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