mL/min/1.73 m2 * †
FC notes: Greenbaum, p3B, p5B
*P≤0.05
†P≤0.001
Only n>5 are shown.
Dialysis at baseline in
24 (59%)
Mean (SD) change from baseline at week 26:
29 (24) mL/min/1.73 m2
(P<0.001)
n = 41 40 38 39 35 36 37 29
eGFR, estimated glomerular filtration rate; SD, standard deviation; TMA, thrombotic microangiopathy.
1. Fakhouri et al. Am J Kidney Dis. 2016;68(1): Greenbaum et al. Kidney Int. 2016;89(3):

15. Earlier Eculizumab Initiation Leads to Improved Renal Recovery
Retrospective analysis with pooled data from 4 prospective clinical studies
Evaluated changes in eGFR in patients initiating eculizumab ≤7 days or >7 days after onset of last TMA manifestation 80
≤7 days
>7 days 70 60 50
Mean Change in eGFR ± SE
(mL/min/1.73 m2) 40 30
FC notes: Vande Walle, p5C 20 10
0.25 1 2 3 4 5 6 7 8 9 10 11 12
Time From Start of Eculizumab Treatment (months)
Patients (N)
Treatment
Initiated in
≤7 days
21 20 18 20 20 19 19 20 17 14
>7 days
76 74 69 74 74 75 72 74 60 54
eGFR, estimated glomerular filtration rate; SE, standard error; TMA, thrombotic microangiopathy.
Vande Walle et al. J Nephrol. 2017;30(1):

16. Continued Improvement in eGFR Over 2 Years With Eculizumab Therapy
C (N=17): Progressing TMA
Pretreatment Period
26-Week Treatment
Extension Treatment
Median (range) time from diagnosis to screening: 9.7 (0.3–235.9) months
Median (range) eGFR at baseline: 19 (5–59) mL/min/1.73 m2
Mean (SD) change from baseline at week 104:
37 (30) mL/min/1.73 m2 (P=0.0062)
Dialysis at baseline in
6 (35%) * †
*P≤0.05
†P≤0.01
N =
C (N=20): Long Duration of aHUS and CKD
Pre-treatment Period
26-Week Treatment
Extension Treatment
Median (range) time from diagnosis to screening: 48.3 (0.7–285.8) months
Median (range) eGFR at baseline: 28 (6–72) mL/min/1.73 m2
Mean (SD) change from baseline at week 104:
8 (17) mL/min/1.73 m2 (P=0.0959)
FC notes: GMA aHUS Expanded Continuation of Treatment MSL Slide Deck FINAL MLR Approved , slide 22 † * ‡
Dialysis at baseline in
2 (10%)
*P≤0.05 ‡P≤0.001
†P≤0.01 §P≤0.0001
N =
aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; TMA, thrombotic microangiopathy.
Legendre et al. N Engl J Med. 2013;369(14): Licht et al. Kidney Int. 2015;87(5):

17. Subgroups of Patients and Specific Topics
Group/Topic
Available Evidence
Results
Pediatric1
Clinical Trial2 and
Case Reports
n=38 Case Reports
Hematologic response to eculizumab ≈100%
Kidney response to eculizumab ≈100%
Adults1
Clinical Trial3 and
n=39 Case Reports
Hematologic response to eculizumab ≈90%
Kidney response to eculizumab ≈56%
Lack of response
Cobalamin C metabolism disease4
Mutation c.2654G→A in C5 in patients with PNH5
Monitoring
Ex vivo Assays
Biomarkers of AP activity Noris et al6
Not agreed upon
O que acha de seguirmos apenas com este, desconsiderando as acimas “escondidos”? Faz um resumo bem interessante da revisão e podemos explorar mais os dados de ECU que você pensou...
FC Notes:
Palma, p44A
Greenbaum, p1A
Fakhouri, p1A
Cornec LeGall, abstract
Nishimura, p632A
Noris, p1725AB
AP, alternative pathway; PNH, paroxysmal nocturnal hemoglobinuria.
1. Palma, Langman. J Blood Med. 2016;7: Greenbaum et al. Kidney Int. 2016;89(3): Fakhouri et al. Am J Kidney Dis. 2016;68(1): Cornec-Le Gall et al. Am J Kidney Dis. 2014;63: Nishimura et al. N Engl J Med. 2014;370: Noris et al. Blood. 2014;124:

18. Limited Evidence Regarding TMA Risk After Discontinuation of Eculizumab
Citation
Evidence Level
Results
Palma & Langman1
Case reports (reviewed)
Varying outcomes from no TMA to TMA events and graft loss
Inconsistent follow-up times across studies
Licht et al2
Clinical trial
C and C08-003: of 4 patients with follow-up after discontinuation, 1 (25%) had a TMA manifestation
Ardissino et al3,4
Prospective study
Home urine dipstick monitoring for TMA (N=16)
Following discontinuation, TMA occurred in 5 patients with CFH variants
Overall TMA rate: 31%
Patients self-selected discontinuation, potentially biasing the findings
Fakhouri et al5
Retrospective study
TMA occurred in 12/38 patients (32%)
TMA limited to patients with CFH or MCP variants
Study excluded patients with challenging clinical courses (ie, transplants, complement-activating conditions or “secondary” disease)
Macia et al6
Report of clinical trial program
12/61 (20%) patients experienced 15 severe TMA complications after a median of 24 weeks discontinuation in aHUS trial program
NCT
Prospective
Ongoing clinical trial of eculizumab discontinuation
FC Notes:
Palma, Table 5
Licht, p11B
Ardissino 2015, p172A
Ardissino 2014, p635A
aHUS, atypical hemolytic uremic syndrome; CFH, complement factor H; MCP, membrane cofactor protein; TMA, thrombotic microangiopathy.
1. Palma, Langman. J Blood Med. 2016;7: Licht et al. Kidney Int. 2015;87(5): Ardissino et al. Am J Kidney Dis. 2014;64: Ardissino et al. Am J Kidney Dis. 2015;66: Fakhouri et al. Clin J Am Soc Nephrol. 2017;12(1): Macia et al. Clin Kidney J. 2016, 1–10.

19. Rate of TMA is Significantly Lower On Eculizumab Compared with Off Therapy
HR: 3.5 (P=0.0048)
C (NCT ) is an ongoing, long-term, observational, multicenter study of patients with aHUS treated with eculizumab in any of 4 prospective or 1 retrospective parent studies
Patients could enroll regardless of whether they continued on eculizumab after the end of the parent study
Primary endpoint: rate of TMA per 100 patient-years off versus on treatment
Interim analysis as of March 28, 2015a
aIn the current C study, patients had a median (range) eculizumab exposure of 26.1 (0.7–64.2) months ON therapy and a median (range) follow-up of
20.1 (0.7–79.5) months during OFF periods.
bThe HR OFF compared with ON periods based on a Cox proportional-hazards model of time to first TMA event during each treatment status.
aHUS, atypical hemolytic uremic syndrome; HR, hazard ratio; TMA, thrombotic microangiopathy.
Menne et al. J Am Soc Nephrol :458.

20. TMA after Discontinuation: evidence from case reports
The authors of this publication reviewed all published cases of patients who discontinued eculizumab treatment; they reported some of their own unpublished cases:
Of six unpublished authors’ cases, four patients had a subsequent thrombotic microangiopathy (TMA) manifestation within 12 months of discontinuation.
Case reports of 52 patients discontinuing eculizumab were identified;16 (31%) had a subsequent TMA manifestation.
TMA were defined by each reporting Dr
TMA reported
No new TMA reported
Macia M et al. CKJ. 2016

21. TMA after Discontinuation: evidence from clinical trials
Median follow-up duration of discontinued patients:
24 months
12 patients experienced 15 severe TMA complications
9/12 restarted eculizumab
TMA complications occurred irrespective of identified genetic mutation, high risk polymorphism or auto-antibody.
Macia M et al. CKJ. 2016

22. Discontinuations and restarts in the global ahus registry
28 (24%) patients aged <18 years discontinued, of whom 7(25%) restarted eculizumab treatment
48 (27%) adult patients discontinued and 5 (10%) subsequently restarted eculizumab treatment
Macia M et al. CKJ. 2016

23. aHUS: Diagnosis and Management
Thrombocytopenia
Platelet count <150 x 109/L
or >25% decrease from baseline
and
Microangiopathic hemolysis
Schistocytes and/or
elevated LDH and/or
decreased haptoglobin and/or
decreased hemoglobin
Plus one or
more of the following:
Neurological symptoms
Confusion and/or
seizures and/or
other cerebral
abnormalities
Renal symptoms
Elevated creatinine and/or
decreased eGFR and/or
elevated blood pressure and/or abnormal urinalysis
GI symptoms
Diarrhea ± blood and/or
nausea/vomiting and/or
abdominal pain and/or
gastroenteritis
Peripheral symptoms
Ischemia and/or
necrosis and/or
gangrene
Establishing a diagnosis of TTP, HUS, or aHUS
What is the molecular cause of the disease? Intrinsic Mechanisms
What has triggered the disease?
Extrinsic Mechanisms
Evaluate ADAMTS13 = TTP
Evaluate Shiga-toxin = STEC-HUS
By exclusion = aHUS
(complement factors?, functional tests?)
Infection, inflammation, malignancy
Medication (CsA, chemotherapy, VEGF-TK)
Immune complexes, autoantibodies, phospholipids
Pregnancy, "malignant" hypertension, scleroderma
Establishing the clinical severity of the disease (organ failure)
Individualized treatment strategy (eculizimab, plasmapheresis, clinical care)
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome; CsA, cyclosporin A; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; LDH, lactate dehydrogenase; STEC, Shiga toxin-producing Escherichia coli; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura; VEGF-TK, vascular endothelial growth factor tyrosine kinase inhibitor.
Reproduced with permission by Haller H.

24. Questions?