Download Thrombocytopenia

Thrombocytopenia
Platelet Counts
• Vary with
– Age (slight decrease in mean with increased age)
– Sex (Slightly lower mean in men)
Consequences of Misdiagnosis of
Inherited Thrombocytopenia
• Wrong therapy
• Wrong prognosis
• Missed opportunity for genetic counseling
Inherited Thrombocytopenias with
Adulthood Presentation
• Italian Experience
• Mean age of diagnosis
– 35 yrs MYH9-related disease
– 33 yrs monoallelic Bernard-Soulier syndrome
– 30 yrs ANKRD26-related thrombocytopenia
Baluini CL et al. JTH. 2013;11:1006-1019
Inherited Thrombocytopenias with
Adulthood Presentation
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MYH9-related disease
monoallelic Bernard-Soulier syndrome
ANKRD26-related thrombocytopenia
Familial platelet disorder with predisposition to AML
(RUNX1)
ITGA2B/ITGB3-associated thrombocytopenia
TUBB1-related thrombocytopenia
CYCS-related thrombocytopenia
Thrombocytopenia associated with sitosterolemia*
Red=syndromic vs. Blue=non-syndromic
*Autosomal recessive (all others dominant)
MYH9-RELATED DISEASE
MHY9-Related Disease
• MHY9 gene at chromosome 22q12-13
• Autosomal dominant
• Non-syndromic  syndromic over time
– Cataracts, sensorineural deafness, altered liver
enzymes, and/or progressive
glomerulonephropathy (ESRD)
• Associated features
– Giant platelets
• No spontaneous bleeding
MYH9 Gene
• Encodes heavy chain of non-muscle myosin IIA
– aka. Myosin 9
• Non-muscle myosin IIA
– Motor protein involved in cellular force contraction
• N-terminal motor domain
– Mechanical translocation along actin filaments
– Mutations here  severe thrombocytopenia and full syndrome
• Alpha-helical rod domain
– Intermediate phenotype
• C-terminal non-helical domain
– Mildest phenotype with only mild thrombocytopenia
MHY9-Related Disease:
Pathophysiology
• Disease phenotype
– Caused by dominant-negative effect of the
mutated myosin-9
– NOT caused by the loss of myosin-9 function
MHY9-Related Disease:
Pathophysiology
• Non-hematologic manifestions  uncertain
• Thrombocytopenia
– Reduced number and branching of proplatelets
• Leads to fewer number of release platelets from
megakaryocytes
– Impaired migration of megakaryocytes from the
osteoblastic niche to the vascular niche
– Premature release of platelets away from the
vascular sinusoids
MYH9-Related Disease
Mutations in which
domain(s) is/are
most likely
associated with this
phenotypic
morphology?
Journal of Thrombosis and Haemostasis
Volume 11, Issue 6, pages 1006-1019, 3 JUL 2013 DOI: 10.1111/jth.12196
http://onlinelibrary.wiley.com/doi/10.1111/jth.12196/full#jth12196-fig-0003
MHY9-Related Disease: Diagnosis
• Anti-myosin-9 antibodies
– Used to identify the inclusion bodies
• Present in all neutrophils of all affected patients
MONOALLELIC
BERNARD-SOULIER SYNDROME
Benard-Soulier Syndrome
• Genes Associated:
– GP1BA gene at chromosome 17p13
– GB1BB gene at chromosome 22q11
– GP9 at chromosome 3q21
Glycoprotein Ib-IXA-V Receptor
SFKs in GPIb-IX-V proximal signaling.
Yotis A. Senis et al. Blood 2014;124:2013-2024
©2014 by American Society of Hematology
Biallelic Benard-Soulier Syndrome
• Autosomal recessive (>50 mutations described)
• Genes mutations in BOTH alleles of either
– GP1BA gene at chromosome 17p13
– GB1BB gene at chromosome 22q11
– GP9 at chromosome 3q21
• Non-syndromic
• Associated features
– Giant platelets
• Spontaneous bleeding
Biallelic Benard-Soulier Syndrome
• BOTH alleles must be mutated
– Heterozygotes
• Slightly enlarged platelets
OR
• No phenotypic abnormality
Biallelic Benard-Soulier Syndrome:
Pathophysiology
• Mutations prevent receptor assembly in the
Golgi apparatus and migration to surface
– Absence of GP 1B-IXA-V receptor
– Decreased vWF binding
– Decreased platelets adhesion at site of vascular
injury
• Thrombocytopenia with giant platelets BUT
– Bleeding is worse than the platelet numbers
would suggest
Biallelic Benard-Soulier Syndrome:
Pathophysiology
• Mutations prevent receptor assembly in the
Golgi apparatus and migration to surface
– Absence of GP 1B-IXA-V receptor
– Decreased vWF binding
– Decreased platelets adhesion at site of vascular
injury
• Thrombocytopenia with giant platelets BUT
– Bleeding is worse than the platelet numbers
would suggest
Biallelic Benard-Soulier Syndrome:
Diagnosis
• PFA-100
– Both collagen and ADP prolonged
• Platelet aggregation assays
– Decreased aggregation with Ristocetin
• Flow cytometry
– Absence of GP IB-IXA-V
Monoalleleic Bernard-Soulier Syndrome
• Autosomal dominant
• Genes Associated:
– GP1BA gene at chromosome 17p13
– GB1BB gene at chromosome 22q11
– GP9 at chromosome 3q21
• Non-syndromic
• Associated features
– Giant platelets with GP1BA mutations
– Large platelets with GP1BB and GP9 mutations
• No spontaneous bleeding
Monoalleleic Bernard-Soulier Syndrome
• Autosomal dominant
– Far fewer mutations described
• Genes mutations in ONE allele of either
– GP1BA gene at chromosome 17p13
– GB1BB gene at chromosome 22q11
• Non-syndromic
• Associated features
– Large to Giant platelets
• No spontaneous bleeding
Monoallelic Benard-Soulier Syndrome:
Clinical Features
• Thrombocytopenia with giant platelets
– Mean platelet count 81 x 109/L
• No or trivial bleeding tendency usually
– Less commonly more severe thrombocytopenia
and bleeding seen
• 5% of cases in one series had been treated for ITP
Monoallelic Benard-Soulier Syndrome:
Pathophysiology
• WHY monoallelic forms  uncertain
– DiGeorge’s syndrome (22q11 microdeletion) has
50% expression but no giant plaletets or
thrombocytopenia
– Hypothesis
• Mutations must exert some dominant effect ?
Bernard-Soulier Syndrome:
Why Macrothrombocytopenia?
• GP IB-IXA-V needed for platelet production
– Inhibition blocks proplatelet formation
• Proplatelet tips are larger
• a-tubulin distribution altered
– NO effect on differentiation or maturation
ANKRD26-RELATED
THROMBOCYTOPENIA
ANKRD26-Related Thrombocytopenia
• Gene associated
– ANKRD26 gene at chromosome 10p2
• Autosomal dominant
• Non-syndromic
• Associated features
– Normal size platelets
– Increase risk of acute leukemia (?)
• No spontaneous bleeding
ANKRD26-related thrombocytopenia:
Pathophysiology
• Mutations in the 5’-UTR of ANKRD26 on 10p2
• How leads to disease physiology – uncertain
– Possibly enhance expression of ANKRD26
• Deletions and partial inactivations do not lead to
thrombocytopenia
– Bone marrow examinations
• Suggest possible dysmegakaryopoiesis
• Many smaller or dystrophic megakaryocytes
– Hypolobulated nuclei
ANKRD26-related thrombocytopenia:
Clinical Features
• Thrombocytopenia with normal size platelets
– Mean platelet count 47 x 109/L
• No or mild bleeding tendency usually
• Less commonly severe thrombocytopenia (<10 x 109/L)
ANKRD26-Related Thrombocytopenia
Journal of Thrombosis and Haemostasis
Volume 11, Issue 6, pages 1006-1019, 3 JUL 2013 DOI: 10.1111/jth.12196
http://onlinelibrary.wiley.com/doi/10.1111/jth.12196/full#jth12196-fig-0004
ANKRD26-related thrombocytopenia:
Clinical Features
• 30-fold increase in acute leukemia (?)
– Compared with the normal population
FAMILIAL PLATELET DISORDER AND
PREDISPOSITION TO ACUTE
MYELOGENOUS LEUKEMIA
Familial Platelet Disorder and
Predisposition to AML
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RUNX1 gene at chromosome 21q22
Autosomal dominant
Non-syndromic
Associated features
– Normal-size platelets
– HIGH risk of AML and MDS
• No spontaneous bleeding
Familial Platelet Disorder and
Predisposition to AML:
Pathophysiology
• RUNX1 gene at chromosome 21q22
– Encodes for RUNX1 (aka CBFa2)
• Core Binding Factor
– Heterodimeric transcription complex
• CBFa2 important for dimerization and DNA binding
• CBFb helps stabilize CBFa2
– Protecting it from degradation
– Enhancing its DNA affinity
• Mutations usually lead to haploinsufficiency
– Some dominant negative mutations also reported
• Even higher risk of hematologic malignancy
Familial Platelet Disorder and
Predisposition to AML:
Pathophysiology
• RUNX1 gene at chromosome 21q22
– Encodes for RUNX1 (aka CBFa2)
• Core Binding Factor
– Heterodimeric transcription complex
• CBFa2 important for dimerization and DNA binding
• CBFb helps stabilize CBFa2
– Protecting it from degradation
– Enhancing its DNA affinity
– Regulates expression of many hematopoietic-specific genes
• Inversely regulates MYL9 and MYH10
• Directly regulates MYH9
• Thus suggests megakaryopoiesis may be effected in part by deregulation of
myosin IIA and IIb  defective proplatelet formation
• Mutations usually lead to haploinsufficiency
– Some dominant negative mutations also reported
• Even higher risk of hematologic malignancy
Familial Platelet Disorder and
Predisposition to AML:
Clinical Features
• Thrombocytopenia with normal size platelets
– Platelets may look a little paler
– Mild thrombocytopenia
• Reduced platelet aggregation with collagen and epi
– Platelet counts NOT ALWAYS reduced
• Uncertain if also have qualitative platelet defects
• No or mild bleeding tendency usually
• Easy bruising since childhood in some but not all
– Hemoglobin and WBC may be elevated
Familial Platelet Disorder and
Predisposition to AML:
Clinical Features
• Increased risk of hematologic malignancies
– ESPECIALLY MDS and AML
• 40% of affected individual
• Mean age of onset 33 years
Inherited thrombocytopenias frequently diagnosed in adults
Journal of Thrombosis and Haemostasis
Volume 11, Issue 6, pages 1006-1019, 3 JUL 2013 DOI: 10.1111/jth.12196
http://onlinelibrary.wiley.com/doi/10.1111/jth.12196/full#jth12196-fig-0005