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