Thrombocytopenia and erythrocytosis in mice with a mutation in the gene encoding the hemoglobin beta minor chain

Kauppi, M; Hilton, AA; Metcalf, D; Ng, AP; Hyland, CD; Collinge, JE; Kile, BT; Hilton, DJ; Alexander, WS

Author(s): Kauppi, M; Hilton, AA; Metcalf, D; Ng, AP; Hyland, CD; Collinge, JE; Kile, BT; Hilton, DJ; Alexander, WS;
Details: Publication Year 2012-01-10,Volume 109,Issue #2,Page 576-581
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
Abstract: Diverse mutations in the genes encoding hemoglobin (Hb) have been characterized in human disease. We describe here a mutation in the mouse Hbb-b2 gene, denoted Plt12, that precisely mimics the human hemoglobin Hotel Dieu variant. The mutation results in increased affinity of Hb for oxygen and Plt12 mutant mice exhibited reduced partial pressure of O(2) in the blood, accompanied by erythrocytosis characterized by elevated erythropoietin levels and splenomegaly with excess erythropoiesis. Most homozygous Hbb-b2(Plt12/Plt12) mice succumbed to early lethality associated with emphysema, cardiac abnormalities, and liver degeneration. Survivors displayed a marked thrombocytopenia without significant deficiencies in the numbers of megakaryocytes or megakaryocyte progenitor cells. The lifespan of platelets in the circulation of Hbb-b2(Plt12/Plt12) mice was normal, and splenectomy did not correct the thrombocytopenia, suggesting that increased sequestration was unlikely to be a major contributor. These data, together with the observation that megakaryocytes in Hbb-b2(Plt12/Plt12) mice appeared smaller and deficient in cytoplasm, support a model in which hypoxia causes thrombocytopenia as a consequence of an inability of megakaryocytes, once formed, to properly mature and produce sufficient platelets. The Plt12 mouse is a model of high O(2)-affinity hemoglobinopathy and provides insights into hematopoiesis under conditions of chronic hypoxia.
Publisher: NATL ACAD SCIENCES
Keywords: HIGH OXYGEN-AFFINITY; ERYTHROPOIETIN GENE; PLATELET PRODUCTION; HIGH-ALTITUDE; HOTEL-DIEU; HYPOXIA; MODEL; STRAINS; DISEASE
Research Division(s): Cancer And Haematology; Molecular Medicine
Publisher's Version: https://doi.org/10.1073/pnas.1119146109
Open Access at Publisher's Site: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258592/

Creation Date: 2012-01-10 12:00:00