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Milestones in understanding platelet production: a historical overview
Author(s) -
Kuter David J.
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12781
Subject(s) - thrombopoietin , megakaryocyte , romiplostim , eltrombopag , platelet , thrombopoiesis , bone marrow , immunology , thrombopoietin receptor , biology , transplantation , medicine , cancer research , haematopoiesis , stem cell , microbiology and biotechnology , immune thrombocytopenia
Summary The discovery of thrombopoietin ( TPO , also termed THPO ) in 1994 was a major achievement in understanding the regulation of platelet production. In prior decades, physiological studies had demonstrated that platelets were produced from bone marrow megakaryocytes and that the megakaryocytes responded to thrombocytopenia by increasing their number, size and DNA ploidy. In 1958, it was proposed that a ‘thrombopoietin’ must exist that regulated this interaction between the circulating platelet mass and the bone marrow megakaryocytes. After over three decades of effort, TPO was finally purified by five independent laboratories. TPO stimulated megakaryocyte colony‐forming cell growth and increased the number, size and ploidy of megakaryocytes. When the genes for TPO or TPO receptor were eliminated in mice, megakaryocytes grew and platelets were made, but at 15% of their normal number. A first generation of recombinant human (rh) TPO molecules [rh TPO and pegylated recombinant human megakaryocyte growth and development factor ( PEG ‐rh MGDF )] rapidly entered clinical trials in 1995 and increased platelet counts in humans undergoing non‐myeloablative chemotherapy but not in those undergoing stem cell transplantation. Antibodies developed against PEG ‐rh MGDF and development of these recombinant thrombopoietins ended. A second generation of TPO receptor agonists (romiplostim and eltrombopag) was then developed. Neither of these TPO receptor agonists demonstrated any significant untoward effects and both are now licensed in many countries for the treatment of immune thrombocytopenia. This review describes the significant experiments that have surrounded the discovery of TPO and its clinical development.