Thrombocytopenia is a common manifestation in many bone marrow disorders. As bone marrow is the site of platelet production, it is not surprising that bone marrow diseases would cause thrombocytopenia. It is pertinent to review briefly the regulation of platelet production, and how it could be adversely affected by bone marrow diseases.

Regulation of platelet production

Platelets are produced in the bone marrow by cytoplasmic budding of their precursor cell, the megakaryocyte. The megakaryocyte itself is derived from the hematopoietic stem cell by a series of cell proliferation and differentiation processes. These processes are controlled by a network of growth factors, the most important of which is thrombopoietin, TPO. These processes also involve a specific program of gene expression mediated by transcription factors such as GATA-1, FOG-1, Fli-1 and NF-F2. Mouse knockout studies revealed that disruption of the TPO gene, and genes of these transcription factors, resulted in marked impairment of megakaryocyte development, severe thrombocytopenia and/or serious bleeding.

TPO exerts its effect by binding to its receptor, c-mpl on megakaryocytes and their precursor cells. TPO-c-mpl interaction induces activation of intracellular signal transduction pathways (Fig. 35.1) including Jak2 / STAT 3/5, protein kinase C (PKC) and MAPK kinase pathways. The signalling pathway activation ultimately leads to activation of specific transcription factors, e.g. GATA-1. The activated factor then translocates to the nucleus and binds to the regulatory region of a target gene involved in megakaryocyte proliferation and differentiation.