Transcript Bernard-Soulier syndrome

Platelet structure 1
• Membrane glycoproteins
– IIb-IIIa: integrin, cryptic in resting platelet,
after platelet activation binds fibrinogen
and other adhesive proteins, necessary for
aggregation
– Ib-IX-V: binds VWF, necessary for platelet
adhesion at high shear rates
– Ia-IIa: integrin, binds collagen, mediates
adhesion at low shear rates and platelet
spreading (also acts as receptor)
Platelet structure 2
• Membrane receptors
– Thrombin receptors (2): cleaved and
activated by thrombin
– Thromboxane A2 receptor
– ADP receptors (3)
– Epinephrine receptor
– Serotonin receptor
– Cytokine, chemokine receptors
– Fc receptor
Platelet structure 3
• Granules
– Dense granules: small molecules involved
in platelet activation (ATP/ADP, serotonin)
– Alpha granules: fibrinogen, fibronectin,
thrombospondin, P-selectin, plasminogen,
alpha-2 antiplasmin, factor V, PF4, PDGF,
TGF-alpha and beta, ECGF
Bernard-Soulier syndrome
• Pathophysiology:
– Deficiency of platelet membrane glycoprotein Ib-IX (VWF
“receptor”)
– Defective platelet adhesion
• Clinical: Moderate to severe bleeding
• Inheritance: autosomal recessive
• Morphology:
– Giant platelets
– Thrombocytopenia (20-100K)
• Diagnosis:
– No agglutination with ristocetin, decr thrombin response,
responses to other agonists intact
– Morphology
– Decreased GP Ib expression
Bernard-Soulier syndrome
Glanzmann thrombasthenia
• Pathophysiology:
– Deficiency of platelet membrane GPIIb-IIIa
– Absent platelet aggregation with all agonists;
agglutination by ristocetin intact
•
•
•
•
Clinical: Moderate to severe bleeding
Inheritance: autosomal recessive
Morphology: normal
Diagnosis:
– Defective platelet aggregation
– Decreased GP IIb-IIIa expression
Gray platelet syndrome
•
•
•
•
Pathophysiology: Empty platelet alpha granules
Clinical: Mild bleeding
Inheritance: Autosomal dominant or recessive
Morphology:
–
–
–
–
Hypogranular platelets
Giant platelets
Thrombocytopenia (30-100K)
Myelofibrosis in some patients
• Diagnosis
– Variably abnormal platelet aggregation (can be normal)
– Abnormal platelet appearance on blood smear
– Electron microscopy showing absent alpha granules
Gray platelet syndrome
Giant platelet syndromes associated
with MYH9 mutations
1.
2.
3.
4.
May-Hegglin anomaly
Fechtner syndrome
Sebastian syndrome
Epstein syndrome
•
All associated with mutations in the non-muscle
myosin heavy chain gene MYH9
Thrombocytopenia with giant platelets, but mild
bleeding
Autosomal dominant inheritance
No consistent defects of platelet function detectable
in the clinical laboratory
Diagnosis usually based on clinical picture, family
history, examination of blood smear for neutrophil
inclusions
•
•
•
•
Giant platelet syndromes associated
with MYH9 mutations
Syndrome
MayHegglin
Fechtner
Sebastian
Epstein
Neutrophil Hereditary Deafness
inclusions nephritis
Yes
No
No
Yes
Yes
Yes
Yes*
No
No
No
Yes
Yes
*Neutrophil inclusions have different structure from those in May-Hegglin
Neutrophil inclusions in May-Hegglin
anomaly
Neutrophil inclusions in MYH9 giant
platelet syndromes
May-Hegglin
Sebastian
In both cases an oval cytoplasmic inclusion (*) not bounded by a membrane and
lacking specific granules is evident (original magnification 7,000). At higher
magnification (insets, original magnification 13,400), inclusion bodies in MHA contain
clusters of ribosomes oriented along parallel filaments 7?10 nm in diameter, whereas
in SBS they are composed of highly dispersed filaments and randomly distributed
ribosomes.
Wiskott-Aldrich syndrome
• Pathophysiology
– Mutation in WASP signaling protein
– Decreased secretion and aggregation with multiple
agonists; defective T-cell function
• Clinical:
– Mild to severe bleeding
– Eczema, immunodeficiency
• Inheritance: X-linked
• Morphology:
– Thrombocytopenia (20-100K)
– Small platelets with few granules
• Diagnosis: Family hx, clinical picture, genetic
testing
Wiskott-Aldrich syndrome
Hermansky Pudlak syndrome
Chédiak-Higashi syndrome
• Pathophysiology:
– Platelet dense granule deficiency: decreased aggregation &
secretion with multiple agonists
– Defective pigmentation
– Defective lysosomal function in other cells
• Clinical:
– Mild to moderate bleeding
– Oculocutaneous albinism (HPS)
– Lysosomal storage disorder with ceroid deposition, lung & GI
disease (HPS)
– Immunodeficiency, lymphomas (CHS)
• Inheritance: autosomal recessive
• Morphology
– Reduced dense granules
– Abnormal neutrophil granules (CHS)
• Diagnosis: clinical picture, neutrophil inclusions (CHS), genetic
testing
HPS, with oculocutaneous
albinism
Chédiak-Higashi,
showing neutrophil
inclusions
Hermansky-Pudlak syndrome
Br J Haematol 2007;138:671
Disaggregation after primary aggregation with ADP
Dense granule deficiency
Control platelet
Platelet type von Willebrand disease
• Pathophysiology: Gain of function mutation in GP
Ib, with enhanced binding to VWF and clearance of
largest multimers from blood
• Clinical: Mild to moderate bleeding
• Inheritance: Autosomal dominant
• Morphology: Normal, but platelet count often low
• Diagnosis: Variably low VWF antigen,
disproportionately low ristocetin cofactor activity,
loss of largest VWF multimers on electrophoresis,
enhanced platelet agglutination by low dose
ristocetin (indistinguishable from type 2B VWD)
• Can distinguish from 2B VWD by mixing studies with
normal/pt platelets and plasma and low dose
ristocetin, or by genetic testing
Von Willebrand multimer analysis