Thrombotic Microangiopathy (TMA) and Acute Kidney Injury Diagnosis

Thrombotic Microangiopathy (TMA)
in Adults and Acute Kidney Injury
Mohammed Abdel Gawad MD Neph, ESENeph
Lecturer of Nephrology, School of Medicine, NewGiza University
Nephrology Consultant, Alexandria
Founder of NephroTube.com
Co-chair of AFRAN Web/Media Committee
ISN Education SoMe Team Member
30, January 2023

To download the lecture contact me
drgawad@gmail.com
For more Nephrology lectures visit
www.NephroTube.com

Visit
www.NephroTube.com
for more lectures

⚫ 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?
Questions

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

What are the causes of
TMA?
TTP/HUS
Am J Kidney Dis. 2022 Dec 9;S0272-6386(22)01056-3

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

Thrombocytopenia
Consumption of
platelets
TTP
Shiga toxin HUS
(Typical HUS)
TMA in TTP-HUS?
Complement
mediated TMA
(Atypical HUS)

Thrombocytopenia
Consumption of
platelets
TTP
TMA in TTP-HUS?
TTP
Shiga toxin HUS
(Typical HUS)
Complement
mediated TMA
(Atypical HUS)

H-M Tsai. Kidney International (2006) 70, 16–23.
What is ADAMTS 13, and What is its
role?

Autoantibodies
against ADAMTS13
Acquired TTP
(60% to 90% of the
cases)
Inherited
deficiency
of ADAMTS13
Congenital TTP
- Am J Kidney Dis. 2022 Dec 9;S0272-6386(22)01056-3
- 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.
TTP - Classification

Res Pract Thromb Haemost. 2022 Apr 22;6(3):e12708.

Thrombocytopenia
Consumption of
platelets
TTP ADAMTS 13
TMA in TTP-HUS?
Shiga toxin HUS
(Typical HUS)
Complement
mediated TMA
(Atypical HUS)

Thrombocytopenia
Consumption of
platelets
TTP
Shiga toxin HUS
(Typical HUS)
ADAMTS 13
TMA in TTP-HUS?
Complement
mediated TMA
(Atypical HUS)

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
Morigi M et al. Blood. 2001;98:1828-1835.
Morigi M et al. J Immunol. 2011;187:172-180.

Other Infections
Associated TMA

Thrombocytopenia
Consumption of
platelets
TTP
Shiga toxin HUS
(Typical HUS)
ADAMTS 13
Toxin binds
endothelium
TMA in TTP-HUS?
Complement
mediated TMA
(Atypical HUS)

Thrombocytopenia
Consumption of
platelets
TTP ADAMTS 13
TMA in TTP-HUS?
Shiga toxin HUS
(Typical HUS)
Toxin binds
endothelium
Complement
mediated TMA
(Atypical HUS)

Atypical HUS
Low serum C3 levels in aHUS with
normal C4 indicate selective
alternative pathway activation.

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

Atypical HUS

Atypical HUS
• The absence of a detectable mutation does not preclude a
genetic form. More variants are emerging as genetic testing
increases in quality and frequency, and as patient registries
expand.
• The penetrance of familial CM-TMA is incomplete and may
present with more advanced age, suggesting that a second
hit is needed to unmask overt TMA.
• Age can help narrow the differential diagnosis, as the
majority of patients who develop CM-TMA are less than 60
years.

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.

Thrombocytopenia
Consumption of
platelets
TTP ADAMTS 13
TMA in TTP-HUS?
Shiga toxin HUS
(Typical HUS)
Toxin binds
endothelium
Alternative
Complement
Complement
mediated TMA
(Atypical HUS)

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

TMA – MAHA
Shistocytes
Elevated LDH & Bilirubin
Mechanical fragmentation
of erythrocytes
during flow through partially
occluded, high shear small
vessels

Anaemia, thrombocytopenia
reticulocyte count, LDH, bilirubin raised
Am J Kidney Dis. 2022 Dec
9;S0272-6386(22)01056-3
Systematic Approach
of Diagnosis

9;S0272-6386(22)01056-3
Systematic Approach
of Diagnosis
• Systemic findings of TMA (i.e. MAHA and thrombocytopenia) are
not required for the diagnosis of TMA. Indeed, renal-limited TMA
is not infrequently observed in clinical practice.
• Isolated renal TMA lesions with may be observed more often in
the setting of glomerulonephritides (e.g. ANCA-associated
vasculitis, IgA nephropathy), solid organ transplantation (e.g.
calcineurin inhibitor (CNI) or antibody-mediated rejection (ABMR))
and in drug-induced TMA.

9;S0272-6386(22)01056-3
DD of
thrombocytopenia
& MAHA
Systematic Approach
of Diagnosis
TTP/HUS

9;S0272-6386(22)01056-3
Systematic Approach
of Diagnosis
Step 1 –
Exclude Drugs

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

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

Coomb’s test
-ve & Schistocytes
on blood film
Other causes of
TMA
+ve:
Autoimmune Hemolysis/Evans
syndrome
- Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335.
- Patton JF et al. Am J Hematol. 1994;47:94-99.
Systematic Approach
of Diagnosis
Step 2 – Autoimmune
Hemolysis
Step
3

PTT, PT, INR
Abnormal
FDP
High in DIC
Normal in
HELLP
Normal
TTP / HUS
Or
others
Systematic Approach
of Diagnosis
Step 3 –
Coagulation Profile
Step 4 – Exclude other causes

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.
Systematic Approach
of Diagnosis

DD Suggestive Criteria
Sepsis
• Sepsis patients have hypotension, fever
• Raised white count with left shift.
• Blood cultures might be positive.
Pregnancy Must be excluded.
Autoimmune
Disease
ANA, RF, antiDNA, ACLA, lupus anticoagulant
Cobalamin
deficiency
Vit B12 level
Systematic Approach
of Diagnosis

Systematic Approach
of Diagnosis

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

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

Systematic Approach
of Diagnosis
Step 5 –
TTP vs HUS
Shiga toxin-
HUS
TTP Atypical HUS
- Occurs primarily in children,
(except in epidemics with any age)
- Watery or bloody diarrhoea.
- Stool Culture, PCR or ELISA for
shiga toxin

PLASMIC score for estimating the likelihood of
severe ADAMTS13 deficiency in adults with
suspected TTP

Systematic Approach
of Diagnosis
Difficult to distinguish on clinical grounds only
Differential diagnosis of aHUS is made on exclusion:
• Of infections by STEC or other infections
• Of ADAMTS13 deficiency or autoantibodies
• Of Systemic-associated diseases
TTP Atypical HUS

• It is recognized that in clinical practice the full spectrum
of these tests is often not often readily available.
Furthermore, results of some of these tests may not be
available for days to months.
• Prompt initiation of targeted therapies such as
therapeutic plasma exchange (TPE) or eculizumab should
not be delayed.
Systematic Approach
of Diagnosis

Systematic Approach
of Diagnosis
TTP Atypical HUS
Moschcowitz E. Mt Sinai J Med. 2003;70:352-355.

Systematic Approach
of Diagnosis
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.
-Vesely SK et al. Blood. 2003;102:60-68.
-Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335.
TTP Atypical HUS

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?

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.
O157:H7

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

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
HUS Treatment

Is there a role for plasma exchange?
No prospective RCTs are available
There is insufficient evidence to support TPE in routine
management of infection-associated HUS; however, it can be
considered in severe cases.
Dundas S et al. Lancet. 1999;354:1327-1330.
Carter AO et al. N Engl J Med. 1987;317:1496-1500.
HUS Treatment

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

Atypical HUS
Treatment
Plasma Exchange:
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.
4. Plasma exchange can be considered in patients
with life threatening end-organ injury
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.

Atypical HUS
Treatment
Immunosuppressants:
Patients with anti-FH antibodies may also benefit
from TPE and immunosuppression (rituximab or
cyclophosphamide) to clear circulating antibodies
and prevent relapse.
Dragon-Durey MA et al. J Am Soc Nephrol. 2010;21:2180-2187.
Plasma exchange

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

Autoantibodies
against ADAMTS13
Acquired TTP
(60% to 90% of the
cases)
Inherited
deficiency
of ADAMTS13
Congenital TTP
TTP

Autoantibodies
against ADAMTS13
Acquired TTP
(60% to 90% of the
cases)
TTP

Autoantibodies
against ADAMTS13
Acquired TTP
(60% to 90% of the
cases)
TTP
ADAMTS13 activity < 10% +
Abs to ADAMTS13
(N.B. some individuals with
acquired TTP do not have a
detectable inhibitor for a variety
of reasons!!)

Caplacizumab does not however target antibody-production and
consequently disease relapses occur without targeted B-cell depletion.

Expert Rev Hematol. 2020 May;13(5):461-470.
Lack of a clinical
response
Recurrence of thrombocytopenia
following a remission without
another cause (subsequently must
be confirmed by documenting
ADAMTS13 activity <10 percent).

What is the ideal time to start PEX sessions?
Acquired TTP Treatment
First Line Therapy

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

When to stop PEX?
First Line Therapy

When Plasma infusion (25 to 30
mL/kg per day) 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.
First Line Therapy
Pereira A, Mazzara R, Monteagudo J, et al. Ann Hematol. 1995;70:319-323.

PEX
+ CST
Adjuvant
Anti
Platelets
Folic
Acid
Blood
Transfusion
Platelets
Transfusion
Thrombop-
rophylaxis
??
If platelets
> 50
Specially
when
hemolysis
Clinical situation/
Hemolysis
!!!! Only if sever bleeding
or require an invasive
procedure
??
If platelets > 50
Adjuvant Therapy

Inherited
deficiency
of ADAMTS13
Congenital TTP
TTP

Inherited
deficiency
of ADAMTS13
Congenital TTP
TTP
ADAMTS13 activity
< 10%, absence of
Abs to ADAMTS13.

97
Am J Kidney Dis. 2022 Dec 9;S0272 6386(22)01056-3
Treatment of other forms
of TMA

98
Am J Kidney Dis. 2022 Dec 9;S0272 6386(22)01056-3
Treatment of other forms
of TMA

⚫ Transplant-Associated TMA:
❖ Hematopoietic stem cell Transplant
❖ Kidney transplant
What I didn’t mention?

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

Thrombotic Microangiopathy (TMA) and Acute Kidney Injury Diagnosis

Recomendados

Recomendados

Más contenido relacionado

La actualidad más candente

La actualidad más candente (20)

Similar a Thrombotic Microangiopathy (TMA) and Acute Kidney Injury Diagnosis

Similar a Thrombotic Microangiopathy (TMA) and Acute Kidney Injury Diagnosis (20)

Más de NephroTube - Dr.Gawad

Más de NephroTube - Dr.Gawad (20)

Último

Último (20)

Thrombotic Microangiopathy (TMA) and Acute Kidney Injury Diagnosis