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

cellsFli-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 PTSWhite, 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 (10-20,000/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 GrossfeldPlatelet Disorder Support Association