A DIAGNOSTIC ALGORITHM FOR

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A DIAGNOSTIC ALGORITHM FOR INHERITED
THROMBOCYTOPENIAS Carlo L. Balduini Dep. of
Internal Medicine IRCCS Policlinico S.
Matteo- University of Pavia, Italy
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INHERITED THROMBOCYTOPENIAS A DEFINITE DIAGNOSIS
IS DIFFICULT
81 consecutive patients with inherited
thrombocytopenias mean age at diagnosis 38 y
(range 5-76) 7 undue splenectomies 3
homozygous BSS 1 heterozygous BSS 3 MYH9-RD
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INHERITED THROMBOCYTOPENIAS A DEFINTE DIAGNOSIS
IS USEFUL
genetic counseling prenatal diagnosis
CAMT bed TAR spontaneous recovery
prognostic definition
WAS, XLT splenectomy WAS, BSS, CAMT, CTRUS
HSCT BSS, MYH9-RD, GPS DDAVP
therapy
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Carlo L. Balduini Marco Cattaneo Fabrizio
Fabris Paolo Gresele Achille Iolascon Fabio
Pulcinelli Anna Savoia
Corbara, 2002
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(No Transcript)
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Which classification(s) of inherited
thrombocytopenias? PATHOGENETIC MECHANISM not
identifiable in most cases
INHERITANCE PATTERN not identifiable in several
cases
SYNDROMIC OR NON-SYNDROMIC useful for patients
with syndromic forms
PLATELET SIZE useful for all patients it is a
constant feature of each illness it is easy to
determine
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SYNDROMIC THROMBOCYTOPENIAS Wiskott-Aldrich
syndrome Syndromic MYH9-related disease
Amegakaryocytic thrombocytopenia with radio-ulnar
synostosis Thrombocytopenia with absent radii
Familial platelet disorder and predisposition
to AML Dyserythropoietic anemia with
thrombocytopenia Paris-Trousseau
thrombocytopenia - Jacobsen's syndrome
NON-SYNDROMIC THROMBOCYTOPENIAS Congenital
amegakaryocytic thrombocytopenia X-linked
thrombocytopenia with thalassemia
Thrombocytopenia 2 Bernard-Soulier syndrome
Non-syndromic MYH9-related disease
Platelet-type or pseudo von Willebrand disease
Gray platelet syndrome Montreal platelet
syndrome
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INHERITED THROMBOCYTOPENIAS WITH SMALL
PLATELETS Wiskott-Aldrich syndrome X-linked
thrombocytopenia   INHERITED THROMBOCYTOPENIAS
WITH NORMAL-SIZE PLATELETS Congenital
amegakaryocytic thrombocytopenia Congenital
amegakaryocytic thrombocytopenia with radio-ulnar
synostosis Thrombocytopenia with absent radii
Familial platelet disorder with predisposition to
AML Thrombocytopenia 2 INHERITED
THROMBOCYTOPENIAS WITH LARGE PLATELETS
Bernard-Soulier syndrome Platelet-type
vWD/Pseudo-vWD Dyserythropoietic anemia with
thrombocytopenia X-linked thrombocytopenia
with thalassemia Paris-Trousseau
thrombocytopenia and Jacobsen syndrome
MYH9-related disease Gray platelet syndrome
Montreal platelet syndrome
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ELECTRONIC COUNTERS DO NOT RECOGNIZE GIANT
PLATELETS
MYH9-RELATED DISEASE
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PLATELET DIAMETER ON PERIPHERAL BLOOD FILMS IN
INHERITED THROMBOCYTOPENIAS
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PHERIPHERAL BLOOD FILM EXAMINATION IN INHERITED
THROMBOCYTOPENIAS Giant platelets
Bernard-Soulier syndrome
MYH9-related disease
vWD 2B platelet type
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PHERIPHERAL BLOOD FILM EXAMINATION IN INHERITED
THROMBOCYTOPENIAS
Small platelets
WAS and XLT
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PHERIPHERAL BLOOD FILM EXAMINATION IN INHERITED
THROMBOCYTOPENIAS
Red cell anisopoikilocytosis with microcytosis
X-linked thrombocytopenias due to GATA-1 mutations
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PHERIPHERAL BLOOD FILM EXAMINATION IN INHERITED
THROMBOCYTOPENIAS
Döhle-like bodies
MYH9-related disease (May-Hegglin anomaly,
Sebastian and Fechtner syndromes)
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DIAGNOSTIC FLOW-CHART FOR INHERITED
THROMBOCYTOPENAS
screening phase to provide a diagnostic suspicion
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DIAGNOSTIC FLOW-CHART FOR INHERITED
THROMBOCYTOPENAS
patients history and examination peripheral
blood film observation to evaluate platelet size
and morphology red cell and leukocyte
morphology in vitro platelet aggregation spontan
eous and ristocetin-induced
specialized investigations to
confirm the diagnostic suspicion
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DIAGNOSTIC FLOW-CHART FOR INHERITED
THROMBOCYTOPENIAS
History and examination
Syndromic
Non-syndromic
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History Examination
Inherited thrombocytopenia
SYNDROMIC THROMBOCYTOPENIAS Wiskott-Aldrich
syndrome MYH9-related disease, syndromic
Familial platelet disorder with predisposition
to myeloid malignancy Dyserythropoietic anemia
with thrombocytopenia Thrombocytopenia with
absent radii Congenital thrombocytopenia with
radio-ulnar synostosis Paris-Trousseau type of
thrombocytopenia and Jacobsen syndrome
Velo-cardio-facial syndrome
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SDS-PAGE Flow cytometry Mutation screening
D I A G N O S T I C C O N F I R M A T I O N
XLT
Flow cytometry Mutation screening
CAMT
Linkage analysis
THC2
SDS-PAGE Flow cytometry Molecular biology
WAS
MYH9- related disease
Immunomorphology Mutation screening
SYNDROMIC THROMBOCYTOPENIAS
FDP AML
Mutation screening
Dyserythropoietic anemia and thrombocytopenia
Bone marrow Mutation screening
Bone marrow Mutation screening
CTRUS
Bone marrow
TAR
Electron microscopy Caryotype
VCFS
TCPT JBS
Caryotype
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Syndromic thrombocytopenias
History Examination
Inherited thrombocytopenia
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History Examination
Inherited thrombocytopenia
Syndromic forms
Large platelets
GPS MYH9-RD XLTT Homozygous BSS PTvWD MPS
Blood film Platelet aggregation
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D I A G N O S T I C C O N F I R M A T I O N
Electron microscopy SDS-PAGE
GPS
MYH9- related disease
Immunomorphology Mutation screening
a/non-a globin chains Bone marrow Mutation
screening
XLTT
MACROTHROMBOCYTOPENIAS
RIPA of washed platelets Mutation screening
PTvWD
Flow cytometry SDS-PAGE Mutation screening
BSS
Montreal platelet syndrome
?
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History Examination
Inherited thrombocytopenia
Syndromic thrombocytopenias
Diagnostic confirmation SDS-PAGE
flow-cytometry mutation screening
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Syndromic thrombocytopenias
History Examination
Inherited thrombocytopenia
Normal sized platelets
Bone marrow examination
Congenital amegakaryocytic thrombocytopenia
Thrombocytopenia 2
Diagnostic confirmation
Diagnostic confirmation
mutation screening
linkage analysis
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Hereditary thrombocytopenia
History and examination
Immunodeficiency? Hearing loss?
Abnormal renal function? Cataract?
AML in family members? Anemia and
anisopoichilocytosis? Abnormalities
of radii? Cleft palate/cardiac
abnormalities?
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SCREENING PHASE History and examination Blood
film evaluation Platelet aggregation
SECOND LEVEL INVESTIGATIONS SDS-PAGE or flow
cytometry Optical immunomorphology Electron
microscopy Bone marrow evaluation Genetic analyses
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APPLICATION OF THE DIAGNOSTIC ALGORITHM TO 50
CONSECUTIVE PATIENTS WITH GENETIC
THROMBOCYTOPENIAS Results of the screening phase
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APPLICATION OF THE DIAGNOSTIC ALGORITHM TO 50
CONSECUTIVE PATIENTS WITH GENETIC
THROMBOCYTOPENIAS Final results
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FURTHER INVESTIGATION OF THE 20 FAMILIES WITH AN
UNKNOWN FORM OF GENETIC THROMBOCYTOPENIA
2 families with reduced amount of GPIa-IIa 2
families with the clinical phenotype of MYH9-RD
but without MYH9 mutations
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The proposed diagnostic algorithm for inherited
thrombocytopenias allows an easy diagnosis of
patients with well known disorders and
facilitates the identification of patients with
new illnesses