Transcript Bleeding in Paris-Trousseau syndrome

Bleeding in Paris-Trousseau
syndrome
11q23 Family Conference
July, 2010
Paris-Trousseau Syndrome
• Inherited disorder in which children may have:
– Heart defects
– Neurologic impairment
– Growth delay
– Low platelets
• Due to deletion of the terminal
portion of chromosome 11q
Why does a deletion matter?
-Normally there are 2 copies of each
gene in the body, one from each parent
-If one copy is lost, there may not be
enough of the protein product for the cell
to work normally
-Even if the cell can work normally, any
problem with the remaining copy can be
disastrous
-A deleted region of chromosome
contains many genes
Fli-1 in megakaryocyte development
• Fli-1 is one gene that is lost in
Paris-Trousseau syndrome
• Fli-1 is essential for
megakaryocyte and platelet
development
• Fli-1 promotes platelet
development and inhibits red
cells
Fli-1
X
Megakaryocytes
• Large cells in the bone
marrow
• Produce up to 150 billion
circulating platelets each day,
1000 platelets/ MK
Proplatelet formation
Italiano, et al., J. Cell Biol. 1999
Platelet granules are important for their function
• Alpha granules and dense granules contain substances that
promote platelet aggregation and clotting
• In the body, granules are released when platelets are
activated
• In the lab, platelet function is often tested by treating
platelets with different chemicals that stimulate granule
release and measuring platelet aggregation
How are platelets in Paris-Trousseau syndrome
different?
• PTS platelets have large, fused alpha granules, may
have reduced dense granules
Normal
PTS
White, Platelets 2007
How are platelets in Paris-Trousseau syndrome
different?
• Platelet function in PTS is not well defined
• Bleeding times may be prolonged even when platelet
numbers are normal
• Overall measurements of platelet function are normal but
subpopulation of platelets with abnormal alpha granules
do not release granules in response to thrombin
• Fewer dense granules may cause storage pool
deficiency
Breton-Gorius et al., Blood 1995; Grossfeld et al.,Am JMG 2004; White, Platelets 2007
Natural history of thrombocytopenia in PTS
• Thrombocytopenia at birth may be severe (1020,000/microliter; normal is >150,000)
• With time (months-years), platelet counts improve in
most to normal or near normal levels
• Bleeding symptoms due to low platelets commonly
include:
–
–
–
–
Bruising
Nosebleeds
Bleeding from tooth extractions or tonsillectomy
Heavy menses
Management of bleeding symptoms
• Amicar
– For dental procedures, mouth or nose bleeding
– Use as a mouthwash or take as a pill or liquid
• Oral contraceptives
– For girls with heavy periods
• DDAV P
– May improve platelet aggregation
– IV or nasal spray
• Platelet transfusion
– For serious bleeding or before major surgeries
Acknowledgements and resources:
Paul Grossfeld
Platelet Disorder Support Association