Platelets are heterogeneous with respect to both physical and functional properties. The overall objective of this project is to deterine the biologic significance of platelet heterogeneity. It will test the hypothesis that platelet heterogeneity is in part determined by aging in the peripheral circulation. This postulate aging process is superimposed upon inborn platelet heterogeneity and is due to selective organelle loss resulting in decreasing density. The hypothesis will be tested through the use of four specific aims. 1. Old and young platelet cohorts will be produced in a murine model using either Sr89 bone marrow ablation or Co60 external irradiation. The density distribution of these age dependent cohorts will be analyzed on isomolar density gradients to determine the effect of platelet age on platelet density and mean platelet volume (MPV). Bone marrow and spleen megakaryocyte colony forming capacity (Meg-CFC), megakaryocyte DNA content, and megakaryocyte maturation stage will be studied to evaluate the contribution of each thrombopoietic component to platelet heterogeneity. 2. A stimulated murine rhrombopoiesis model will be used to study the effects of altered thrombopoiesis on platelet density distribution, MPV, megakaryocyte ploidy distribution, megakaryocyte maturation, and Meg-CFC. The model will utilize acute and chronic immune thrombocytopenia, acute hemorrhage, 5-fluorouracil and cytoxan to perturb platelet production. 3. Two models of human platelet production will be used to examine the density distribution of newly produced human platelets. Study of patients during the recovery phase of autoimmune thrombocytopenia will provide a young platelet cohort in a perturbed state; and the density distribution of platelet thromboxane B2 synthesis during recovery from aspirin inhibition will provide an unperturbed labelled cohort of newly released platelets to examine the relationship between platelet age and density. 4. The organelle content of platelets of various densities will be measured. If selective organelle loss or secretion during aging alters density, then the levels of those constitutents which are lost should decline while the levels of those which are not lost should remain constant. Representative constituents of mitochondria, lysosome, peroxisomes, dense bodies, alpha granules, and cytoplasm of different platelet density cohorts will be quantitated to test this proposition.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Davis, E; Corash, L; Stenberg, P et al. (1992) Histologic studies of splenic megakaryocytes after bone marrow ablation with strontium 90. J Lab Clin Med 120:767-77
Stenberg, P E; Levin, J; Baker, G et al. (1991) Neuraminidase-induced thrombocytopenia in mice: effects on thrombopoiesis. J Cell Physiol 147:7-16
Hill, R J; Warren, M K; Stenberg, P et al. (1991) Stimulation of megakaryocytopoiesis in mice by human recombinant interleukin-6. Blood 77:42-8
Corash, L (1990) Measurement of platelet activation by fluorescence-activated flow cytometry. Blood Cells 16:97-106;discussion 107-8
Stenberg, P E; Levin, J; Corash, L (1990) Sustained thrombocytopenia in mice: serial studies of megakaryocytes and platelets. Exp Hematol 18:124-32
Corash, L; Mok, Y; Levin, J et al. (1990) Regulation of platelet heterogeneity: effects of thrombocytopenia on platelet volume and density. Exp Hematol 18:205-12
Davis, E; Corash, L; Baker, G et al. (1990) Splenic thrombopoiesis after bone marrow ablation with radiostrontium: a murine model. J Lab Clin Med 116:879-88
Corash, L; Levin, J (1990) The relationship between megakaryocyte ploidy and platelet volume in normal and thrombocytopenic C3H mice. Exp Hematol 18:985-9
Corash, L; Levin, J; Mok, Y et al. (1989) Measurement of megakaryocyte frequency and ploidy distribution in unfractionated murine bone marrow. Exp Hematol 17:278-86
Corash, L (1989) The relationship between megakaryocyte ploidy and platelet volume. Blood Cells 15:81-107

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