Platelet structure 1

1
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)

2
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

3
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

4
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

5
Bernard-Soulier syndrome
6
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

7
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

8
Gray platelet syndrome
9
Giant platelet syndromes associated with MYH9
mutations

• 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

10
Giant platelet syndromes associated with MYH9
mutations
Neutrophil inclusions have different structure
from those in May-Hegglin
11
Neutrophil inclusions in May-Hegglin anomaly
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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.
13
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

14
Wiskott-Aldrich syndrome
15
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

16
HPS, with oculocutaneous albinism
Chédiak-Higashi, showing neutrophil inclusions
17
Hermansky-Pudlak syndrome
Br J Haematol 2007138671
Disaggregation after primary aggregation with ADP
Dense granule deficiency
Control platelet
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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

19
Von Willebrand multimer analysis