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Thrombotic Microangiopathies: Current Insight Into Organ dysfunction
Élie AZOULAY,
Hôpital Saint-Louis, Service de Réanimation
Université Paris-Diderot, Sorbonne Paris-Cité
Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH)
CarIng for CrItIcally Ill ImmunocompromIzed PatIents– The Nine-I Network
C3
B factor
C5
TTPH
U
S
T
M
A
Steroids?
Rituximab
Hypertension
AKI
Renal
Neurological
C
A
R
D
I
A
C
ADAMTS 13
Complement
Ischemia
Thrombosis
Hemorrhage
STEC
aHUS
ICU Renal replacement therapy
Coma
Stroke
Medical emergency
Auto-immunity
O
U
T
C
O
M
E
SGenetic
Elie Azoulay, Do-Not-replicate
Differential diagnosesEvans, B12 deficiency, sepsis, HIT
Seizures
Eculizumab
Unresponsive
First line therapy
Second line therapy
H
E
M
O
L
Y
S
I
S
T
H
R
O
M
B
O
C
Y
T
O
P
E
N
I
A
Multiple Organ Failure
Drug-Transplantation
Cancer
Infection
H Factor
CD46 (MCP)
I Factor
S
C
H
I
S
T
O
C
Y
T
E
S
Idiopathic
COOMBS TEST
Pregnancy
Troponin
Plasma exchange
Sudden death
Thrombotic Microangiopathies
1. Understand the disease
2. Identify clinical entities: HUS, aHUS,
TTP
3. Organ dysfunction in TMAs
❶. Understanding TMAs
Normal Erythrocyte
Mechanical (non-immune) Hemolysis
Microvascular Thrombosis
Platelet-WB aggregation
Ischemia
Thrombotic Microangiopathy syndromes
3. Microvascular occlusive disorders by platelet aggregation
TTP, ischaemia in the brain, heart, etc… and most organs
HUS, platelet–fibrin thrombi occlude predominantly, but not only, the renal circulation
1. Mechanical
(non-
immune)
injury to
normal
erythrocytes
2. Consumption
(Peripheral )
thrombocytopenia
TMA diagnosis: basics
Fremeaux-Bacchi V, et al. Clin J Am Soc Nephrol 2013;8:554-61
George JN, et al. N Engl J Med 2014;371:654–66
Scully M, et al. Br J Haematol 2014;164:759–66
TMA= a Multiple Organ Dysfunction
TMA
• Severe
• Reversible
• Prognostic factors hardly apply
• Duration of life support
• Impact of early appropriate management
Myocardial infarctionThromboembolismCardiomyopathyDiffuse vasculopathy
Elevated creatinineEdemaMalignant hypertensionRenal failureDialysisTransplant
ConfusionSeizuresStrokeEncephalopathyDiffuse cerebral dysfunction
Liver necrosisPancreatitisDiabetes MellitusColitisDiarrheaNausea/vomitingAbdominal pain
Hemolysis
Decreased platelets
Fatigue
Transfusions
Mesentericischaemia
Stroke
Myocardial
Infarction
Hospitalacquiredinfection
Varia
- AKI
- Alveolarhaemorrhage Thrombosis
>
Haemorrhage
Peigne V, et al. Intensive Care Med 2012;38:1810–7
57 TMA patients who died
compared to 48 TMA
survivors matched on age,
gender, and baseline platelet
count and creatinine level.
Noris M, et al. N Engl J Med 2009;361:1676–87
Tsai H, et al. Am J Med 2013;126:200–9
Orth D, et al. J Immunol 2009;182:6394–400
Johnson S, et al. Immunobiology 2012;217:235–43 ❷. TTP, atypical HUS and STEC-HUS
From bedside to bench (and back again)
TTP: Neuro, E Moschowitz
Arch Intern Med 1924
HUS: Renal, Gasser
Schweiz Med Wochenschr
1952
TTP/HUS, Remuzzi
Kidney Int 1987
HUS, Karmali
Diarrhea, Shigatoxin
J Infect Dis 1985
TTP, Tsaï, Furlan,
Undetectable ADAMTS13
N Engl J Med 1998
Atypical HUS, Warwicker
Excessive complement
activation
Kidney Int 1998
56 TMA
25 TTP
Platelet-rich thrombi
heart, pancreas, kidney, adrenal gland, and brain
31 HUS
Fibrin/red cell-rich thrombi
Largely confined to the kidney and severe, 6 pancreas, 4 adrenal gland,
2 brain, and 1 heart
TTP and HUS: two distinct pathologic entitiesA review of 56 autopsy cases
Hosler GA, et al. Arch Pathol Lab Med 2003;127:834–9
Atypical HUS is not exclusively renal
Noris M, et al. Clin J Am Soc Nephrol 2010;5:1844–59
Presentation of aHUS from the largest European cohort
Algorithm for differential diagnosis
CLINICAL SUSPICION OF TMA
Organ damage (> 1) Thrombocytopaenia
Microangiopathic
haemolysis
GI
Abdominal pain
Nausea
Vomiting
Diarrhoea
Diarrhoea with blood
PLT consumption
PLT <150 x109/L
or
PLT reduction >25%
LDH >N.V.or
Close to the limit of N.V.(if Hb <N.V. check LDH)
Elevated reticulocytes
CNS
Confusion
Seizures
Stroke
Coma
OTHER
Fatigue/asthenia
Purpura/petechiae
Dyspnoea
Hypertension
Fever
RENAL
Oligoanuria
Oedema
sCr >N.V.
Proteinuria
Micro/Macrohaematuria
Repeat test
after 24 hours
+ +
TMA DIAGNOSIS CONFIRMATION
Presence of schistocytes in blood smear
(specify % and number/field)
Negative
Reduction <N.V.
Tests within normal range
SCHISTOCYTES
DIRECT ANTIGLOBULIN
(COOMBS) TEST
HAPTOGLOBIN
COAGULATION
Repeat test after
24 hours if both
not present
Please consult a haematologist and / or nephrologist where appropriate
EXCLUDE OTHER CAUSES OF TMA
DIC: prothrombin time and aPTT prolonged; fibrinogen low (or low-normal with infection);
D-dimers high; anti-thrombin and protein C low
Drug use: heparin use, alcohol toxicity, ADP- receptor antagonists, GP IIb/IIIa inhibitors,
calcineurin inhibitors, mitomycin C, quinine etc.
Disseminated malignancy/bone marrow carcinosis
Organ transplantation, including haematopoietic stem cell transplantation
Evans syndrome, S. pneumoniae HUS, Autoimmune hemolytic anaemia: Positive Coombs test
If symptoms persist after treatment of one of the above mentioned causes of TMA, consider
differential diagnosis of aHUS, STEC-HUS or TTP
Others*
ADAMTS13 activity < 10% ADAMTS13 activity > 10% Shiga-toxin/EHEC positivity
TTP aHUS STEC-HUS
TMA DIFFERENTIAL DIAGNOSIS
Family history of TMA and/or renal failure supports a diagnosis of aHUS or congenital TTP
Azoulay E, et al. Chest 2017
Adult Shiga toxin–associated HUS patients are older, present more frequently with
digestive symptoms, higher hemoglobin and fibrinogen levels than other TMAs.
However, overlap remains substantial
Need to implement early PEX until TTP and a HUS can be ruled out.
Mannucci PM. Intensive Care Med 2015
ADAMTS 13
TMA
PEX
60ml/kg/d
100% plasma
Corticosteroids
1mg/kg/dayBP control
Differential diagnosesADAMTS13, Complement
TTP HUS
Platelet count
Creatinine
ADAMTS 13
ADAMTS 13
makes the
diagnosis of
TTP and of
aHUS
Chronic uncontrolled complement activation leads to systemic TMA in aHUS
Platelet
Platelets:
− activation
− aggregation
Chronic
uncontrolled
complement
activation
Endothelial swelling and
disruption Clinical consequences:
Platelet consumption
Mechanical haemolysis
Blood clot formation
Vessel occlusion
Inflammation
Ischaemia
Hypoxia
Platelet
aggregation
Systemic multi-organ complications
Leukocytes:
− activation
Red cells:
− complement deposits
− haemolysis
Endothelial cells:
− activation
− swelling and disruption
Meri S, et al. Eur J Int Med 2013;24:496–502; Zipfel PF, et al. Curr Opin Nephrol Hypertens 2009;19:372–8
Desch K, et al. JASN 2007;18:2457–60; Licht C, et al Blood 2009;114:4538–45
Noris M, et al. N Engl J Med 2009;361:1676–87; Ståhl A, et al. Blood 2008;111:5307–15
Morigi M, et al. J Immunol 2011;187:172–80
Unlike TTP, aHUS cannot be
diagnosed based on
Complement data, the diagnosis
of aHUS is made once
ADAMTS13 is found detectable
Steroid pulses?
Aspirin?
Anticoagulants?
Caplacizumab?
Vincristine?
More plasma?
BP control?
More plasma?
Vincristine?
Splenectomy?
Steroid pulses?
More plasma?
BP control?
In addition to early Rituximab
❸. Organ dysfunction
HUS: Mesangiolysis, fibrin thrombi and fibrinoidnecrosis involving the glomerular vascular pole
Mesangiolysis
Fibrin thrombi Fibrinoid necrosis
El Husseini et al. Am J Kidney Dis. 65(1):127-130
Arteriolar & capillary microthrombi (white clots, platelet-rich fibrin-poor)
AKI in STEC-induced HUS
AKI appeared during the first
days of diarrhoea onset
160 patients (54%) required RRT
• Dialysis was required for 10.3 (SD 11.5) days, with 7.7 (SD 8.1) sessions
• In most patients renal function normalised within 4–6 weeks
• At discharge 13 of 238 patients were receiving dialysis; only three (2%)
required long term RRT
Clinical presentation of aHUS in the French genotyped cohort
Frémeaux-Bacchi V et al. CJASN 2013;8:554–62
Genetics and Outcome of Atypical HUS: A Series Comparing Children and Adults
Fremeaux-Bacchi et al. Clin J Am Soc Nephrol. 2013 Apr 5; 8(4): 554–562.
• Open-label single-arm phase 2 trial. Multicenter multinational study of aHUS patients.
• 41 patients were treated with IV eculizumab for 26 weeks. 30 (73%) had complete TMA response.
• All 35 patients on baseline plasma exchange/plasmainfusion discontinued by week 26.
• Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation
and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment.
• Two patients developed meningococcal infections
Dialysis could be discontinued
20/24 (83%) of patients on dialysis at
baseline could discontinue dialysis
15/17 (88%) patients not on dialysis at
baseline, remained dialysis-free through
the study evaluation period
Evolution of eGFR under eculizumab treatment in adults with aHUS
29.3 mL/min/1.73m2: mean change from baseline in eGFR at Week 26
37 patients (2 cohorts)
with PEX observation
followed by Eculizumab
Earlier intervention with eculizumab in patients with aHUS leads to greater improvement in eGFR
Combined dataset – C08 and C10
Vande Walle J et al. J Nephrol 2015;30:127–134 eGFR, estimated glomerular filtration rate
Neurological symptoms
Headache
Aphasia
Hemianopsia
Visual bluring
Amnesia
Hemiparesis
Encephalopathy
Seizures
Dysarthria
Cortical blindness
Cerebral Imaging
Petechial hemorrhage
Edema
Infarction (hemorrhagic)
White and gray matter
Every possible location
Strokes involved large- or small-vessel:
– posterior cerebral artery
– middle cerebral artery
– Lenticulostriate
No correlation between clinical symptoms and MRI findings
Patients with infarction or hematoma had unfavorable outcome
Reversible cerebral edema (reversible posterior leukoencephalopathy) associated with TTP.
12 weeks later
Depression
Mental
Performance
Mild, moderate or severe depression: 80%
- previous diagnosis of depression
- being unemployed due to reasons attributed to TTP
PTSD: 32.4%
- younger age, pre-existing anxiety disorder and being
unemployed due to reasons attributed to TTP
- Neurologic manifestations during acute TTP were not.
• Angina pectoris
• ECG changes
• Troponin
• Echography
• Almost all possible manifestations
a 77-yo Japanese man diagnosed with TTP. The patient suddenly died.
On autopsy, myocardial infarction manifested as petechiae and fibrotic foci.
The microthrombi in the small arterioles and capillaries were platelet thrombi,
which showed positive results for periodic acid-Schiff stain and factor VIII on
immunohistochemical staining.
The thrombus stains purple-red
with the periodic acid Schiff stain
= Platelet thrombi
The thrombus shows positive
results for immunohistochemical
staining for factor VIII
Takotsubo cardiomyopathy
Two-chamber view of the left ventricle, obtained in diastole (A) and systole (B). Panel
B demonstrates the akinetic and balloon apex in systole with a hypercontractile base.
Ventriculogram
1. Diagnostic challenges exist even for seniors/specialists.
2. Delayed diagnosis and treatment impacts on survival
3. Sudden deterioration.
4. Access to resuscitation facilities.
5. Adjuvant/novel therapies may be required.
6. Lack of awareness of intervention required to diagnose TMA cause
7. Organ involvement = severe and poor prognosis.
8. Treatment should not be delayed.
9. Specialist-led, multi-specialty input achieves high-quality care
10. There is the need for both acute and long-term care for a condition
that carries a significant risk of relapse.
Dutt T, et al. BJH 2015;170:737–42
Key points
Thank you for your attention