Initial management of TMA syndromes

Elie Azoulay,

Saint-Louis Hospital, Medical Intensive Care Unit

Paris Diderot Sorbonne UniversityGroupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH)

C3B factorC5

TTPHUS

T

M

A

Steroids?

Rituximab

Hypertension

AKI

Renal

Neurological

CARDIAC

ADAMTS 13

Complement

Ischemia

Thrombosis

Hemorrhage

STEC

aHUS

ICU Renal replacement therapy

Coma

Stroke

Medical emergency

Auto-immunity

OUTCOMES Genetic

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-TransplantationCancerInfection

H FactorCD46 (MCP)I Factor

S

C

H

I

S

T

O

C

Y

T

E

S

Idiopathic

COOMBS TEST

Pregnancy

Troponin

Plasma exchange

Sudden death

TMA ?

Understanding TMAs

Normal erythrocytes

Mechanical (non-immune) haemolysis

Microvascular thrombosis

Aggregation of platelets

Ischaemia

Thrombotic microangiopathies

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 infarction▪Thromboembolism▪Cardiomyopathy▪Diffuse vasculopathy

▪Elevated creatinine▪Edema▪Malignant hypertension▪Renal failure▪Dialysis▪Transplant

▪Confusion▪Seizures▪Stroke▪Encephalopathy▪Diffuse cerebral dysfunction

▪Liver necrosis▪Pancreatitis▪Diabetes Mellitus▪Colitis▪Diarrhea▪Nausea/vomiting▪Abdominal pain

▪ Hemolysis▪ Decreased platelets▪ Fatigue▪ Transfusions

TMA

PEX

60ml/kg/d

Corticosteroids

1mg/kg/dayBP control

Differential diagnosesADAMTS13, Complement

TTP HUS

Platelet countCreatinine

ADAMTS 13

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

TTP, atypical HUS and STEC-HUS

Mannucci PM. Intensive Care Med 2015 [Epub ahead of print]

Mesentericischaemia

Stroke

Myocardial

Infarction

Hospitalacquiredinfection

Varia

- AKI

- Alveolarhaemorrhage

Thrombosis>

Haemorrhage

Peigne V, et al. Intensive Care Med 2012;38:1810–7

No platelet transfusion

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

2001-2010 Nationwide Inpatient Sample

database 4032 TTP patients

Mortality 11%

Independent predictors of hospital mortality were older age (OR 1.03 (1.02-1.04), acute

myocardial infarction (OR 1.89 (1.24-2.88), acute renal failure (OR 2.75 (2.11-3.58), congestive

heart failure (OR 1.66 (1.17-2.34), acute cerebrovascular disease (OR 2.68 (1.87-3.85), cancer

(OR 2.49 (1.83-3.40), and sepsis (OR 2.59 (1.88-3.59).

Independent predictors of acute myocardial infarction were older age (OR 1.03 (1.02-1.04),

smoking (OR 1.60 (1.14-2.24), known coronary artery disease (OR 2.59 (1.76-3.81), and

congestive heart failure (OR 2.40 (1.71-3.37).

Cases with higher Troponin T levels (>0.1 µg/L) had higher IgG level at presentation (p=0.03)

<0. 01n=13

0. 01-0. 09n=11

>0. 1n=14

0

25

50

75

100

125

150

175

200

An

ti-A

DA

MTS

13 Ig

G (

%)

Troponin T (µg/L)

Median IgG: 35% Median IgG: 45% Median IgG: 69.5%

Scully M et al. J Thromb Haemost 2009

Anti-ADAMTS13 IgG antibodies and Troponin T levels during acute TTP

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

Management of TTP

Admission to an ICU/HDU (intense needs, lines, PEX).

Urgent (within 4-8h) PEX 60ml/kg: ADAMTS13 sup + AB removal,

daily and until 2 days after platelet count normalizes. 100% plasma.

Corticosteroids 1mg/kg/day (high doses for 3 days?)

Low-dose aspirin, DVT prophylaxis, central venous access without

platelet transfusion, and Folic acid.

Rituximab is safe and effective for newly diagnosed TTP: decrease

the number of PEX. Early?

• Plasma 40-60 ml/kg (1-1,5 blood mass)

• Within 6h of admission

• Massive transfusion of functionnal ADAMTS13

• Clear anti-ADAMTS13 antibody

• Clear UL Wb factor

Rock et al. The Canadian Apheresis Group

103 pts, 7 y, 18 centers

PEX vs. Plasma transfusion

Group 1: 15.8 EP (3 à 36), 21.5+7.8 liters PVI

Group 2: 7.7 jours de PVI. 6.7+3.3 liters PVI

0

,2

,4

,6

,8

1

0 5 10 15 20 25 30 35

G1: Plasma exchange

G2: Plasma infusion

Weeks

P=0,03

Survival

N Engl J Med. 1991 Aug 8;325(6):393-7.

Darmon M, et al. Crit Care Med 2006;34:2127–33

Management of unresponsive TTP

Unresponsive to PEX + steroids

Check everything, avoid differential diagnoses

Rituximab

High dose steroids

Vincristine, other IS agents (cyclophosphamide etc…)

Splenectomy: late line option

…

OR 95% CI P value

Age >60y 7.90 1.06-78.34 0.04

Neurological symptoms

- Headaches

- Severe symptoms

8.04

1.71

1.27-51.03

0.42-7.09

0.02

0.45

Cardiac signs at presentation 3.44 1.63-16.39 <0.01

Platelet rate at day 2<15 G/L 3.88 1.30-11.62 0.01

Mariotte E, et al. Intensive Care Med 2013;39:1272–81

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)

Chronic uncontrolled complement activationleads 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

aHUS confirmed clinically

ADAMTS13>10% (result within 24 hours) Samples for complement (serum & EDTA)

DO NOT WAIT FOR RESULTS Complement analysis does not support diagnosis of aHUS, Diagnosis of aHUS does not require identification of a genetic

mutation

Vaccinations: tetravalent meningococcal and Bexsero(meningococcal B)

Antibiotics: penicillin based Eculizumab:

900 mg x 4 weeks 1200 mg every 2 weeks Monitor effect : CH50/CH100

Eculizumab Summary of Product Characteristics. Alexion Europe SAS, 2014Legendre CM et al. N Engl J Med 2013;368:2169–81

23-27%

5-7%

4-8%

1-4%

2-8%3%

X Eculizumab (SOLIRIS®)

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

• 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 aHUS29.3 mL/min/1.73m2: mean change from baseline in eGFR at Week 26

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 differentially

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: TMA and the intensivists

Thank you for your attention