Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (Questions & Answers) - Dr. Gawad

TTP/HUS r
Questions & Answers
Mohammed Abdel Gawad
Nephrology Specialist
Kidney & Urology Center (KUC)
Alexandria
drgawad@gmail.com
ESNT Outreach Program, Sohag, December 4-7, 2014

To download the lecture with full
animations please contact me on
drgawad@gmail.com

Questions
What is meant by Thrombotic Microangiopathy
(TMA)?
What are the causes of TMA?
What is the mechanism of TMA in TTP-HUS?
What is the diagnostic approach of TTP-HUS &
TMA?
What are the treatment protocols of TTP-HUS?
1

What is meant by Thrombotic
Microangiopathy (TMA)?
Intraluminal platelet thrombosis
Thrombocytopenia
Microangiopathic hemolytic
anemia
Consumption of
platelets
Hemolysis, Anemia, ↑LDH &
Bilirubin
1

Questions
(TMA)?
TMA?
2

What are the causes of
?TMA
HIV,
TTP/HUS
2

What is the mechanism of
TMA in TTP-HUS?
Thrombocytopenia
anemia
Consumption of
platelets
Bilirubin
2

TMA in TTP-HUS?
Consumption of
platelets
Thrombocytopenia
TTP
Shiga toxin HUS
Neuraminidase HUS
Atypical HUS
3

What is vWF role in
?body
Flora Peyvandi et al. Blood Transfus 2011; 9 Suppl 2:s3-s8-
. Romijn RAP et al. J Biol Chem 2001; 276: 9985-91-
·Leo T. Kroonen et al. Orthopedics. March 2008 - Volume 31-
3

What is vWF role in
?body
vWF activation = Platelets
Aggregation & Adhesion
Flora Peyvandi et al. Blood Transfus 2011; 9 Suppl 2:s3-s8-
. Romijn RAP et al. J Biol Chem 2001; 276: 9985-91-
·Leo T. Kroonen et al. Orthopedics. March 2008 - Volume 31-
3

TTP - Classification
- H-M Tsai. Kidney International (2006) 70, 16–23.
-Tsai HM. Annu Rev Med 2006; 57: 419–436.
- Allford SL et al. Br J Haematol. 2003;120:556-573.
5

TMA in TTP-HUS?
Consumption of
platelets
Thrombocytopenia
TTP
Shiga toxin HUS
ADAMTS 13
Neuraminidase HUS
Atypical HUS
6

Shiga Toxin
Associated HUS
E. coli (STEC)
S. dysenteriae
watery or most
often bloody
diarrhea
E.Coli:
Mostly the serotype O157:H7,
but also other serotypes, such
as O111:H8, O103:H2, O123,
O26, O145, and the O104:H4
strain of the recent German
outbreak
Mead PS, Griffin PM. Lancet.1998;352:1207-1212.
Ruggenenti P, Remuzzi G.Lancet. 2011;378:1057-1058.
6

Shiga Toxin
Associated HUS
E. coli (STEC)
S. dysenteriae
watery or most
often bloody
diarrhea
Mead PS, Griffin PM. Lancet.1998;352:1207-1212.
Ruggenenti P, Remuzzi G.Lancet. 2011;378:1057-1058.
6

Shiga Toxin
Associated HUS
E. coli (STEC)
S. dysenteriae
watery or most
often bloody
diarrhea
Morigi M et al. Blood. 2001;98:1828-1835.
Morigi M et al. J Immunol. 2011;187:172-180.
7

Shiga Toxin
Associated HUS
E. coli (STEC)
S. dysenteriae
watery or most
often bloody
diarrhea
Complement
activation by
alternative
pathway:
High plasma
levels of
complement
activation
products
Bb and C5b-9
were
measured in
children with
STEC-HUS
7

Consumption of
platelets
Thrombocytopenia
TTP
Shiga toxin HUS
ADAMTS 13
Neuraminidase HUS
Atypical HUS
Toxin binds
endothelium
TMA in TTP-HUS?
8

Neuraminidase
Associated HUS
In infants and children. Complicate pneumonia, or less
frequently, meningitis caused by S. pneumoniae
erythrocytes, platelets,
glomerular cells
Brandt J, Wong C, Mihm S, et al. Pediatrics. 2002;110:371-376.
Thomsen-Friedenreich antigen
8

Neuraminidase
Associated HUS
glomerular cells
Polyagglutination
8

Neuraminidase
Associated HUS
glomerular cells
Polyagglutination
8
Coomb’s +ve

Atypical HUS
Low serum C3 levels in aHUS with
normal C4 indicate selective
.alternative pathway activation
Noris M, Ruggenenti P, Perna A, et al. J Am Soc Nephrol. 1999;10:281-293.
9

Atypical HUS
Caprioli J et al. Blood. 2006;108:1267-1279.
Manuelian T, et al. J Clin Invest. 2003;111:1181-1190.
9

Atypical HUS
Acquired defects of CFH function are also
seen in the form of inhibitory antibodies,
reported in 5% to 10% of aHUS patients.
Dragon-Durey MA, Loirat C, Cloarec S, et al. J Am Soc Nephrol. 2005;16:555-563.
10

Consumption of
platelets
Thrombocytopenia
TTP
Shiga toxin HUS
ADAMTS 13
Neuraminidase HUS
Atypical HUS
Toxin binds
endothelium
Alternative
Complement
TMA in TTP-HUS?
10

TMA in TTP-HUS?
Thrombocytopenia
anemia
Consumption of
platelets
Bilirubin
11

Questions
(TMA)?
TMA?
12

Marie Scully et al. British Journal
of Haematology, 2012, 158, 323–
335.
HIV,
DD of
thrombocytopenia
& MAHA
Systematic Approach
of Diagnosis
12

Systematic Approach
Marie Scully et al. British Journal
of Haematology, 2012, 158, 323–
335.
of Diagnosis
Step 1 –
Exclude Drugs
12

Systematic Approach
Piero Ruggenenti, Comprehensive
Clinical Nephrology. 4th edition,
chapter 28, p353
of Diagnosis
Step 1 –
Exclude Drugs
12

Systematic Approach
of Diagnosis
Step 1 – Exclude
Drugs
Step 1 –
Exclude Drugs
12

Systematic Approach
of Diagnosis
- Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335.
- Patton JF et al. Am J Hematol. 1994;47:94-99.
Step 2 – Autoimmune
Hemolysis
13

Systematic Approach
of Diagnosis
- Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335.
- Patton JF et al. Am J Hematol. 1994;47:94-99.
Step 2 – Autoimmune
Hemolysis
Step
3
13

Systematic Approach
of Diagnosis
Step 3 –
Coagulation Profile
Step 4 – Exclude other causes
14

Systematic Approach
of Diagnosis
DD Suggestive Criteria
Malignant
Hypertension
• Patient will have severe HTN: for example, systolic BP >200
mmHg, diastolic BP >130 mmHg.
• It is extremely unlikely that a patient with TTP will present with
severe HTN.
• Microangiopathic haemolysis in patients with malignant HTN
clears and thrombocytopenia resolves with BP management.
Pre-eclampsia
• New BP elevation and proteinuria after 20 weeks of gestation
in a pregnant woman.
• Although pregnancy is a risk factor for TTP and proteinuria
can be present, patients with TTP do not generally have raised
BP.
15

Systematic Approach
of Diagnosis
DD Suggestive Criteria
Sepsis
• Sepsis patients have hypotension
• More pronounced fever
• Raised white count with left shift.
• Peripheral smear: vacuoles in the cytoplasm of
neutrophils (highly specific for bacteraemia)
• Blood cultures might be positive.
Pregnancy Must be excluded.
Autoimmune
Disease
ANA, RF, antiDNA, ACLA, lupus anticoagulant
16

Systematic Approach
of Diagnosis
HIV,
17

Systematic Approach
of Diagnosis
17

Systematic Approach
of Diagnosis
• TTP has been reported in
association with acute pancreatitis.
• Sometimes a number of days
after resolution of pancreatitis.
• All patients were successfully
treated with PEX and
corticosteroids (McDonald et al,
2009).
An association between
thrombocytopenia and
thyrotoxicosis has been
reported
17

Systematic Approach
of Diagnosis
Atypical HUS TTP
Step 5 –
TTP vs HUS
Shiga toxin-
HUS
Neuraminidase
-HUS
18

Systematic Approach
of Diagnosis
Step 5 – TTP vs HUS
Shiga toxin-
HUS
- Less than 2 years old
- Respiratory distress,
neurologic
involvement,
and coma.
Neuraminidase
-HUS
- Occurs primarily in children, (except
in epidemics with any age)
-Watery or bloody diarrhoea.
- Stool Culture: detection of E. coli
O157:H7 and other STEC and their
products in stool cultures (sorbitol-containing
MacConkey agar - SMAC)
Mead PS, Griffin PM. Lancet. 1998;352:1207-1212.
18

Systematic Approach
of Diagnosis
Atypical HUS TTP
Step 5 –
TTP vs HUS
Shiga toxin-
HUS
Neuraminidase
-HUS
19

Systematic Approach
of Diagnosis
Atypical HUS TTP
Difficult to distinguish on clinical grounds only
Moschcowitz E. Mt Sinai J Med. 2003;70:352-355.
19

Systematic Approach
of Diagnosis
Atypical HUS TTP
TTP Pentad:
1. Microangiopathic haemolytic anaemia
2. Thrombocytopenia with purpura
3. Acute renal insufficiency
4. Neurological abnormalities
5. Fever
is rare for all of these features (TTP pentad) to be seen.
19
-Vesely SK et al. Blood. 2003;102:60-68.
-Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335.

Systematic Approach
of Diagnosis
Atypical HUS TTP
Differential diagnosis of aHUS is made on exclusion:
• Of infections by STEC or neuraminidase - producing
S.pneumoniae,
• Of ADAMTS13 deficiency,
• Of Systemic-associated diseases
20

Systematic Approach
of Diagnosis
Atypical HUS TTP
Moschcowitz E. Mt Sinai J Med. 2003;70:352-355.
Eknoyan G, Riggs SA. Am J Nephrol. 1986;6:117-131. 20

Systematic Approach
of Diagnosis
Step 1: Exclusion of drugs
Step 2: Exclusion of Autoimmune hemolysis
Step 3: Coagulation Profile
Step 4: Exclusion of other systemic causes
Step 5: TTP vs HUS?
20

Questions
(TMA)?
TMA?
21

Shiga Toxin
Associated HUS
E. coli (STEC)
S. dysenteriae
watery or most
often bloody
diarrhea
21

Shiga Toxin Associated
HUS Treatment
Generally Supportive (including RRT if required)
No role for anticoagulation
No role for Antitimotility agents
21

HUS Treatment
No role for Antibiotics except:
1.Patients presenting with bacteremia
2.HUS, hemorrhagic colitis and HUS caused by Shigella
dysentery type 1
3.Azithromycin had some benefit on the duration of bacterial
shedding in adult patients from the German O104:H4
epidemic
21

HUS Treatment
Is there a role for plasma exchange?
No prospective RCTs are available
But comparative analyses of two large series of patients
treated or not treated with plasma suggest that plasma
therapy may dramatically decrease overall mortality of STEC
O157:H7–associated HUS.
Dundas S et al. Lancet. 1999;354:1327-1330.
Carter AO et al. N Engl J Med. 1987;317:1496-1500.
22

Atypical HUS
Mutations or
Antibodies
Caprioli J et al. Blood. 2006;108:1267-1279.
Manuelian T, et al. J Clin Invest. 2003;111:1181-1190.
22

Atypical HUS Treatment
Plasma exchange vs Plasma infusion
Plasma Exchange is superior to Infusion:
1.Plasma exchange allows supplying larger amounts of
plasma than would be possible with infusion while
avoiding fluid overload.
2.Remission and prevention of recurrences, by
removal of mutant CFH.
3.Plasma exchange is used to remove anti-CFH
antibodies, but the effect is usually transient.
Noris M, Remuzzi G. N Engl J Med. 2009;361:1676-1687.
Dragon-Durey MA, et al. J Am Soc Nephrol. 2005;16:555-563.
23

Plasma exchange
Immunosuppressants (corticosteroids
and azathioprine or mycophenolate mofetil)
combined with plasma exchange allowed long-term
dialysis-free survival in 60% to 70% of
patients.
Dragon-Durey MA et al. J Am Soc Nephrol. 2010;21:2180-2187.
24

Licht C et al. J Am Soc Nephrol. 2011;22:197A.
Greenbaum LA et al. J Am Soc Nephrol. 2011;22:197A.
24

HUS Treatment
24
STEC - HUS Atypical HUS
• General supportive
• No anticoagulation
• No antimotility drugs
• No antibiotics (except some
situations)
• ??? PEX
• Plasma Therapy (PEX is
better) +
Immunosuppressives
• Eculizmab

TTP - Classification
- H-M Tsai. Kidney International (2006) 70, 16–23.
-Tsai HM. Annu Rev Med 2006; 57: 419–436.
- Allford SL et al. Br J Haematol. 2003;120:556-573.
25
ADAMTS13 activity
< 5%, absence of
Abs to ADAMTS13.

Acquired TTP Treatment
First Line Therapy
25

What is the ideal time to start PEX sessions?
25
First Line Therapy

What is the ideal initial volume of exchange?
X plasma 5·1
volume (PV)
exchange on the
first 3 d
followed by 1·0 PV
exchange
thereafter
Canadian (
apheresis trial
)regimen
26
First Line Therapy

When to intensify PEX?
1. Refractory TTP (Progression of clinical
symptoms or persistent thrombocytopenia despite
seven daily PEX procedures)
2. New neurological insult
3. New cardiac insult
26
First Line Therapy

When to stop PEX?
27
First Line Therapy

When Plasma infusion is indicated?
Although PEX remains the treatment
of choice, large volume plasma
infusions are indicated if there is to
be a delay in arranging PEX.
27
First Line Therapy
Pereira A, Mazzara R, Monteagudo J, et al. Ann Hematol. 1995;70:319-323.

First line within 4-6 hrs
)volume exchange(
Highly recommended
?? although no RCT
If platelets
> 50
Specially
when
hemolysis
/Clinical situation
Hemolysis
Only if !!!!
sever bleeding
??
If platelets > 50
?When to intensify
?When to stop
28
First Line Therapy

Other Options
29

Other Options
29
Refractory
??TTP
Relapse
??TTP

Refractory/
Relapsing TTP
29
Refractory TTP:
Progression of clinical symptoms or persistent
thrombocytopenia despite seven daily PEX procedures
Relapsing TTP:
Episode of acute TTP more than
30 d after remission, and occurs in 20–50% of cases.

30
Other Options

Refractory/ -
Resistant Cases
Initiation -
(cardiac,
)neurological
Case Reports &
small trials but
recommended ??
Trials
30
Other Options

TTP - First described
Dr. Eli Moschcowitz
Arch Intern . Med. 1925;36:89
30

Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (Questions & Answers) - Dr. Gawad

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