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 (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 Grossfeld Platelet Disorder Support Association