Introduction
Platelets are an essential component of coagulation and therefore conserved in all vertebrates. An increase in platelets counts can be either induced by a myeloproliferative process or be reactive. Secondary thrombocytosis may be a response to acute infection or inflammation, chronic inflammatory diseases, postoperative stress, post‐splenectomy, or malignancy. Iron deficiency (ID) is a recognized cause of reactive thrombocytosis, even outside the setting of inflammation. This finding is supported by clinical reports 1, also by our group 3, as well as animal studies 5.
The clinical significance of increased platelet counts is not established. Although reactive thrombocytosis has been generally considered benign, there are numerous case reports describing both arterial and venous thrombotic events in ID‐associated platelet elevation 7. Prospective studies identified elevated platelet counts as an independent risk factor for the development of venous thromboembolism (VTE) in cancer patients 8. Another study in ID patients with inflammatory bowel disease demonstrated thrombocytosis, aggregation, and P‐selectin expression that was reversed by iron replacement independent of disease activity 4. The extent to which ID‐induced thrombocytosis plays a role in VTE in noncancer patients remains elusive.
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Platelets are derived from megakaryocytes (MEGs) which constitute the least numerous but largest cells in the bone marrow (BM). MEGs develop from the common hematopoietic progenitor cells which differentiate into mature platelet producing cells over several steps. A proliferation phase at the burst forming unit (BFU)‐MEG and colony forming unit (CFU)‐MEG level is followed by an endomitotic phase. Endomitosis is characterized by incomplete mitosis with failure of cytokinesis 11. Endomitosis increases ploidy in geometric progression (i.e., 2n, 4n, 8n, 16n etc). In parallel, MEGs undergo expansion and reorganization of the cytoplasm, expression of MEG‐specific surface markers such as CD41, CD61, and CD42, and, finally, formation of proplatelets. Thus, each MEG generates 1,000-3,000 platelets. Megakaryopoiesis and platelet formation are governed by hematopoietic growth factors. Thrombopoietin (TPO) is the principal regulator of megakaryopoiesis, affecting self‐renewal and expansion of hematopoietic stem cells, proliferation of megakaryocyte progenitors, and supporting their maturation into platelet‐producing cells 14. Other contributing mediators are stem cell factor, stromal‐derived factor 1, and interleukins 3, 6, and 11. It is currently unknown how ID leads to increased platelet counts, but direct effects on megakaryopoiesis as well as a cytokine‐mediated enhancement of thrombopoiesis have been proposed 1.
Here we studied the mechanisms underlying ID‐induced thrombocytosis. We present an animal model that displays thrombocytosis upon ID diet. We show that such platelets have an increased aggregation capability. BM and cell culture studies suggest that this effect may be driven by increased MEG endomitosis and accelerated MEG differentiation.
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