Transcript les thrombopenies - Association des Médecins Intrahospitaliers en

LES THROMBOPENIES
W.FEREMANS
CHU ERASME
ULB
Introduction à l ’hémostase
H E M O S TA S E
P A R O I V A S C U L A IR E
P L A Q U E TTE S
C O A G U L A TIO N
PURPURA
PURPURA
E C C H YM O S E S
MK & PLAQUETTES
Durée de vie 8-10 J
Destruction splénique
Pool circulant 2/3
Pool splénique 1/3
(Hypersplenisme
85%)
CFU-Meg
TPO
IL11
(IL6)
5J
Endomitose
Anatomie plaquettaire
Récepteur
Thrombine
Corps dense
(ADP,Ca++)
GPIIb/IIIa
Fibrinogène
Alpha
(fVW,fibri)
GPIb
F VW
Hémostase primaire
Prostacycline
+++
Collagène
P-Lipase
FVW
fibrinogène
TF
VIIa
THROMBOPENIE
INSUFFISANCE DE PRODUCTION
C O N G E N IT A L E
FAN C O N I
PU R PU R A AM E G AK .
T H IA Z ID E M E R E
A C Q U IS E
A P L A S IE M E D U L L A IR E
L E U C E M IE S , M D S , L Y M P H O M E S
M E T AS T AS E S BM
M Y E L O F IB R O S E
B IE R M E R /C A R E N C E F H 4
C H IM IO /R A D IO T H E R A P IE
T H IA Z ID E ,C 2 H 5 O H ,IF N ,O E S T R O G E N E S
THROMBOPENIE
HYPERDESTRUCTION /
SEQUESTRATION
IM M UNO L O G IQ UE
NO N-IM M UNO L O G IQ UE
PT I
C IV D
ID IO S YN C H R AS IE M E D IC AM E N T E U S E
HUS / TTP
M AL AD IE S AU T O -IM M U N E S
M AY-H E G G L IN (+ tro u b le s
q u a lita tifs)
S .L YM PH O PR O L IF E R AT IF S
AN T IC O R PS M AT E R N E L S
PO S T -T R AN S F U S IO N N E L
S E Q UE S T RA T IO N
H YPE R S PL E N IS M E
Cas Clinique
Un homme de 47 ans consulte sur conseil
de la médecine du travail pour
thrombopénie chronique s’étalant sur
plusieurs années: Plt 70000, 52000, plus
récemment 25000.
 Il ne se plaint de rien et a même subi une
avulsion dentaire sans Hg
 Il ne prend aucun médicament et n’est pas
en contact avec des toxiques

Examen clinique & Hémato
Pas de splénomégalie ni d’adénopathie
 Pas de purpura ou ecchymoses mises en
évidence
 Contrôle hémato:

 Hb
15,4 g/dl
 GB 5400 / µL
 Formule : N
 Plaquettes : 6000 / µL !!!

Quel examen s’impose avant tout ?
1.
2.
3.
4.
Ponction sternale
Screening de coagulation
Ac antiplaquettes
Numération des plaquettes sur héparine
et/ou citrate
1.
2.
3.
4.
Ponction sternale : en suspens
Screening de coagulation : N
Ac antiplaquettes : non demandé
Numération des plaquettes sur
héparine et/ou citrate :
confirmation de la thrombopénie

Quel autre examen simple aurait permis
de confirmer la thrombopénie?

Frottis sanguin coloré MGG

A ce stade quel autre examen livrera
rapidement le diagnostic ?
1.
2.
3.
Ponction sternale
Ac anti-plaquettes
Ac anti-DNA
La ponction sternale montre de
nombreux MK
 La CRP, le FAN et la sérologie HIV sont
rentrés N


Quel traitement préconiseriez-vous ?
1.
2.
3.
4.
Splénectomie
IVIG
Azathioprine
Corticoïdes

Corticoïdes: mais à quelle dose ?
1.
2.
3.
1mg / kg / J Prednisolone pendant 3
semaines
0,5 mg /kg/ J même durée
Bolus IV de solumedrol 500 mg

Proposition 1 puis lentement dégressif
après réduction à 0,5 mg/kg/J
PTI :épidémiologie,
physiopathologie, évolution

ENFANT
début explosif
 notion de virose (MNI)
 Guérison en 6 mois
dans 90 % des cas
 Rémissions
spontanées fréquentes
 Mécanisme:
CIC anti-virus

ADULTE
 Rémission spontanée
rare (5 %)
 40 % d ’évolution
chronique de > 3 ans
 20-40 ans; F > M
 Exclure
LED,LLC,médicaments
,HIV…(10 % des cas)
 Mécanisme:
autoanticorps anti-GP

RESULTS IN CHRONIC ITP
TRT
n
Steroids
CR
PR
F-UP
1,420 29.5 %
15.2 %
0.5-20 Y
Splenec
669
59.9 %
12.3 %
0.5-20 Y
Vinca
pulse
Danazol
§§
CPM
88
11.4 %
0.5-6 Y
120
25.0 %
35.2 %
**
18.3 %
132
28.7 %
AZA §§
133
12.0 %
§§ Continuous TRT
** Transient
0.1-1.2 Y
1-9 Y
39.8 %
0.5-4 Y
Thrombopénies médicamenteuses
auto-immunes

Haptène


Auto-Ac vrai (anti-GP
plaquettaire)




CIC (innocent
bystander); le plus
courant




Traitement: STOP drogue
ne plus jamais la prendre

Antibiotiques
Anti-épileptiques
Diurétiques
Anti-diabétiques
Anti-malariques
Psychotropes
Héparine
Sels d ’or (!!!Long)
Oestrogènes (aussi
central)
DRUG-INDUCED THROMBOCYTOPENIA: REVIEW
n = 774
E xclu d ed : n = 2 5 9
u n evalu ab le
S tu d ied : n = 5 1 5
D efin ite / P rob ab le
n = 247
P ossib le / U n likely
n = 268
P L T > 1 0 0 .0 0 0
9 8 d ru g s
2 3 m ajor b leed in g
u se of C ytotoxic d ru g
Q u in id in e
n = 38
2 d isease-related
d eath s
n on -th erap eu tic ag en t
G old salts
n = 11
D ru g -in d u ced syst.d is.
SXT
n = 10
ch ild ren
oth er m ech an ism
ex h ep arin
George et al. 1998
Danish committee for adverse drug reaction
(Pedersen-Bjergaard et al 1997)
n = 309
m e d ia n le n g h t o f e xp o s u re b e fo re o n s e t
M E D IA N 2 1 d a ys (1 d - 1 1 y )
1 6 % > 1 Year
R a s h , fe v e r , liv e r to x ic ity 2 0 %
m e d ia n n a d ir P L T : 1 1 0 0 0 / µ L
C lin ic a l H g 7 4 %
D is e a s e -r e la te d M o r ta lity
4 %
s k in 6 7 %
n a sa l / o ra l 3 1 %
G -I tr a c t 1 2 %
u r o g e n ita l 1 0 %
b r a in 3 %
lu n g s < 1 %
P la te le t a n tib o d ie s in 2 7 %
Drugs incriminated :
Danish registry
50
45
40
35
30
25
20
15
10
5
0
Quinidine
SXT
AINS
Gold salts
Penicillamine
Anti-Epilep
Anti-malar
Treatment guidelines?









76 % of the patients admitted to hospital
Corticosteroid given in 53 % ; initiated the day of diagnosis
in 72 %
PLT > 40000 / µL : 19 % treated by corticoids
PLT < 40000 / µL : 63 % received corticoids
No bleeding : 20 % treated by corticoids
Clinical bleeding : 62 % received corticoids
9 % received PLT transfusion (28/29 PLT < 10000/µL;
27/29 clinical Hg)
16 % received RBC transfusion
Complete recovery in 87 % : no difference corticoid-treated
and untreated; trend for persisting thrombocytopenia > 14
d
CAS CLINIQUE
Patient de 58 ans , tabagique
 « NSCL » carcinome traité par
chimiotherapie adjuvante comportant du
cisplatine 3 ans auparavant
 Developpement progressif: fatigue,
essoufflement, gingivorrhagies

Examen clinique
Pâleur
 Purpura membres
 Légère confusion
 T° 37°6 sans aucun point d’appel
infectieux

Biologie
Hb 9.9 g/dl
 MCV 92 fL
 GB 8300 / µL
 Formule : PMN 78 % , Mono 6 %, Lympho
12 %, eosino 4 %
 2 Eblastes / 100 GR
 Plaquettes: 22000 / µL


A ce stade quel examens biologique
complémentaire de chimie générale serait
le plus utile ?
1.
2.
3.
4.
F rénale
LDH
CRP
Calcémie
1.
2.
3.
4.
F rénale : 1,6 mg/dl
LDH : >> N
CRP : 2 mg / dl
Calcémie : N

Vous avez droit à un seul examen de 2°
ligne. Lequel choisirez vous?
1.
2.
3.
4.
Coombs
Screening de coagulation
Ponction sternale / Biopsie médullaire
Frottis sanguin avec recherche de
schistocytes
1.
2.
3.
4.
Coombs : négatif
Screening de coagulation: D-dim 550
ng/ml; APTT limite sup N
Ponction sternale / Biopsie médullaire :
non faite
Frottis sanguin avec recherche de
schistocytes : +++

Quel traitement d’urgence préconiseriezvous ?
1.
2.
3.
4.
Corticoïdes
Transfusion de plaquettes
Infusion de FFP
Plasmaphérèse
Plasmaphérèses
 A quelle fréquence ?

1.
2.
3.
3 X par semaine
2 x par jour
1 X par jour
60 ml / kg FFP 1x / J
 Résolution temporaire de la thrombopénie
avec Plaquettes > 110000 / µL
 Rechute avec développement d’une
insuffisance rénale puis décès
 A l’autopsie: aucun signe de rechute du
cancer pulmonaire

Causes d ’anémie par
fragmentation GR
1. E Coli; Shigella; Virus…
2. Grossesse:pré-éclampsie/éclampsie
(syndrome de HELLP)
3. Cancer +/- Mitomycine C ou Pt
4. Vasculites (Wegener…)
5. HTA maligne
6. Allogreffe +/- CyA
7. CIVD
TTP : Pathophysiology
-the presence of ULVWF multimers due to constitutional
absence of a cleaving metalloprotease or acquired IgG
autoantibodies that inhibit protease activity
The ADAMTS13 gene (A) contains 29 exons on chromosome 9q34.
B shows the structural domains of the ADAMTS13 protein
In line C mutations in patients with inherited TTP are shown
Mécanisme TTP
vWF multimers
PLT
---------------------
UL vWF
multimers
-GP1b
--GPIIb/IIIa
Endothélium lésé
ADAMTS13 activity in thrombotic thrombocytopenic
purpura–hemolytic uremic syndrome: relation to
presenting features and clinical outcomes in a prospective
cohort of 142 patients
Sara K. Vesely, James N. George, Bernhard Lämmle, Jan-Dirk Studt, Lorenzo Alberio, Mayez A. ElHarake and Gary E. Raskob
Initial management of patients with thrombotic thrombocytopenic purpura—hemolytic uremic syndrome (TTPHUS) is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment,
and risks of plasma exchange. Although severe ADAMTS13 (a disintegrin-like and metalloprotease with
thrombospondin type 1 repeats) deficiency may be specific for TTP, the role of ADAMTS13 activity measurements
for initial management decisions is unknown. ADAMTS13 was measured before beginning plasma exchange
treatment in 142 (88%) of 161 consecutive patients with clinically diagnosed TTP-HUS with assignment to 1 of 4
categories: less than 5% (severe deficiency), 5% to 9%, 10% to 25%, and more than 25%. Eighteen (13%) of
142 patients had severe ADAMTS13 deficiency. Among 6 predefined clinical categories (stem cell transplantation,
pregnant/postpartum, drug association, bloody diarrhea, additional/alternative disorder, idiopathic), severe
deficiency occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. The presenting
features and clinical outcomes of the 16 patients with idiopathic TTP-HUS who had severe ADAMTS13 deficiency
were variable and not distinct from the 32 patients with idiopathic TTPHUS who did not have severe ADAMTS13
deficiency. Many patients in all ADAMTS13 activity categories apparently responded to plasma exchange
treatment. Therefore, severe ADAMTS13 deficiency does not detect all patients who may be appropriately
diagnosed with TTP-HUS and who may respond to plasma exchange treatment.
(Blood. 2003;102:60-68)
Specific von Willebrand factor-cleaving protease in thrombotic
microangiopathies: a study of 111 cases
Agnès Veyradier, Bernadette Obert, Anne Houllier, Dominique Meyer, and Jean-Pierre Girma
Blood, 15 September 2001, Vol. 98, No. 6, pp. 1765-1772
= TTP
= HUS
= TTP
=HUS
Table 3. Follow-up of vWF-protease in 15 patients in remission of TMA
%Protease/Ab
Sex/age
TMA
Associated context
Treatment
Acute phase
Remission
F/51
Sporadic TTP
None
Plasmapheresis and corticosteroids
0/ -
100/ -
F/53
Sporadic TTP
None
Plasmapheresis and corticosteroids
0/+
100/ -
F/23
Sporadic TTP
Neoplasia
Chemotherapy
0/+
100/ -
F/61
Sporadic TTP
Neoplasia
Chemotherapy
0/ -
75/ -
F/18
Sporadic TTP
Neoplasia
Plasma infusion and corticosteroids
0/+
50/ -
F/28
Sporadic HUS
Infection
Plasmapheresis
0/ -
100/ -
M/32
Sporadic HUS
Infection
Plasmapheresis
0/ -
100/ -
F/36
Sporadic TTP
Pregnancy
Plasmapheresis
20/ -
70/ -
F/53
Intermittent TTP
None
Plasmapheresis
0/+
70/ -
M/32
Intermittent TTP
Drug
Plasmapheresis
0/+
50/ -
M/36
Intermittent TTP
Drug
Plasma infusion
0/+
100/-
F/35
Intermittent TTP
Lupus
Plasmapheresis and corticosteroids
0/+
100/ -
F/35
Intermittent TTP
Pregnancy
Plasma infusion and corticosteroids
0/ -
0/ -
F/19
Recurrent TTP
None
Plasmapheresis
0/ -
0/ -
M/18
Recurrent TTP
None
Plasmapheresis
0/+
0/+
Blood, 1 August 2002, Vol. 100, No. 3, pp. 778-785
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent
and familial thrombotic thrombocytopenic purpura and hemolytic uremic
syndrome
Giuseppe Remuzzi, Miriam Galbusera, Marina Noris, Maria Teresa Canciani, Erica Daina,
Elena Bresin, Silvia Contaretti, Jessica Caprioli, Sara Gamba, Piero Ruggenenti, Norberto
Perico, and Pier Mannuccio Mannucci for the Italian Registry of Recurrent and Familial
HUS/TTP
Whether measurement of ADAMTS13 activity may enable physicians to distinguish thrombotic thrombocytopenic
purpura (TTP) from hemolytic uremic syndrome (HUS) is still a controversial issue. Our aim was to clarify whether
patients with normal or deficient ADAMTS13 activity could be distinguished in terms of disease manifestations and
multimeric patterns of plasma von Willebrand factor (VWF). ADAMTS13 activity, VWF antigen, and multimeric
pattern were evaluated in patients with recurrent and familial TTP (n = 20) and HUS (n = 29). Results of the
collagen-binding assay of ADAMTS13 activity were confirmed in selected samples by testing the capacity of
plasma to cleave recombinant VWF A1-A2-A3. Most patients with TTP had complete or partial deficiency of
ADAMTS13 activity during the acute phase, and in some the defect persisted at remission. However, complete
ADAMTS13 deficiency was also found in 5 of 9 patients with HUS during the acute phase and in 5 patients during
remission. HUS patients with ADAMTS13 deficiency could not be distinguished clinically from those with normal
ADAMTS13. In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by
half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with the heterozygous carrier state. In
patients with TTP and HUS there was indirect evidence of increased VWF fragmentation, and this occurred also in
patients with ADAMTS13 deficiency. In conclusion, deficient ADAMTS13 activity does not distinguish TTP from
HUS, at least in the recurrent and familial forms, and it is not the only determinant of VWF abnormalities in these
conditions.