Inherited thrombocytopenia: novel insights into megakaryocyte maturation, proplatelet formation and platelet lifespan

Abstract

The study of patients with inherited bleeding problems is a powerful approach in determining the function and regulation of important proteins in human platelets and their precursor, the megakaryocyte. The normal range of platelet counts in the bloodstream ranges from 150 000 to 400 000 platelets per microliter and is normally maintained within a narrow range for each individual. This requires a constant balance between thrombopoiesis, which is primarily controlled by the cytokine thrombopoietin (TPO), and platelet senescence and consumption. Thrombocytopenia can be defined as a platelet count of less than 150 000 per microliter and can be acquired or inherited. Heritable forms of thrombocytopenia are caused by mutations in genes involved in megakaryocyte differentiation, platelet production and platelet removal. In this review, we will discuss the main causative genes known for inherited thrombocytopenia and highlight their diverse functions and whether these give clues on the processes of platelet production, platelet function and platelet lifespan. Additionally, we will highlight the recent advances in novel genes identified for inherited thrombocytopenia and their suggested function.

Keywords: Inherited thrombocytopenia; bleeding; gene mutations; megakaryocytes; platelets.

Figure 1.

Megakaryopoiesis, platelet production and other causes of IT. Differentiation from HSCs to platelets proceeds by a number of intermediate cell types, which leads to the formation of megakaryocytes which fragment via proplatelet formation to produce mature platelets. This process is driven by a number of genes encoded a number of transcription factors and proteins. Defects in these genes have been shown to give rise to thrombocytopenia by mostly affecting the relevant stage of platelet production they are labeled under. Variants that do not play a role in platelet production by megakaryopoiesis are included in the third subgroup entitled platelet removal, death and other. HSC: Hematopoietic stem cell, CMP: Common myeloid progenitor, MEP: Megakaryocyte-erythroid progenitor.